Antiviral compounds and methods for making and using same

Abstract

Disclosed are antiviral compounds of formula I, methods of using the antiviral compounds alone or in combination with additional agents, and pharmaceutical compositions of the antiviral compounds for the treatment of viral infections. TIFF2025508922000205.tif23128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 316,273, filed March 3, 2022, which is incorporated herein in its entirety for all purposes.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The .XML copy, created on February 10, 2023, is named 1394-WO-PCT.xml and is 3,489 bytes in size. [Background technology]

[0003] There is a need for compounds, pharmaceutical compositions, and methods for treating viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, and Orthomyxovirus families. Embodiments of the present disclosure can address these and other needs. Summary of the Invention

[0004] As used herein, for example, compounds of formula I, [ka] During the ceremony, R 1 OH or OC(O)R 4 and R 2 But OH or OC(O)R 5 or R 1 and R 2 together to form -OC(O)O-, R 3 But H or C(O)R 7 or R 1 and R 3 together to form -OC(O)-, R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 O, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 , R 5 , and R 7 wherein the alkyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are each independently halo, oxo, cyano, N, -OR 8 , C1-C8 alkyl, -NR 9 R 10 , C-C carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The base is [ka] and In the formula, R 11 -OP(O)(OH)2 or -OC(O)R 12 C1-C6 alkyl substituted with R 12 is C1-C8 alkyl, R 13 -OP(O)(OH)2 or -OC(O)R 12 or a pharmaceutically acceptable salt thereof.

[0005] Also disclosed herein are compounds of subformulas of Formula I, such as Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, and Formula XI.

[0006] Disclosed herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0007] Also disclosed herein is a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0008] Also disclosed herein is a method of treating or preventing a viral infection in a human in need thereof, comprising administering to the human a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0009] The present disclosure provides a method for manufacturing a medicament for treating or preventing a viral infection in a subject in need thereof, wherein a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used.

[0010] The present disclosure provides a method for the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof, wherein a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used.

[0011] The present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

[0012] The present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0013] I. Overview The present disclosure relates generally to methods and compounds for treating or preventing viral infections, such as Paramyxoviridae, Pneumoviridae, Pneumoviridae, Flaviviridae, Filoviridae, and Orthomyxoviridae infections. The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the disclosure, but instead is provided as a description of exemplary embodiments. II. Definition

[0014] As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups can be drawn with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0016] For example, [ka] A squiggly line on a chemical group shown in indicates a point of attachment, i.e., it indicates a broken bond where the group is attached to another depicted group.

[0017] As used herein, "a compound of the present disclosure" can refer to any compound of Formulas I-XI or a pharmaceutically acceptable salt thereof. Similarly, the phrase "a compound of Formula (number)" refers to a compound of that formula and its pharmaceutically acceptable salts.

[0018] "C u~ C v " prefix indicates that the following group has u to v carbon atoms. For example, "C 1~ "C8 alkyl" indicates that the alkyl group has from 1 to 8 carbon atoms.

[0019] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1 to C6). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- Propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH 2CH3), 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)( Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0020] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0021] "Carbocyclyl" or "carbocycle" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, and in certain embodiments from 3 to 15 carbon atoms, and in certain embodiments from 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 7 carbon atoms, or 3 to 6 carbon atoms, which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Examples of carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0022] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, and include fused ring systems having one aromatic ring and one non-aromatic ring, but not entirely aromatic.

[0023] "Cyano" or "carbonitrile" refers to the group CN.

[0024] A "haloalkyl" is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0025] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0026] "Hydroxy" refers to --OH.

[0027] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0028] "Heteroaryl" refers to aromatic groups, including groups having aromatic tautomers or resonance structures, having monocyclic, polycyclic, or multiple fused rings with at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur can be oxidized. Thus, the term includes rings having one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. The term includes rings having one or more cyclic C(O) groups. As used herein, heteroaryl includes groups having 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, as well as oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0029] "Heterocycle" or "heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heterocyclyl can be monocyclic or polycyclic, and polycyclic rings can be fused, bridged, or spiro. As used herein, a heterocyclyl has 3 to 20 ring atoms (i.e., 3-20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3-12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3-8-membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., 4-12-membered heterocyclyl), 4 to 8 ring atoms (i.e., 4-8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., 4-6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0030] The term "optionally substituted" with respect to a particular moiety in a compound disclosed herein (e.g., an optionally substituted aryl group) refers to a moiety where all of the substituents are hydrogen, or where one or more of the hydrogens on the moiety can be replaced with the listed substituents.

[0031] "Oxo" refers to the (=O) or (O) radical.

[0032] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, formulations, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0033] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic bases. For example, compounds containing a basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne, hexyne-1,4-diol, hexyne-2 ... 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0034] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. +(wherein X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0035] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom can be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and therefore can be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium. The compounds disclosed herein can be deuterated at various positions, including (but not limited to) the following positions: [ka]

[0036] Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125Also included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Formulas I-XI can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples below, using appropriately isotopically labeled reagents in place of conventionally employed non-labeled reagents.

[0037] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, can contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Where compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both the E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. Where compounds are represented in their chiral form, it is understood that embodiments encompass, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0038] The term "prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The term "prevention" or "preventing" also encompasses administering a compound or composition according to the embodiments disclosed herein after a subject has been exposed to a virus but before symptoms of the disease appear and / or before the virus is detectable in the blood, to prevent symptoms of the disease from appearing and / or the virus from reaching detectable levels in the blood, and administering a compound or composition according to the embodiments disclosed herein to a mother before birth and to a child within the first few days of life, to prevent perinatal transmission of a viral infection from mother to infant.

[0039] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0040] "Stereoisomer(s)" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms when they have one or more asymmetric centers or double bonds with asymmetric substitution, and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the present specification is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley & Sons, New York, 1992).

[0041] "Subject" or "patient" is intended to describe a human or vertebrate, including dogs, cats, pocket pets, marmosets, horses, cows, pigs, sheep, goats, elephants, giraffes, chickens, lions, monkeys, owls, rats, squirrels, slender lorises, and mice. "Pocket pets" refers to the group of vertebrates that can fit into a commodity coat pocket, such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes before or after chemical groups are for convenience; chemical groups can be drawn with or without one or more dashes without losing their normal meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. A dashed line indicates an optional bond. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or their point of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both can be attached in either direction. Similarly, for example, an "arylalkyl" group can be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u~v " or (C u ~C v ) indicates that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has from 1 to 6 carbon atoms.

[0043] Unless otherwise specified, the carbon atoms of the compounds of Formulas I-XI are intended to have a valence of 4. If a carbon atom in some chemical structure representation does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0044] As used herein, the terms "treating" and "treatment" are intended to mean administering a compound or composition according to an embodiment disclosed herein to reduce or eliminate symptoms of a viral infection and / or reduce viral load in a subject.

[0045] As used herein, the term "therapeutically effective amount" refers to the amount of a compound disclosed herein present in a formulation described herein required to provide a desired level of drug in the subject's secretions and airway and lung tissues, or alternatively, in the bloodstream of the subject being treated, that will produce an expected physiological response or desired biological effect when such formulation is administered via a selected route of administration. The exact amount will depend on numerous factors, such as the specific compound disclosed herein, the specific activity of the formulation, the delivery device used, the physical characteristics of the formulation, its intended use, and subject considerations such as the severity of the disease state and the subject's cooperation, and can be readily determined by one of skill in the art based on the information provided herein. The term "therapeutically effective amount" or "effective amount" also refers to an amount that eliminates or reduces a subject's viral load and / or viral reservoir.

[0046] As used herein, the term "adjacent carbons" refers to consecutive carbon atoms that are directly bonded to each other. For example, [ka] In the formula, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons. [ka] In the example, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0047] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0048] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through some chemical or enzymatic pathway.

[0049] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include, but are not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulation. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0050] III.Compound As used herein, compounds of formula I, [ka] During the ceremony, R 1 But OH or OC(O)R 4 and R 2 But OH or OC(O)R 5 or R 1 and R 2 together to form -OC(O)O-, R 3 But H or C(O)R 7 or R 1 and R 3 together to form -OC(O)-, R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 O, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 , R 5 , and R 7 wherein alkyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are each independently halo, oxo, cyano, -N, -OR 8 , C1-C8 alkyl, -NR 9 R 10 , C3-C8 carbocyclyl optionally substituted with C1-C6 alkyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The base is [ka] and In the formula, R 11 -OP(O)(OH)2 or -OC(O)R 12 C1-C6 alkyl substituted with R 12 is C1-C8 alkyl, R 13 -OP(O)(OH)2 or -OC(O)R12 or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, R 4 , R 5 , and R 7 The alkyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl are each independently halo, oxo, cyano, N, -OR 8 , C1-C8 alkyl, -NR 9 R 10 , C3-C8 carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0052] R 1 is OH or OC(O)R 4 In some embodiments, R 1 is OH. In some embodiments, R 1 is OC(O)R 4 is.

[0053] R 2 is OH or OC(O)R 5 In some embodiments, R 2 is OH. In some embodiments, R 2 is OC(O)R 5 is.

[0054] In some embodiments, R 1 is OH and R 2 is OH. In some embodiments, R 1 and R 2 together to form -OC(O)-.

[0055] R 3 is H or C(O)OR 7 In some embodiments, R3 is H. In some embodiments, R 3 is C(O)OR 7 In some embodiments, R 3 teeth, [ka] In some embodiments, R 7 is C1-C6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, C3-C6 carbocyclyl, phenyl, and NH2. In some embodiments, R 7 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, 1-ethylpropyl, 2,2-dimethylpropyl, 2,2-dimethylbutyl, 1,1-dimethylpropyl, 3,3-dimethylbutyl, 1-methylpropyl, 2-fluoro-1,1-dimethylethyl, benzyl, [ka] In some embodiments, R 7 is C4-C6 alkyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is C3-C8 carbocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C3 alkyl. 7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] In some embodiments, R 7 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C3 alkyl. 7is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-C3 alkyl. 7 is a 4-6 membered heterocyclyl containing 1, 2, or 3 O, and R 7 The heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C3 alkyl and oxo.

[0056] In some embodiments, R 1 and R 3 together to form -OC(O)-.

[0057] R 4 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 O, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 is halo, oxo, cyano, N3, OR 8 , C1-C8 alkyl, NR 9 R 10 , C-C carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl; R 8 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 9 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 10 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0058] In some embodiments, R 4is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl. In some embodiments, C1-C6 alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, C1-C6 alkyl is C1-C3 alkyl. In some embodiments, the C1-C6 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C6 alkyl is a C4-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched unsubstituted C1-C6 alkyl.

[0059] In some embodiments, R 4is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0060] In some embodiments, R 4 is C6~C 10 In some embodiments, C6-C 10 Aryl is an unsubstituted C6-C 10 In some embodiments, C6-C 10 Aryl is a substituted C6-C 10 In some embodiments, C6-C 10 Aryl is phenyl. In some embodiments, C6-C 10 Aryl is naphthyl.

[0061] In some embodiments, R 4is a 4- to 6-membered (e.g., 4, 5, 6)-membered heterocyclyl containing 1, 2, or 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is an unsubstituted 4- to 6-membered heterocyclyl. In some embodiments, the 4- to 6-membered heterocyclyl is a substituted 4- to 6-membered heterocyclyl.

[0062] In some embodiments, R 4is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is pyridinyl. In some embodiments, the 5- to 6-membered heteroaryl is pyrimidinyl. In some embodiments, the 5- to 6-membered heteroaryl is an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is a substituted 5- to 6-membered heteroaryl.

[0063] In some embodiments, R 4 is unsubstituted. In some embodiments, R 4 is substituted with one substituent. In some embodiments, R 4 is substituted with two substituents. In some embodiments, R 4 is substituted with 3 substituents. In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is halo. In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, and at least one substituent is oxo. In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is cyano.4 is substituted with 1, 2, or 3 substituents, with at least one substituent being N3. In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is OR 8 is.

[0064] In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is C1 to C8 (e.g., C1, C2, C3, C4, C5, C6, C7, or C8) alkyl. In some embodiments, the C1-C8 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, or 3,3-dimethyl-2-butyl. In some embodiments, the C1-C8 alkyl is a C1-C6 alkyl. In some embodiments, the C1-C8 alkyl is a C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C8 alkyl is a C4-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched unsubstituted C1-C8 alkyl.

[0065] In some embodiments, R 4is substituted with 1, 2, or 3 substituents, at least one of which is NR 9 R 10 In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is NH2.

[0066] In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0067] In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl. In some embodiments, R 4 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents, and at least one of which is halo (e.g., fluoro, chloro, iodo, bromo). 4 is substituted with 1, 2, or 3 substituents, at least one substituent is phenyl substituted with 1, 2, or 3 substituents, and at least one substituent is cyano. 4 is substituted with at least one halo and at least one oxo. In some embodiments, R 4 is substituted with at least one halo and at least one cyano. In some embodiments, R 4 is substituted with at least one halo and at least one N. In some embodiments, R 4 is at least one halo and at least one OR 8 In some embodiments, R 4 is at least one halo and at least one NR 9 R 10 In some embodiments, R 4 is substituted with at least one halo and at least one C-C carbocyclyl. 4 is substituted with at least one halo and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one halo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4 is substituted with at least one oxo and at least one cyano. In some embodiments, R 4 is substituted with at least one oxo and at least one N. In some embodiments, R 4 is at least one oxo and at least one OR 8 In some embodiments, R4 is substituted with at least one oxo and at least one C1-C8 alkyl. In some embodiments, R 4 is at least one oxo and at least one NR 9 R 10 In some embodiments, R 4 is substituted with at least one oxo and at least one C3-C8 carbocyclyl. 4 is substituted with at least one oxo and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one oxo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4 is substituted with at least one cyano and at least one N. In some embodiments, R 4 is at least one N3 and at least one OR 8 In some embodiments, R 4 is substituted with at least one cyano and at least one C1-C8 alkyl. In some embodiments, R 4 is at least one cyano and at least one NR 9 R 10 In some embodiments, R 4 is substituted with at least one cyano and at least one C3-C8 carbocyclyl. 4 is substituted with at least one cyano and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one cyano and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4 is at least one N3 and at least one OR 8In some embodiments, R 4 is substituted with at least one N and at least one C-C alkyl. In some embodiments, R 4 is at least one N3 and at least one NR 9 R 10 In some embodiments, R 4 is substituted with at least one N3 and at least one C3-C8 carbocyclyl. 4 is substituted with at least one N and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one N and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl. 4 At least one OR 8 and substituted with at least one C1-C8 alkyl. In some embodiments, R 4 At least one OR 8 and at least one NR 9 R 10 In some embodiments, R 4 At least one OR 8 and at least one C3-C8 carbocyclyl. In some embodiments, R 4 At least one OR 8 and at least one unsubstituted phenyl. In some embodiments, R 4 At least one OR 8 and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4 is at least one C1-C8 alkyl and at least one NR 9 R 10 In some embodiments, R 4is substituted with at least one C1-C8 alkyl and at least one C3-C8 carbocyclyl. 4 is substituted with at least one C1-C8 alkyl and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one C1-C8 alkyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 4 is substituted with at least one C3-C8 carbocyclyl and at least one unsubstituted phenyl. In some embodiments, R 4 is substituted with at least one C3-C8 carbocyclyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0068] R 5 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 O, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 5 is halo, oxo, cyano, N3, -OR 8 , C1-C8 alkyl, -NR 9 R 10 , C-C carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl; R 8 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 9 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 10can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0069] In some embodiments, R 5 is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl. In some embodiments, C1-C6 alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, C1-C6 alkyl is C1-C3 alkyl. In some embodiments, the C1-C6 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C6 alkyl is a C4-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched unsubstituted C1-C6 alkyl.

[0070] In some embodiments, R 5is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0071] In some embodiments, R 5 is C6~C 10 In some embodiments, C6-C 10 Aryl is C aryl (e.g., phenyl) or C 10 aryl (e.g., naphthyl). In some embodiments, C6-C 10 Aryl is an unsubstituted C6-C 10 In some embodiments, C6-C 10 Aryl is a substituted C6-C 10 In some embodiments, C6-C 10 Aryl is phenyl. In some embodiments, C6-C 10 Aryl is naphthyl.

[0072] In some embodiments, R 5is a 4- to 6-membered (e.g., 4, 5, 6)-membered heterocyclyl containing 1, 2, or 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is an unsubstituted 4- to 6-membered heterocyclyl. In some embodiments, the 4- to 6-membered heterocyclyl is a substituted 4- to 6-membered heterocyclyl.

[0073] In some embodiments, R 5is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is pyridinyl. In some embodiments, the 5- to 6-membered heteroaryl is pyrimidinyl. In some embodiments, the 5- to 6-membered heteroaryl is an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is a substituted 5- to 6-membered heteroaryl.

[0074] In some embodiments, R 5 is unsubstituted. In some embodiments, R 5 is substituted with one substituent. In some embodiments, R 5 is substituted with two substituents. In some embodiments, R 5 is substituted with 3 substituents. In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is halo. In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, and at least one substituent is oxo. In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is cyano.5 is substituted with 1, 2, or 3 substituents, with at least one substituent being N3. In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is OR 8 is.

[0075] In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is C1 to C8 (e.g., C1, C2, C3, C4, C5, C6, C7, or C8) alkyl. In some embodiments, the C1-C8 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, or 3,3-dimethyl-2-butyl. In some embodiments, the C1-C8 alkyl is a C1-C6 alkyl. In some embodiments, the C1-C8 alkyl is a C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C8 alkyl is a C4-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched unsubstituted C1-C8 alkyl.

[0076] In some embodiments, R 5is substituted with 1, 2, or 3 substituents, at least one of which is NR 9 R 10 In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is NH2.

[0077] In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0078] In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl. In some embodiments, R 5 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents, and at least one of which is halo (e.g., fluoro, chloro, iodo, bromo). 5 is substituted with 1, 2, or 3 substituents, at least one substituent is phenyl substituted with 1, 2, or 3 substituents, and at least one substituent is cyano. 5 is substituted with at least one halo and at least one oxo. In some embodiments, R 5 is substituted with at least one halo and at least one cyano. In some embodiments, R 5 is substituted with at least one halo and at least one N. In some embodiments, R 5 is at least one halo and at least one OR 8 In some embodiments, R 5 is at least one halo and at least one NR 9 R 10 In some embodiments, R 5 is substituted with at least one halo and at least one C-C carbocyclyl. 5 is substituted with at least one halo and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one halo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5 is substituted with at least one oxo and at least one cyano. In some embodiments, R 5 is substituted with at least one oxo and at least one N. In some embodiments, R 5 is at least one oxo and at least one OR 8 In some embodiments, R5 is substituted with at least one oxo and at least one C1-C8 alkyl. In some embodiments, R 5 is at least one oxo and at least one NR 9 R 10 In some embodiments, R 5 is substituted with at least one oxo and at least one C3-C8 carbocyclyl. 5 is substituted with at least one oxo and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one oxo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5 is substituted with at least one cyano and at least one N. In some embodiments, R 5 is at least one N3 and at least one OR 8 In some embodiments, R 5 is substituted with at least one cyano and at least one C1-C8 alkyl. In some embodiments, R 5 is at least one cyano and at least one NR 9 R 10 In some embodiments, R 5 is substituted with at least one cyano and at least one C3-C8 carbocyclyl. 5 is substituted with at least one cyano and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one cyano and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5 is at least one N3 and at least one OR 8In some embodiments, R 5 is substituted with at least one N and at least one C-C alkyl. In some embodiments, R 5 is at least one N3 and at least one NR 9 R 10 In some embodiments, R 5 is substituted with at least one N3 and at least one C3-C8 carbocyclyl. 5 is substituted with at least one N and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one N and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl. 5 At least one OR 8 and substituted with at least one C1-C8 alkyl. In some embodiments, R 5 At least one OR 8 and at least one NR 9 R 10 In some embodiments, R 5 At least one OR 8 and at least one C3-C8 carbocyclyl. In some embodiments, R 5 At least one OR 8 and at least one unsubstituted phenyl. In some embodiments, R 5 At least one OR 8 and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5 is at least one C1-C8 alkyl and at least one NR 9 R 10 In some embodiments, R 5is substituted with at least one C1-C8 alkyl and at least one C3-C8 carbocyclyl. 5 is substituted with at least one C1-C8 alkyl and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one C1-C8 alkyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 5 is substituted with at least one C3-C8 carbocyclyl and at least one unsubstituted phenyl. In some embodiments, R 5 is substituted with at least one C3-C8 carbocyclyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0079] R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 O, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 is halo, oxo, cyano, N3, -OR 8 , C1-C8 alkyl, -NR 9 R 10 , C-C carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl; R 8 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 9 can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 10can be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0080] In some embodiments, R 7 is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl. In some embodiments, C1-C6 alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, C1-C6 alkyl is C1-C3 alkyl. In some embodiments, the C1-C6 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C6 alkyl is a C4-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched unsubstituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched unsubstituted C1-C6 alkyl.

[0081] In some embodiments, R 7is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0082] In some embodiments, R 7 is C6~C 10 In some embodiments, C6-C 10 Aryl is C aryl (e.g., phenyl) or C 10 aryl (e.g., naphthyl). In some embodiments, C6-C 10 Aryl is an unsubstituted C6-C 10 In some embodiments, C6-C 10 Aryl is a substituted C6-C 10 In some embodiments, C6-C 10 Aryl is phenyl. In some embodiments, C6-C 10 Aryl is naphthyl.

[0083] In some embodiments, R 7is a 4- to 6-membered (e.g., 4, 5, 6)-membered heterocyclyl containing 1, 2, or 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 4-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 5-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 1 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 2 O. In some embodiments, the 4- to 6-membered heterocyclyl is a 6-membered heterocyclyl containing 3 O. In some embodiments, the 4- to 6-membered heterocyclyl is an unsubstituted 4- to 6-membered heterocyclyl. In some embodiments, the 4- to 6-membered heterocyclyl is a substituted 4- to 6-membered heterocyclyl.

[0084] In some embodiments, R 7is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 5-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing one heteroatom selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing two heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is a 6-membered heteroaryl containing three heteroatoms selected from N, O, and S. In some embodiments, the 5- to 6-membered heteroaryl is pyridinyl. In some embodiments, the 5- to 6-membered heteroaryl is pyrimidinyl. In some embodiments, the 5- to 6-membered heteroaryl is an unsubstituted 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is a substituted 5- to 6-membered heteroaryl.

[0085] In some embodiments, R 7 is unsubstituted. In some embodiments, R 7 is substituted with one substituent. In some embodiments, R 7 is substituted with two substituents. In some embodiments, R 7 is substituted with 3 substituents. In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is halo. In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, and at least one substituent is oxo. In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is cyano.7 is substituted with 1, 2, or 3 substituents, with at least one substituent being N3. In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is OR 8 is.

[0086] In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is C1 to C8 (e.g., C1, C2, C3, C4, C5, C6, C7, or C8) alkyl. In some embodiments, the C1-C8 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, or 3,3-dimethyl-2-butyl. In some embodiments, the C1-C8 alkyl is a C1-C6 alkyl. In some embodiments, the C1-C8 alkyl is a C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C8 alkyl is a C4-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched substituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched unsubstituted C1-C8 alkyl.

[0087] In some embodiments, R7 is substituted with 1, 2, or 3 substituents, at least one of which is NR 9 R 10 In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is NH2.

[0088] In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is a C3-C8 (e.g., C3, C4, C5, C6, C7, or C8) carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is saturated. In some embodiments, the C3-C8 carbocyclyl is partially unsaturated. Exemplary C3-C8 carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. In some embodiments, the C3-C8 carbocyclyl is an unsubstituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a substituted C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is an unbranched C3-C8 carbocyclyl. In some embodiments, the C3-C8 carbocyclyl is a branched C3-C8 carbocyclyl.

[0089] In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl. In some embodiments, R 7 is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7is substituted with 1, 2, or 3 substituents, at least one of which is phenyl substituted with 1, 2, or 3 substituents, and at least one of which is halo (e.g., fluoro, chloro, iodo, bromo). 7 is substituted with 1, 2, or 3 substituents, at least one substituent is phenyl substituted with 1, 2, or 3 substituents, and at least one substituent is cyano. 7 is substituted with at least one halo and at least one oxo. In some embodiments, R 7 is substituted with at least one halo and at least one cyano. In some embodiments, R 7 is substituted with at least one halo and at least one N. In some embodiments, R 7 is at least one halo and at least one OR 8 In some embodiments, R 7 is at least one halo and at least one NR 9 R 10 In some embodiments, R 7 is substituted with at least one halo and at least one C-C carbocyclyl. 7 is substituted with at least one halo and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one halo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7 is substituted with at least one oxo and at least one cyano. In some embodiments, R 7 is substituted with at least one cyano and at least one N. In some embodiments, R 7 is at least one oxo and at least one OR 8 In some embodiments, R7 is substituted with at least one oxo and at least one C1-C8 alkyl. In some embodiments, R 7 is at least one oxo and at least one NR 9 R 10 In some embodiments, R 7 is substituted with at least one oxo and at least one C3-C8 carbocyclyl. 7 is substituted with at least one oxo and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one oxo and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7 is substituted with at least one cyano and at least one N. In some embodiments, R 7 is at least one N3 and at least one OR 8 In some embodiments, R 7 is substituted with at least one cyano and at least one C1-C8 alkyl. In some embodiments, R 7 is at least one cyano and at least one NR 9 R 10 In some embodiments, R 7 is substituted with at least one cyano and at least one C3-C8 carbocyclyl. 7 is substituted with at least one cyano and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one cyano and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7 is at least one N3 and at least one OR 8In some embodiments, R 7 is substituted with at least one N and at least one C-C alkyl. In some embodiments, R 7 is at least one N3 and at least one NR 9 R 10 In some embodiments, R 7 is substituted with at least one N3 and at least one C3-C8 carbocyclyl. 7 is substituted with at least one N and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one N and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C-C alkyl. 7 At least one OR 8 and substituted with at least one C1-C8 alkyl. In some embodiments, R 7 At least one OR 8 and at least one NR 9 R 10 In some embodiments, R 7 At least one OR 8 and at least one C3-C8 carbocyclyl. In some embodiments, R 7 At least one OR 8 and at least one unsubstituted phenyl. In some embodiments, R 7 At least one OR 8 and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7 is at least one C1-C8 alkyl and at least one NR 9 R 10 In some embodiments, R 7is substituted with at least one C1-C8 alkyl and at least one C3-C8 carbocyclyl. 7 is substituted with at least one C1-C8 alkyl and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one C1-C8 alkyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl. 7 is substituted with at least one C3-C8 carbocyclyl and at least one unsubstituted phenyl. In some embodiments, R 7 is substituted with at least one C3-C8 carbocyclyl and at least one phenyl substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0090] Each R 8 can independently be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, at least one R 8 is H. In some embodiments, at least one R 8 is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl, such as methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. 8 is C1-C3 alkyl. In some embodiments, at least one R 8is C2-C5 alkyl. In some embodiments, at least one R 8 is C4-C6 alkyl. In some embodiments, at least one R 8 is a branched C1-C6 alkyl. In some embodiments, R 8 is an unbranched C1-C6 alkyl. In some embodiments, at least one R 8 is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 8 is a branched unsubstituted C1-C6 alkyl. In some embodiments, at least one R 8 is an unbranched unsubstituted C1-C6 alkyl.

[0091] In some embodiments, at least one R 8is a C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) haloalkyl, wherein the C1-C6 alkyl is substituted with at least one halo (e.g., fluoro, iodo, chloro, or bromo). Exemplary C1-C6 haloalkyls include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halo-isobutyl, halo-s-butyl, halo-t-butyl, halo-n-pentyl, halo-2-pentyl, halo-3-pentyl, halo-2-methyl-2-butyl, halo-3-methyl-2-butyl, halo-3-methyl-1-butyl, halo-2-methyl-1-butyl, halo-1-hexyl, halo-2-hexyl, halo-3-hexyl, halo-2-methyl-2-pentyl, halo-3-methyl-2-pentyl, halo-4-methyl-2-pentyl, halo-3-methyl-3-pentyl, halo-2-methyl-3-pentyl, halo-2,3-dimethyl-2-butyl, or halo-3,3-dimethyl-2-butyl. In some embodiments, the C1-C6 haloalkyl includes at least one (e.g., 1, 2, 3, 4, or 5) halo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro. In some embodiments, the C1-C6 haloalkyl includes at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one iodo and at least one bromo.Examples of suitable C1-C6 haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentfluoroethyl.

[0092] In some embodiments, at least one R 8 is C3-C6 (e.g., C3, C4, C5, or C6) cycloalkyl. In some embodiments, R 8 is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl. In some embodiments, 10 Cycloalkyl is saturated. In some embodiments, C3-C6 cycloalkyl is partially saturated. In some embodiments, C3-C6 cycloalkyl includes partially unsaturated ring systems containing at least one (e.g., one, two) double bond. In some embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0093] Each R 9 can independently be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, at least one R 9 is H. In some embodiments, at least one R 9is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl, such as methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. 9 is C1-C3 alkyl. In some embodiments, at least one R 9 is C2-C5 alkyl. In some embodiments, at least one R 9 is C4-C6 alkyl. In some embodiments, at least one R 9 is a branched C1-C6 alkyl. In some embodiments, R 9 is an unbranched C1-C6 alkyl. In some embodiments, at least one R 9 is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 9 is a branched unsubstituted C1-C6 alkyl. In some embodiments, at least one R 9 is an unbranched unsubstituted C1-C6 alkyl.

[0094] In some embodiments, at least one R 9is a C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) haloalkyl, wherein the C1-C6 alkyl is substituted with at least one halo (e.g., fluoro, iodo, chloro, or bromo). Exemplary C1-C6 haloalkyls include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halo-isobutyl, halo-s-butyl, halo-t-butyl, halo-n-pentyl, halo-2-pentyl, halo-3-pentyl, halo-2-methyl-2-butyl, halo-3-methyl-2-butyl, halo-3-methyl-1-butyl, halo-2-methyl-1-butyl, halo-1-hexyl, halo-2-hexyl, halo-3-hexyl, halo-2-methyl-2-pentyl, halo-3-methyl-2-pentyl, halo-4-methyl-2-pentyl, halo-3-methyl-3-pentyl, halo-2-methyl-3-pentyl, halo-2,3-dimethyl-2-butyl, or halo-3,3-dimethyl-2-butyl. In some embodiments, the C1-C6 haloalkyl includes at least one (e.g., 1, 2, 3, 4, or 5) halo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro. In some embodiments, the C1-C6 haloalkyl includes at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one iodo and at least one bromo.Examples of suitable C1-C6 haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentfluoroethyl.

[0095] In some embodiments, at least one R 9 is C3-C6 (e.g., C3, C4, C5, or C6) cycloalkyl. In some embodiments, R 9 is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl. In some embodiments, 10 Cycloalkyl is saturated. In some embodiments, C3-C6 cycloalkyl is partially saturated. In some embodiments, C3-C6 cycloalkyl includes partially unsaturated ring systems containing at least one (e.g., one, two) double bond. In some embodiments, R 9 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0096] Each R 10 can independently be H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, at least one R 10 is H. In some embodiments, at least one R 10is C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl, such as methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. 10 is C1-C3 alkyl. In some embodiments, at least one R 10 is C2-C5 alkyl. In some embodiments, at least one R 10 is C4-C6 alkyl. In some embodiments, at least one R 10 is a branched C1-C6 alkyl. In some embodiments, R 10 is an unbranched C1-C6 alkyl. In some embodiments, at least one R 10 is an unsubstituted C1-C6 alkyl. In some embodiments, at least one R 10 is a branched unsubstituted C1-C6 alkyl. In some embodiments, at least one R 10 is an unbranched unsubstituted C1-C6 alkyl.

[0097] In some embodiments, at least one R 10is a C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) haloalkyl, wherein the C1-C6 alkyl is substituted with at least one halo (e.g., fluoro, iodo, chloro, or bromo). Exemplary C1-C6 haloalkyls include halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halo-n-butyl, halo-isobutyl, halo-s-butyl, halo-t-butyl, halo-n-pentyl, halo-2-pentyl, halo-3-pentyl, halo-2-methyl-2-butyl, halo-3-methyl-2-butyl, halo-3-methyl-1-butyl, halo-2-methyl-1-butyl, halo-1-hexyl, halo-2-hexyl, halo-3-hexyl, halo-2-methyl-2-pentyl, halo-3-methyl-2-pentyl, halo-4-methyl-2-pentyl, halo-3-methyl-3-pentyl, halo-2-methyl-3-pentyl, halo-2,3-dimethyl-2-butyl, or halo-3,3-dimethyl-2-butyl. In some embodiments, the C1-C6 haloalkyl includes at least one (e.g., 1, 2, 3, 4, or 5) halo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro. In some embodiments, the C1-C6 haloalkyl includes at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one chloro. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one fluoro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one iodo. In some embodiments, the C1-C6 haloalkyl includes at least one chloro and at least one bromo. In some embodiments, the C1-C6 haloalkyl includes at least one iodo and at least one bromo.Examples of suitable C1-C6 haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentfluoroethyl.

[0098] In some embodiments, at least one R 10 is C3-C6 (e.g., C3, C4, C5, or C6) cycloalkyl. In some embodiments, R 10 is C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl. In some embodiments, 10 Cycloalkyl is saturated. In some embodiments, C3-C6 cycloalkyl is partially saturated. In some embodiments, C3-C6 cycloalkyl includes partially unsaturated ring systems containing at least one (e.g., one, two) double bond. In some embodiments, R 10 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0099] The base is [ka] In some embodiments, the base can be: [ka] In some embodiments, the base is [ka] In some embodiments, the base is [ka] In some embodiments, the base is [ka] The base is [ka] is.

[0100] R 11 is -OP(O)(OH)2 or -OC(O)R 12 In some embodiments, the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -s-butyl, -t-butyl, n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, the C1-C6 alkyl is C1-C3 alkyl. In some embodiments, the C1-C6 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C6 alkyl is a C4-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is substituted with -OP(O)(OH). In some embodiments, the C1-C6 alkyl is -OC(O)R 12 is replaced by .

[0101] R 12 can be C1-C8 alkyl or C1-C8 alkoxy. In some embodiments, R 12is C1-C8 (e.g., C1, C2, C3, C4, C5, C6, C7, or C8) alkyl. In some embodiments, the C1-C8 alkyl is methyl, ethyl, -n-propyl, isopropyl, -n-butyl, isobutyl, -s-butyl, -t-butyl, -n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, the C1-C8 alkyl is a C1-C6 alkyl. In some embodiments, the C1-C8 alkyl is a C1-C3 alkyl. In some embodiments, the C1-C8 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C8 alkyl is a C4-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is a branched unsubstituted C1-C8 alkyl. In some embodiments, the C1-C8 alkyl is an unbranched unsubstituted C1-C8 alkyl.

[0102] In some embodiments, R 12is a C1-C8 (e.g., C1, C2, C3, C4, C5, C6, C7, or C8) alkoxy. The alkyl portion of the alkoxy group can have 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., a C1-C6 alkoxy), or 1, 2, or 3 carbon atoms (i.e., a C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), isopropoxy (-O-CH(CH3)2), t-butoxy (-OC(CH3)3 or -OtBu), and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0103] R 13 is -OP(O)(OH)2 or -OC(O)R 12In some embodiments, the C1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -s-butyl, -t-butyl, n-pentyl, -2-pentyl, -3-pentyl, -2-methyl-2-butyl, -3-methyl-2-butyl, -3-methyl-1-butyl, -2-methyl-1-butyl, -1-hexyl, -2-hexyl, -3-hexyl, -2-methyl-2-pentyl, -3-methyl-2-pentyl, -4-methyl-2-pentyl, -3-methyl-3-pentyl, -2-methyl-3-pentyl, -2,3-dimethyl-2-butyl, or -3,3-dimethyl-2-butyl. In some embodiments, the C1-C6 alkyl is C1-C3 alkyl. In some embodiments, the C1-C6 alkyl is a C2-C5 alkyl. In some embodiments, the C1-C6 alkyl is a C4-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is a branched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is an unbranched substituted C1-C6 alkyl. In some embodiments, the C1-C6 alkyl is substituted with -OP(O)(OH). In some embodiments, the C1-C6 alkyl is -OC(O)R 12 is replaced by .

[0104] In some embodiments, R 1 is OH or OC(O)R 4 and R 2 is OH or OC(O)R 5 and R 3 is H or C(O)R 7 and R 4 is a C1-C8 alkyl, and R 5 is a C1-C8 alkyl, and R 7is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4-6 membered heterocyclyl containing one O, R 7 is optionally substituted with one or two substituents independently selected from the group consisting of halo, oxo, C1-C8 alkyl, NH2, C3-C8 carbocyclyl, and phenyl, and the base is [ka] where R 11 is OC(O)R 12 C1-C6 alkyl substituted with R 12 is a C1-C8 alkyl, and R 13 is -OP(O)(OH)2 or -OC(O)R 12 is a C1-C6 alkyl substituted with

[0105] In some embodiments, R 1 is OH and R 2 is OH. In some embodiments, R 1 is OH and R 2 is OC(O)R 5 In some embodiments, R 1 is OH and R 2 is OC(O)R 5 and R 5 is C1-C8 alkyl. In some embodiments, R 2 is OH and R 1 is OC(O)R 4 In some embodiments, R 2 is OH and R 1 is OC(O)R 4 and R 4 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 In some embodiments, R 1 is OC(O)R 4 and R 2is OC(O)R 5 and R 4 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 and R 5 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 and R 4 is a C1-C8 alkyl, and R 5 is C1-C8 alkyl. In some embodiments, R 1 is OH and R 2 is OC(O)R 5 and R 5 is C1-C3 alkyl (e.g., methyl, isopropyl). In some embodiments, R 2 is OH and R 1 is OC(O)R 4 and R 4 is C1-C3 alkyl (e.g., methyl, isopropyl). In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 and R 4 is C1-C3 alkyl (e.g., methyl, isopropyl). In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 and R 5 is C1-C3 alkyl (e.g., methyl, isopropyl). In some embodiments, R 1 is OC(O)R 4 and R 2 is OC(O)R 5 and R 4 is C1-C3 alkyl (e.g., methyl, isopropyl), and R 5is C1-C3 alkyl (for example, methyl, isopropyl).

[0106] In some embodiments, R 1 is OH and R 3 is H. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with 1 NH2. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl substituted with 1 NH2. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a C4-C6 alkyl substituted with one NH2. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with 1 halo. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7is C1-C6 alkyl substituted with one fluoro. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C4-C6 alkyl substituted with one fluoro. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C8 alkyl substituted with a C3-C8 carbocycle. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C6 alkyl substituted with a C3-C8 carbocycle. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl substituted with spiro[3,3]heptyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7and R 7 is a C1-C3 alkyl substituted with a C3-C8 carbocycle. 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl substituted with cyclobutyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C3 alkyl substituted with cyclobutyl substituted with methyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with phenyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C8 alkyl, and R 7 is C1-C8 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C6 alkyl, and R 7 is C1-C6 alkyl. In some embodiments, R 1 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C3 alkyl, and R 7 is C1-C3 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C6~C 10In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is phenyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a C6-C alkyl group substituted with one C1-C8 alkyl group. 10 In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is phenyl substituted with methyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is C3-C8 carbocyclyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclohexyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cycloheptyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with one or two C1-C8 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C8 alkyl. In some embodiments, R 1is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C6 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C3 alkyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two methyls. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is cyclopropyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a 4- to 6-membered heterocyclyl. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a 4-6 membered heterocyclyl containing one O. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a 4- to 6-membered heterocyclyl containing one O, and R 7 is substituted with oxo.

[0107] In some embodiments, R 2 is OH and R 3 is H. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl. In some embodiments, R 2 is OH and R3 is C(O)R 7 and R 7 is C1-C6 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with 1 NH2. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl substituted with 1 NH2. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is a C4-C6 alkyl substituted with one NH2. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with 1 halo. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl substituted with one fluoro. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C4-C6 alkyl substituted with one fluoro. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl. In some embodiments, R2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C8 alkyl substituted with a C3-C8 carbocycle. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C6 alkyl substituted with a C3-C8 carbocycle. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C6 alkyl substituted with spiro[3,3]heptyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is a C1-C3 alkyl substituted with a C3-C8 carbocycle. 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C3 alkyl substituted with cyclobutyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7is a C1-C3 alkyl substituted with cyclobutyl substituted with methyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 7 is C1-C8 alkyl substituted with phenyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C8 alkyl, and R 7 is C1-C8 alkyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C6 alkyl, and R 7 is C1-C6 alkyl. In some embodiments, R 2 is OC(O)R 4 and R 3 is C(O)R 7 and R 4 is a C1-C3 alkyl, and R 7 is C1-C3 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C6~C 10 In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is phenyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is a C6-C alkyl group substituted with one C1-C8 alkyl group. 10 In some embodiments, R 2 is OH and R 3 is C(O)R7 and R 7 is phenyl substituted with methyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is C3-C8 carbocyclyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclohexyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cycloheptyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with one or two C1-C8 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C8 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C6 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclobutyl substituted with two C1-C3 alkyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7is cyclobutyl substituted with two methyls. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is cyclopropyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is a 4- to 6-membered heterocyclyl. In some embodiments, R 2 is OH and R 3 is C(O)R 7 and R 7 is a 4-6 membered heterocyclyl containing one O. In some embodiments, R 1 is OH and R 3 is C(O)R 7 and R 7 is a 4- to 6-membered heterocyclyl containing one O, and R 7 is substituted with oxo.

[0108] In some embodiments, R 1 is OH and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4 is a C1-C8 alkyl, and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4 is a C1-C6 alkyl, and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4 is a C1-C3 alkyl, and the base is [ka] is. In some embodiments, R 1 is OC(O)R 4 and R 4 is isopropyl or methyl, and the base is [ka] In some embodiments, R 1 is OH and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4 is a C1-C8 alkyl, and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4 is a C1-C6 alkyl, and the base is [ka] In some embodiments, R 1 is OC(O)R 4 and R 4is a C1-C3 alkyl, and the base is [ka] In some embodiments, R 1 is OH and the base is [ka] In some embodiments, R 1 is OH and the base is [ka] and R 11 is C1-C6 alkyl. In some embodiments, R 1 is OH and the base is [ka] and R 11 is OC(O)R 12 In some embodiments, R 1 is OH and the base is [ka] and R 11 is OC(O)R 12 C1-C6 alkyl substituted with R 12 is C1-C3 alkyl. In some embodiments, R 1 is OH or OC(O)R 4 and R 4 is a C1-C8 alkyl, and the base is [ka] is.

[0109] In some embodiments, R 2 is OH and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C8 alkyl, and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C6 alkyl, and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C3 alkyl, and the base is [ka] is. In some embodiments, R 2 is OC(O)R 5 and R 5 is isopropyl or methyl, and the base is [ka] In some embodiments, R 2 is OH and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C8 alkyl, and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C6 alkyl, and the base is [ka] In some embodiments, R 2 is OC(O)R 5 and R 5 is a C1-C3 alkyl, and the base is [ka] In some embodiments, R 2 is OH and the base is [ka] In some embodiments, R 2 is OH and the base is [ka] and R 11 is C1-C6 alkyl. In some embodiments, R 2 is OH and the base is [ka] and R 11 is OC(O)R 12 In some embodiments, R 2 is OH and the base is [ka] and R11 is OC(O)R 12 C1-C6 alkyl substituted with R 12 is C1-C3 alkyl. In some embodiments, R 2 is OH or OC(O)R 5 and R 5 is a C1-C8 alkyl, and the base is [ka] is.

[0110] In some embodiments, the compound of formula I is [ka] isn't it.

[0111] In some embodiments, the compounds of Formula I and pharmaceutically acceptable salts thereof include the compounds of Table 1 and their pharmaceutically acceptable salts. [Table 1-1] [Table 1-2] [Table 1-3]

[0112] In some embodiments, the compound of formula I has formula II. [ka] Compounds and pharmaceutically acceptable salts of Formula II are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula II as relevant.

[0113] In some embodiments, compounds of Formula II and pharmaceutically acceptable salts thereof include the compounds of Table 2 and pharmaceutically acceptable salts thereof. [Table 2-1] [Table 2-2]

[0114] In some embodiments, the compound of Formula I or Formula II has Formula III. [ka]

[0115] Compounds and pharmaceutically acceptable salts of Formula III are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula III as relevant.

[0116] In some embodiments, the compounds of Formula III and pharmaceutically acceptable salts thereof include the compounds of Table 3 and pharmaceutically acceptable salts thereof. [Table 3-1] [Table 3-2]

[0117] In some embodiments, the compound of Formula I or Formula II has Formula IV. [ka]

[0118] Compounds and pharmaceutically acceptable salts of Formula IV are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula IV as relevant.

[0119] In some embodiments, compounds of Formula IV and pharmaceutically acceptable salts thereof include compounds in Table 4 and pharmaceutically acceptable salts thereof. [Table 4-1] [Table 4-2]

[0120] In some embodiments, the compound of Formula I, Formula II, Formula III, or Formula IV has Formula V: [ka]

[0121] Compounds and pharmaceutically acceptable salts of formula V are disclosed herein, and the descriptions of substituents and compounds of formula I apply to formula V as relevant.

[0122] In some embodiments, compounds of Formula V and pharmaceutically acceptable salts thereof include the compounds of Table 5 and pharmaceutically acceptable salts thereof. [Table 5-1] [Table 5-2]

[0123] In some embodiments, the compound of Formula I or Formula II has Formula VI. [ka]

[0124] Compounds and pharmaceutically acceptable salts of Formula VI are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula VI as relevant. In some embodiments, compounds and pharmaceutically acceptable salts of Formula VI include the compounds of Table 6 and their pharmaceutically acceptable salts. [Table 6-1] [Table 6-2]

[0125] In some embodiments, the compound of formula I has formula VII. [ka]

[0126] Compounds and pharmaceutically acceptable salts of Formula VII are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula VII as relevant.

[0127] In some embodiments, compounds of Formula VII and pharmaceutically acceptable salts thereof include compounds in Table 7 and pharmaceutically acceptable salts thereof. [Table 7]

[0128] In some embodiments, the compound of formula I has formula VIII. [ka]

[0129] Compounds and pharmaceutically acceptable salts of Formula VIII are disclosed herein, and the descriptions of substituents and compounds of Formula I apply to Formula VIII as relevant.

[0130] In some embodiments, compounds of Formula VIII and pharmaceutically acceptable salts thereof include compounds in Table 8 and pharmaceutically acceptable salts thereof. [Table 8]

[0131] In some embodiments, the compound of Formula I, Formula VII, or Formula VIII has Formula IX. [ka]

[0132] Compounds and pharmaceutically acceptable salts of formula IX are disclosed herein, and the descriptions of substituents and compounds of formula I apply to formula IX as relevant.

[0133] In some embodiments, compounds of Formula IX and pharmaceutically acceptable salts thereof include compounds in Table 9 and pharmaceutically acceptable salts thereof. [Table 9]

[0134] In some embodiments, the compound of formula I has the formula X: [ka]

[0135] Compounds and pharmaceutically acceptable salts of formula X are disclosed herein, and the descriptions of substituents and compounds of formula I apply as relevant to formula X. In some embodiments, compounds and pharmaceutically acceptable salts of formula X include the compounds of Table 10 and their pharmaceutically acceptable salts. [Table 10]

[0136] In some embodiments, the compound of formula I has formula XI. [ka]

[0137] Compounds and pharmaceutically acceptable salts of formula XI are disclosed herein, and the descriptions of substituents and compounds of formula I apply to formula XI as relevant.

[0138] In some embodiments, compounds of Formula XI and pharmaceutically acceptable salts thereof include compounds in Table 11 and pharmaceutically acceptable salts thereof. [Table 11-1] [Table 11-2] [Table 11-3]

[0139] Those of ordinary skill in the art will recognize the groups disclosed herein (e.g., R 1 Any and all embodiments of the remaining groups (e.g., R 2 , R 3 It is recognized that each of the formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or (XI), or the complete compound of any formula described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, each of which is considered to be within the scope of this disclosure.

[0140] In some embodiments, the compounds and pharmaceutically acceptable salts of Formula I include the compounds of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds disclosed herein include the compounds of Table 11A or a pharmaceutically acceptable salt thereof. [Table 11A-1] [Table 11A-2] [Table 11A-3] [Table 11A-4] [Table 11A-5]

[0141] Also included within the scope of this specification are the in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Included therefore are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield metabolic products thereof. Such products are typically radiolabeled (e.g., 14 C or 3 H) Compounds are prepared and identified by administering them at detectable doses (e.g., greater than about 0.5 mg / kg) to animals, such as rats, mice, guinea pigs, monkeys, or humans, allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes surviving in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies. Transformation products are useful in diagnostic assays for therapeutic administration of compounds, even if they do not possess their own HSV antiviral activity unless otherwise found in vivo.

[0142] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids upon incubation at 37° C. for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally within cells. As used herein, a prodrug is understood to be a compound chemically designed to efficiently liberate the parent drug (i.e., Compound 0 below) after overcoming a biological barrier to oral delivery. IV. Pharmaceutical Compositions

[0143] Also disclosed herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I-XI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0144] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can include, for example, excipients, glidants, fillers, binders, or combinations thereof. Aqueous formulations are prepared in sterile form and, if intended for delivery by other than oral administration, are generally isotonic. Exemplary excipients include, but are not limited to, those listed in the "Handbook of Pharmaceutical Excipients" (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and combinations thereof. In some embodiments, the formulation is basic. In some embodiments, the formulation is acidic. In some embodiments, the formulation has a neutral pH. In some embodiments, the pH of the formulation is 2 to 11 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 8 to 9, 8 to 10, 8 to 11, 9 to 10, or 9 to 11).

[0145] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compounds. Formulations suitable for oral administration can be presented, for example, as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be administered, for example, as a bolus, electuary, or paste.

[0146] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, dispersant, or a combination thereof, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0147] For infections of the eye or other external tissues (e.g., mouth and skin), formulations may be applied as a topical ointment or cream containing the active ingredient in an amount, for example, 0.075 to 20% w / w (including active ingredient in ranges of 0.1% to 20% in 0.1% w / w increments, such as 0.6% w / w, 0.7% w / w, etc.), 0.2% to 15% w / w, or 0.5% to 10% w / w. When formulated in an ointment, the active ingredient may, in some embodiments, be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0148] In some embodiments, the aqueous phase of the cream base may comprise, for example, 30% to 90% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. In some embodiments, the cream base may include, for example, a compound that enhances absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include, but are not limited to, dimethyl sulfoxide and related analogs. In some embodiments, the cream or emulsion does not contain water.

[0149] The oily phase of the emulsion can be composed of known ingredients in a known manner. In some embodiments, the phase comprises only an emulsifier (otherwise known as an emulgent). In some embodiments, the phase comprises a mixture of at least one emulsifier with a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that functions as a stabilizer. Taken together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with oils and fats, constitutes a so-called emulsifying ointment base that can form the oily dispersed phase of a cream formulation.

[0150] Emulgents and emulsion stabilizers suitable for use in the formulations may include, but are not limited to, TWEEN® 60, TWEEN® 80, SPAN® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, and combinations thereof.

[0151] The selection of suitable oils or fats for the formulation can be based on achieving the desired aesthetic properties. In some embodiments, the cream can be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. In some embodiments, the ester can include, for example, linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, CRODAMOL® CAP, or a blend of branched esters known as such, or combinations thereof. In some embodiments, a high-melting lipid such as white soft paraffin and / or liquid paraffin or other mineral oils can be included.

[0152] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition is for veterinary use. In some embodiments, the pharmaceutical composition is for human use. In some embodiments, the pharmaceutical composition disclosed herein comprises at least one additional therapeutic agent.

[0153] The pharmaceutical compositions disclosed herein can be in any form suitable for the intended method of administration. The pharmaceutical compositions disclosed herein can be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Exemplary techniques and formulations can be found, for example, in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods can include the step of bringing into association the compounds disclosed herein with the carrier, which constitutes one or more accessory ingredients. In general, the formulations can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0154] For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Preparations intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such preparations can contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture 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 disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, for example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0155] Formulations for oral use may also be presented 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 water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0156] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more coloring agents, one or more flavoring agents, one or more sweeteners (e.g., sucrose or saccharin), or mixtures thereof. Further non-limiting examples of suspending agents include cyclodextrins, hi some embodiments, the suspending agent is sulfobutylether beta-cyclodextrin (SEB-beta-CD), such as CAPTISOL®.

[0157] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil, or a combination thereof), a mineral oil such as liquid paraffin, or a combination thereof. Oral suspensions can contain a thickening agent such as, for example, beeswax, hard paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweetening agents, such as those set forth above, and / or flavoring agents are added to provide a palatable oral preparation. In some embodiments, the formulations disclosed herein are preserved by the addition of an antioxidant, such as ascorbic acid.

[0158] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, a preservative, or combinations thereof. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0159] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations can also contain, for example, demulcents, preservatives, flavorings, coloring agents, or combinations thereof.

[0160] The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparation, for example, a sterile injectable aqueous suspension or an injectable oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable or intravenous preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, solid oils can be used as solvents or suspending media. For this purpose, any solvent-free solid oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables. Acceptable vehicles and solvents that can be used include, but are not limited to, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0161] 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 treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 2000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may vary from 5% to 95% (weight:weight) of the total formulation. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may vary from 5% to 95% (weight:weight) of the total formulation. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain 3 μg to 500 μg of active ingredient per milliliter of solution to allow a suitable volume to be infused at a rate of about 30 mL / hour.

[0162] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. In some embodiments, the compounds disclosed herein are included in the pharmaceutical compositions disclosed herein at a concentration of 0.5% to 20% (e.g., 0.5% to 10%, 1.5% w / w).

[0163] Formulations suitable for topical administration to the mouth include lozenges, which may contain the active ingredient (i.e., a compound disclosed herein and / or additional therapeutic agent) in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes, which contain the active ingredient in a suitable liquid carrier.

[0164] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0165] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0166] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0167] The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0168] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0169] Further provided are veterinary formulations comprising a compound disclosed herein together with a carrier for veterinary use.

[0170] A veterinary carrier is a substance useful for the purpose of administering the formulation and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary formulations may be administered orally, parenterally, or by any other desired route.

[0171] The compounds herein are used to provide controlled-release pharmaceutical compositions ("controlled-release formulations") comprising one or more of the compounds as active ingredients, the release of which can be controlled and regulated to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0172] The effective dose of the active ingredient will depend, at least in part, on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (low dose) or against an active viral infection, the delivery method, and the pharmaceutical composition, and will be determined by the clinician using conventional dose-escalation studies. In some embodiments, the effective dose is 0.0001 to 100 mg / kg body weight per day, e.g., about 10 to about 30 mg / kg body weight per day, 15 to 25 mg / kg body weight per day, 10 to 15 mg / kg body weight per day, or 20 to 30 mg / kg body weight per day. For example, a daily candidate dose for an adult weighing approximately 70 kg can range from 1 mg to 2000 mg (e.g., 5 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg) and can take the form of a single dose or multiple doses. For example, the daily candidate dose for an adult human weighing approximately 70 kg may range from 1 mg to 1000 mg (eg, 5 mg to 500 mg) and may take the form of a single dose or multiple doses. V. Kit

[0173] Also provided herein are kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. In some embodiments, the kits described herein may include a label and / or instructions for using the compound in treating a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0174] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with the compounds disclosed herein in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0175] In some embodiments, the kits provided herein contain individual dosage units of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units may include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kit contains a single dosage unit, while in others, multiple dosage units may be present, such as the number of dosage units required for a particular regimen or time period.

[0176] Also provided is an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer. VI. Administration

[0177] One or more compounds of the present disclosure are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. It will be understood that the route may vary depending, for example, on the condition of the recipient.

[0178] In the disclosed methods for treating a viral infection, the compounds of the present disclosure can be administered at any time to a subject who may have come into contact with the virus or who already has the viral infection. In some embodiments, the compounds of the present disclosure can be administered prophylactically to a subject who comes into contact with a subject who has a viral infection or who is at risk of coming into contact with a subject who has a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present disclosure can be to a subject who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In the disclosed methods for treating a viral infection, the compounds of the present disclosure can be administered prophylactically to a person who may have come into contact with the virus or who already has the viral infection, such as a healthcare provider. In some embodiments, the compounds of the present disclosure can be administered prophylactically to a person who comes into contact with a person who has a viral infection or who is at risk of coming into contact with a person who has a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds of the present disclosure can be to a person who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, administration of a compound of the present disclosure may be to a human at the onset of symptoms of a viral infection.

[0179] In some embodiments, the methods disclosed herein include event-driven administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a subject.

[0180] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound of Formula I-XI, or a pharmaceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus), and / or (2) during an event (or two or more recurring events) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the subject to the virus (or otherwise increases the subject's risk of being infected with the virus). In some embodiments, event-driven administration occurs before the subject's exposure to the virus. In some embodiments, event-driven administration occurs after the subject's exposure to the virus. In some embodiments, event-driven administration occurs before the subject's exposure to the virus and after the subject's exposure to the virus.

[0181] In certain embodiments, the methods disclosed herein include administering a medicament before and / or after an event that exposes a subject to the virus or that otherwise increases the subject's risk of becoming infected with the virus, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0182] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered prior to the subject's exposure to the virus.

[0183] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered before and after exposure of the subject to a virus.

[0184] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is administered after the subject's exposure to the virus.

[0185] An example of an event-driven dosing regimen includes administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by another administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, after the final exposure, and finally another administration of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0186] A further example of an event-driven dosing regimen includes administering a compound of any one of Formulas I-XI, or a pharmaceutically acceptable salt thereof, within 24 hours before exposure to the virus, followed by daily dosing for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0187] The effective dose of the active ingredient will depend, at least, on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically or against an active viral infection, the delivery method, and the pharmaceutical composition, and will be determined by the clinician using conventional dose-escalation studies. It can be expected to be between 0.0001 mg / kg and 100 mg / kg of body weight per day (e.g., 0.01 mg / kg and 10 mg / kg of body weight per day, 0.01 mg / kg and 5 mg / kg of body weight per day, 0.05 mg / kg and 0.5 mg / kg of body weight per day). In some embodiments, the daily candidate dose for an adult weighing approximately 70 kg is between 1 mg and 4000 mg (e.g., 5 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg, 2000 mg to 3000 mg, 3000 mg to 4000 mg) and can take the form of a single dose or multiple doses (e.g., twice-daily dose, three-daily dose). For example, the daily candidate dose for an adult weighing approximately 70 kg can range between 1 mg and 1000 mg (e.g., 5 mg to 500 mg) and can take the form of a single dose or multiple doses.

[0188] Any suitable period for administering the compounds of the present disclosure is contemplated. For example, administration can be for 1 day to 100 days, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. Administration can also be for 1 week to 15 weeks, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 weeks. Longer administration periods are also contemplated.

[0189] In some embodiments, the compounds disclosed herein are administered once a day. In some embodiments, the compounds disclosed herein are administered twice a day. In some embodiments, the compounds disclosed herein are administered once every other day. In some embodiments, the compounds disclosed herein are administered once a week. In some embodiments, the compounds disclosed herein are administered twice a week.

[0190] In some embodiments, one or more compounds disclosed herein are administered once daily. The once-daily dose can be administered for as long as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, the once-daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0191] In some embodiments, one or more compounds disclosed herein are administered once daily for 6 to 12 days, e.g., 8 to 10 days. In some embodiments, one or more compounds are administered once daily for 9 days. In some embodiments, one or more compounds are administered once daily for 10 days. In some embodiments, 50 to 150 mg of one or more compounds disclosed herein are administered once daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 100 mg of one or more compounds disclosed herein are administered once daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 500-2000 mg (e.g., 500-1000 mg, 1000-1500 mg) of one or more compounds disclosed herein is administered once daily for 5-12 days, e.g., 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days.

[0192] In some embodiments, one or more compounds disclosed herein are administered twice daily. The twice-daily dose can be administered for as long as needed, for example, for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to one month or more. In some embodiments, the twice-daily dose is administered for up to 20 days, up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6 days, up to 4 days, up to 3 days, up to 2 days, or 1 day.

[0193] In some embodiments, one or more compounds disclosed herein are administered twice daily for 6 to 12 days, e.g., 8 to 10 days. In some embodiments, one or more compounds are administered twice daily for 9 days. In some embodiments, one or more compounds are administered twice daily for 10 days. In some embodiments, 1 to 2000 mg of one or more compounds disclosed herein are administered twice daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, 500 to 2000 mg (e.g., 500 to 1000 mg, 1000 to 1500 mg, 1500 to 2000 mg) of one or more compounds disclosed herein are administered twice daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days. VII.How to use

[0194] The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound described herein.

[0195] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject in need thereof a compound described herein.

[0196] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0197] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic agent.

[0198] In some embodiments, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0199] In some embodiments, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0200] Also provided herein is the use of a compound disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein is the use of a compound disclosed herein for use in treating a viral infection in a subject in need thereof. A. Paramyxoviridae

[0201] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein. In some embodiments, the Paramyxoviridae virus comprises a BSL4 pathogen. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0202] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Paramyxoviridae virus infection in a subject (e.g., a human).

[0203] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof. B. Pneumoviridae

[0204] In some embodiments, the viral infection is a Pneumoviridae virus infection. In some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, comprising administering to the subject (e.g., human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0205] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Pneumoviridae virus infection in a subject (e.g., a human). In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0206] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Pneumoviridae virus infection in a human in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Pneumoviridae virus infection in a human. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0207] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0208] In certain embodiments, the present disclosure provides a method for treating a respiratory syncytial virus infection, comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) infected with a respiratory syncytial virus. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0209] In certain embodiments, methods are provided for inhibiting RSV replication, comprising administering to a subject (e.g., a human) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0210] In certain embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a subject (e.g., a human) infected with RSV a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to reduce the RSV viral load in the subject.

[0211] As described in more detail herein, the compounds of the present disclosure can be administered to a subject (e.g., a human) infected with RSV along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected subject (e.g., a human) simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure.

[0212] In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for use in treating or preventing a RSV infection. In certain embodiments, a compound of the present disclosure (e.g., a compound of Formula I-Formula XI), or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for treating or preventing a RSV infection.

[0213] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a subject (e.g., a human) in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0214] In some embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a human infected with RSV a compound disclosed herein. C. Picornaviridae

[0215] In some embodiments, the viral infection is a Picornaviridae virus infection. In some embodiments, the present disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, comprising administering to the subject (e.g., a human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection. In some embodiments, the Picornaviridae virus infection is an enterovirus infection. In some embodiments, the Picornaviridae virus 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. In some embodiments, the Picornaviridae virus is foot and mouth disease virus (FMDV).

[0216] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Picornaviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Picornaviridae virus infection in a subject (e.g., a human). In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0217] In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Picornaviridae virus infection in a subject (e.g., a human) in need thereof, in some embodiments, the Picornaviridae virus infection is a human rhinovirus infection. D. Flaviviridae

[0218] In some embodiments, the viral infection is a Flaviviridae virus infection. In some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, comprising administering to the subject (e.g., human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Representative Flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile, Zika, Japanese encephalitis virus, tick-borne encephalitis virus (TBEV), and hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a tick-borne encephalitis virus (TBEV) infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection. In some embodiments, the Flaviviridae virus infection is a bovine viral diarrhea virus (BVDV). In some embodiments, the Flaviviridae virus infection is a swine fever virus (SFV) infection.

[0219] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Flaviviridae virus infection in a subject (e.g., a human) in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Flaviviridae virus infection in a subject (e.g., a human). In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0220] In some embodiments, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection. E. Filoviridae

[0221] In some embodiments, the viral infection is a Filoviridae virus infection. In some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, comprising administering to the subject (e.g., human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai Forest, or Reston variant) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0222] In some embodiments, the present disclosure provides a method for manufacturing a medicament for treating a Filoviridae virus infection in a human in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used. In some embodiments, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a Filoviridae virus infection in a human. In some embodiments, the Filoviridae virus infection is an Ebola virus infection.

[0223] In some embodiments, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a Filoviridae virus infection in a subject (e.g., a human) in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection. VIII. Combination Therapy

[0224] The compounds described herein can also be used in combination with one or more additional therapeutic or prophylactic agents. Accordingly, also provided herein are methods of treating a viral infection in a subject in need thereof, comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents. In some embodiments, the method comprises administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the compounds disclosed herein are combined with at least one other active therapeutic agent, and the combination is used to treat a viral infection in a subject in need thereof. In some embodiments, the combination can be used to treat multiple separate viral infections (e.g., RSV and HIV) in a single subject. In some embodiments, the compounds disclosed herein are combined with at least one other active therapeutic agent to cover a broader spectrum of respiratory viruses in a single treatment, without the need for diagnosis.

[0225] In some embodiments, the combination can be used to treat the same virus (e.g., RSV) in a single subject. Active therapeutic agents include, but are not limited to, approved drugs, therapeutic agents currently in clinical trials, therapeutic agents that have demonstrated efficacy in animal models, therapeutic agents that have demonstrated efficacy in in vitro assays, or any of the above.

[0226] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A / NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, and combinations thereof.

[0227] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0228] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or a combination thereof.

[0229] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0230] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, hi some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0231] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0232] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0233] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0234] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), varicella-zoster immunoglobulin (VariZIG), varicella-zoster immune globulin (VZIG), and combinations thereof.

[0235] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0236] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0237] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0238] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0239] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0240] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof.

[0241] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0242] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0243] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0244] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria, hi some embodiments, the additional therapeutic agent is chloroquine.

[0245] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemisone, and combinations thereof.

[0246] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus. In some embodiments, the additional therapeutic agent is an agent for the treatment of COVID-19 (coronavirus disease 2019, a disease caused by a virus designated SARS-CoV-2). In some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, remdesivir, VV116, GS-441524, GS-5245, and combinations thereof.

[0247] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, or the like. Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolin[8,7 [-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenoviral vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0248] In some embodiments, the additional therapeutic agent is an agent for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ladarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0249] In some embodiments, the additional therapeutic agent is an NS5A inhibitor, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0250] In some embodiments, the additional therapeutic agent is an anti-HBV agent, for example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, and U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) ... In some embodiments, the additional therapeutic agent includes, but is not limited to, compounds disclosed in US Patent Application Publication Nos. 6128335(A1) (Roche), WO 16120186(A1) (Roche), US Patent Application Publication Nos. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), US Patent Application Publication Nos. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), US Patent Application Publication Nos. 2016220586(A) (Roche), and US Patent Application Publication No. 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, and efavirenz. In some embodiments, the additional therapeutic agent includes, but is not limited to, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filocillovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusorin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, the additional therapeutic agent is an HBV capsid inhibitor.

[0251] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0252] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modulating agents, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0253] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0254] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine) tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and ervivirine. Tegravir; COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat;Atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafena These include, but are not limited to, elsulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine;

[0255] In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor (lenacapavir).

[0256] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and cobicistat. In some embodiments, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0257] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is bictegravir, elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0258] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0259] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0260] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0261] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilp (VM-1500), and combinations thereof.

[0262] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); TDF+FT C); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir; Adefovir dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®, lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate) Salt, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazides; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0263] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovyne, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0264] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9).

[0265] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of 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 KRAS(G12D) selective inhibitory peptides (including KRpep-2, KRpep-2d, and combinations thereof).

[0266] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0267] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., a monovalent influenza A [H5N1] virus vaccine and a monovalent influenza A [H1N1] 2009 virus vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Flude, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (Flumist, Fluarix, Fluzone, and Flulaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9, and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (eg, Havrix and Vaqta).In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a Hepatitis E Virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a SARS-COV-2 vaccine.

[0268] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2 selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (a SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is an aPD-1 antibody.

[0269] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0270] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0271] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0272] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a vananin and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, dihydrotanshinone E-64-C and E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0273] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is a SARS-COV-2 virus antibody.

[0274] The formulations of the present disclosure may also be used in combination with other active ingredients. For the treatment of SARS-COV-2 viral infection, in some embodiments, the other active therapeutic agent is active against coronavirus infection, e.g., SARS-COV-2 viral infection. The compounds and formulations of the present disclosure may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., interferons), other small molecule or biological antivirals targeting SARS-COV-2 (e.g., lopinavir), or other antivirals. The additional therapeutic agent is intended for use in conjunction with the general care provided to patients with SARS-COV-2 virus infection, including medications such as, but not limited to, benzodiazepines (such as, but not limited to, benzodiazepines / ritonavir, EIDD-1931, favipiravir, ribavirin, and neutralizing antibodies), vaccines, analgesics, and medications for other common illnesses in the target population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine.

[0275] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system 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), Proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MPA). mofetil, MMF), ribavirin, polymer polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0276] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0277] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, e.g., the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0278] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof.

[0279] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, eg, pirfenidone.

[0280] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia, for example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and Mycoplasma pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0281] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the subject. Options include: (i) antibiotics; (ii) cough suppressants; and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0282] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from a cured COVID-19 subject. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0283] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531.

[0284] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0285] In some embodiments, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0286] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO2004112687, WO2006135978, WO2018145148, and WO2009018609.

[0287] Any compound of the present disclosure can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a subject. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0288] Co-administration of a compound of the present disclosure with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the present disclosure with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of the present disclosure and the one or more other active therapeutic agents are present in the subject's body.

[0289] Co-administration includes administration of a unit dose of a compound of the present disclosure before or after administration of a unit dose of one or more other active therapeutic agents, e.g., administration of a compound of the present disclosure within seconds, minutes, or hours of administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the present disclosure can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the present disclosure. In some cases, it may be desirable to administer a unit dose of a compound of the present disclosure first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound of the present disclosure.

[0290] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. A synergistic effect can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules, or by different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination. Combination Therapy for the Treatment of A. Pneumoviridae

[0291] The compounds disclosed herein and their pharmaceutically acceptable salts can be used in combination with any of the active therapeutic agents discussed in Section VIII of the present specification and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.A of the present specification. In some embodiments, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. As described in more detail herein, the compounds of the present disclosure can be administered to a subject (e.g., a human) infected with RSV along with one or more additional therapeutic agents. Furthermore, in certain embodiments, when used to treat or prevent RSV, the compounds of the disclosure are selected from the group consisting of RSV combination drugs, RSV vaccines, RSV RNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, respiratory syncytial surface antigen inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, RSV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, farnesoid X receptor agonists, RSV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase inhibitors, and the like. The therapeutic agent may be administered with one or more (e.g., 1, 2, 3, 4 or more) additional therapeutic agents selected from the group consisting of: a PI3K inhibitor, an indoleamine-2,3-dioxygenase (IDO) pathway inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a recombinant thymosin alpha-1 agonist, a Bruton's tyrosine kinase (BTK) inhibitor, a KDM inhibitor, an RSV replication inhibitor, an arginase inhibitor, and other RSV drugs.

[0292] Non-limiting examples of these other active therapeutic agents active against RSV include active monoclonal antibodies and nanobody therapeutics, agents active against RSV infection, respiratory syncytial virus protein F inhibitors, viral replication inhibitors, RNA polymerase inhibitors, siRNA-based therapies, and combinations thereof. Non-limiting examples of active monoclonal antibodies and nanobody therapeutics include palivizumab, RSV-IGIV (RESPIGAM®), MEDI-557 (motavizumab), MEDI8897 (nirsevimab), MK-1654, ALX-0171, A-60444 (also known as RSV604), anti-RSV G protein antibodies, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as MDT-637, BMS-433771, AK-0529, RV-521 (cisnatovir), JNJ-53718678 (lilematovir), BTA-585 and presatovir, RNA polymerase inhibitors (e.g., ribavirin, A-60444 (also known as RSV604), JNJ-64417184, ALS-8112 (JNJ-64041575, lumicitabine)), and ALS-8112 (the parent nuc of lumicitabine), and viral replication inhibitors such as EDP-938 and nitazoxanide, siRNA-based therapies such as ALN-RSV01, and combinations thereof.

[0293] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of RSV, including, but not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI DeltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0294] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181, RNA polymerase inhibitors such as ALS-8112, and antibodies for the treatment of metapneumovirus infection such as EV-046113.

[0295] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of metapneumovirus infection, including, but not limited to, mRNA-1653 and rHMPV-Pa vaccines. B. Combination Therapy for the Treatment of Picornaviridae

[0296] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.B herein. In some embodiments, the other active therapeutic agent is active against Picornaviridae virus infections, particularly Enterovirus infections. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, e.g., pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (U.S. Pat. No. 7,078,403) and Watson (U.S. Pat. No. 7,166,604), fusion sialidase proteins such as DAS-181, capsid protein VP1 inhibitors such as VVX-003 and AZN-001, viral protease inhibitors such as CW-33, phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533, and anti-EV71 antibodies.

[0297] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of Picornaviridae virus infection, including, but not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccine. C. Combination Therapy for the Treatment of Respiratory Infections

[0298] The compounds disclosed herein and their pharmaceutically acceptable salts can be used in combination with any of the active therapeutic agents discussed in Section VIII of this specification and / or other active therapeutic agents specifically discussed in Section VIII.C of this specification. Many infections caused by Pneumoviridae and Picornaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. The additional agents can be administered orally or by direct inhalation. For example, other additional therapeutic agents that can be combined with the compounds provided herein to treat viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0299] Glucocorticoids Glucocorticoids, first introduced as an asthma treatment in 1950 (Carryer, Journal of Allergy, 21, 282–287, 1950), remain the most potent and consistently effective therapy for this disease, although their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt)1–13, 1985). Unfortunately, oral glucocorticoid therapy is associated with significant undesirable side effects, including truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term treatments (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. To mitigate the severe adverse effects of oral steroids, inhaled corticosteroids (ICS) have been developed. Non-limiting examples of corticosteroids that can be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharmaceutically acceptable salt thereof. anti-inflammatory agents

[0300] Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections.The application of "anti-inflammatory signaling modulators" (referred to herein as AISTMs), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stop inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are key points for anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These non-limiting additional 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-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840), N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofuran (PDE-4 inhibitor). N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD12-281), 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch351591), 4-[5-(4-fluorophenyl )-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850), 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657), 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (cilomilast, a 2-diethyl-ethyl ester prodrug of a PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefinib, an EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor). Beta-2 adrenergic receptor agonist bronchodilators

[0301] Combinations including an inhaled β2-adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, together with a compound provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0302] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, with ICS can also be used to treat both bronchial constriction and inflammation (SYMBICORT® and ADVAIR®, respectively). Combinations including these ICS and β2-adrenergic receptor agonists with compounds provided herein are also suitable, but not limited to, combinations useful for treating respiratory viral infections.

[0303] Other examples of beta-2 adrenergic receptor agonists include, but are not limited to, bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergic drugs

[0304] Anticholinergic agents are of potential use for the treatment or prevention of pulmonary bronchoconstriction and are therefore useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic agents include muscarinic receptor antagonists (especially of the M3 subtype) that have shown therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999), such as 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide, 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate), 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin), and 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin). ), 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (levatropate), 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin), 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide), 7-[3-( 2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycinate), 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycinate), dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate), 3-[4,4-bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium, 1-[1-(3-fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one, 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] These include, but are not limited to, oct-3-yl)-1-phenyl-prop-2-yn-1-ol, 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate), or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester, rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, and bencycloquidium bromide. mucolytics

[0305] The compounds provided herein can also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0306] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in subjects with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein can also be combined with nebulized hypertonic saline, especially when viral infections are coexisting with bronchiolitis. The combination of the compounds provided herein and hypertonic saline can also include any of the additional agents discussed above. In some embodiments, 3% hypertonic saline is used. D. Combination Therapy for the Treatment of COPD

[0307] The compounds disclosed herein and their pharmaceutically acceptable salts can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of respiratory exacerbations of COPD, specifically discussed in Section VIII.D herein. In some embodiments, the other active therapeutic agents include other active agents for COPD.Non-limiting examples of these other active therapeutic agents include anti-IL5 antibodies such as benralizumab and mepolizumab, dipeptidyl peptidase I (DPP1) inhibitors such as AZD-7986 (INS-1007), DNA gyrase inhibitors / topoisomerase IV inhibitors such as ciprofloxacin hydrochloride, MDR-related protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors such as RPL-554, CFTR stimulators such as ivacaftor and QBW-251, MMP-9 / MMP-12 inhibitors such as RBx-10017609, adenosine A1 receptor antagonists such as PBF-680, GATA3 transcription factor inhibitors such as SB-010, and muscarinic receptor modulators / nicotinic acetylcholine receptor agonists such as ASM-024. agonists, MARCKS protein inhibitors, e.g., KIT tyrosine kinase / PDGF inhibitors such as BIO-11006 and masitinib, phosphodiesterase (PDE) 4 inhibitors such as roflumilast and CHF-6001, phosphoinositide-3 kinase delta inhibitors such as nemiralisib, 5-lipoxygenase inhibitors such as TA-270, muscarinic receptor antagonists / beta-2 adrenergic agonists such as butefenterol succinate, AZD-887, and ipratropium bromide, elastase inhibitors such as TRN-157 and erdosteine, metalloproteinase-12 inhibitors such as FP-025, interleukin-18 ligand inhibitors such as tadekinig alpha, skeletal muscle troponin activators such as CK-2127107, and p38 inhibitors such as akmapimod These include MAP kinase inhibitors, IL-17 receptor modulators, e.g., CNTO-6785, CXCR2 chemokine antagonists such as danilixin, leukocyte elastase inhibitors such as POL-6014, epoxide hydrolase inhibitors such as GSK-2256294, HNE inhibitors, e.g., CHF-6333, VIP agonists such as aviptadil, phosphoinositide-3 kinase delta / gamma inhibitors such as RV-1729, complement C3 inhibitors such as APL-1, and G protein-coupled receptor-44 antagonists such as AM-211.

[0308] Other non-limiting examples of active therapeutic agents include, but are not limited to, budesonide, adipocytes, nitric oxide, PUR-1800, YLP-001, LT-4001, azithromycin, Gamnex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxofylline, TEV-46017, OligoG-COPD-5 / 20, STEMPEUCEL®, ZP-051, lysine acetylsalicylate.

[0309] In some embodiments, the other active therapeutic agent may be a vaccine that is active against COPD, including, but not limited to, MV-130 and GSK-2838497A. E. Combination Therapy for the Treatment of Flaviviridae Virus Infections

[0310] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.E herein. In some embodiments, the other active therapeutic agent is active against Flaviviridae virus infections.

[0311] Non-limiting examples of other active therapeutic agents for the treatment of Flaviviridae infections are host cell factor modulators such as GBV-006, alpha-glucosidase 1 inhibitors such as fenretinide ABX-220, BRM-211, celgosivir, platelet activating factor receptor (PAFR) antagonists such as modipafant, 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.

[0312] In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of dengue fever, including, but not limited to, TETRAVAX-DV, DENGVAXIA®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2 delta30-7169, and DENV-1 PIV. F. Combination Therapy for the Treatment of Filoviridae Virus Infections

[0313] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII herein and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.F herein. In some embodiments, the other active therapeutic agent is active against Filoviridae virus infections (e.g., Marburg virus, Ebola virus, Sudan virus, and Cueva virus infections). Non-limiting examples of these other active therapeutic agents include: MR186-YTE, remdesivir, ribavirin, palivizumab, motavizumab, RSV-IGIV (RESPIGAM®), 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), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T- 705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir, galidesivir, favipiravir (also known as T-705 or Avigan), RNA polymerase inhibitors such as JK-05, host cell factor modulators such as GMV-006, cadherin-5 / factor Ia modulators such as FX-06, and antibodies for the treatment of Ebola such as INMAZEB (atortivimab, maftivimab, and odesivimab), ZMapp, and mAb114 (EBANGA).

[0314] Other non-limiting active therapeutic agents active against Ebola include, but are not limited to, alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0315] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, which may include, but is not limited to, VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0316] The compounds provided herein can also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs designed to interfere with the translation process 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.

[0317] The compounds provided herein are also intended for use in combination with the general care provided to subjects with Filoviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and medications for other common illnesses in the subject population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. Combination Therapy for the Treatment of G. Influenza

[0318] The compounds disclosed herein and pharmaceutically acceptable salts thereof can be used in combination with any of the active therapeutic agents discussed in Section VIII of the present specification and / or other active therapeutic agents for the treatment of Pneumoviridae virus infections, specifically discussed in Section VIII.G of the present specification. In some embodiments, the compounds provided herein are also used in combination with other active therapeutic agents for the treatment of influenza virus infections. The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In some embodiments, the compounds provided herein can also be combined with influenza therapeutic agents. In some embodiments, the compounds provided herein are used in conjunction with influenza therapeutic agents when treating influenza viruses. In some embodiments, the compounds provided herein are used in conjunction with influenza therapeutic agents to treat a broader spectrum of respiratory viruses, such as those disclosed herein. In some embodiments, the influenza therapeutic agent is a neuraminidase (NA) inhibitor. In some embodiments, the influenza therapeutic agent is an M2 inhibitor.Examples of influenza therapeutic agents include AB-5080, ALS-1, amantadine (GOCOVRI®), AV-001, AV-5124, AVM-0703, baloxavir marboxil (XOFLUZA®), CB-012, CC-42344, CD-388, CT-P27, Codivir, DAS-181, DNK-651, ENOB-FL-01, ENOB-FL-11, favipiravir, GP-584, GP-681, H-015, HC-imAb, HEC-116094HCl·3H2O, HNC-042, histamine glutarimide, IFV-PA, Ingavirin, INI-2004, INNA-051, and KYA. These include, but are not limited to, H01-2019-121, laninamivir, molnupiravir, niclosamide, nitazoxanide, norketotifen, NX-2016, oseltamivir phosphate (TAMIFLU®), peramivir (RAPIVAB®), REVTx-99, rimantadine, S-416, SAB-176, STP-702, T-705IV, TG-1000, TJ-27, TSR-066, 7HP-349, VIR-2482, VIS-410, VIS-FLX, XC-221, zanamivir (RELENZA®), zanamivir-dinitrophenyl conjugate, ZSP-1273, and ZX-7101A. IX. Compound Preparation

[0319] In some embodiments, the present disclosure provides processes and intermediates useful for preparing the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0320] The compounds disclosed herein can be purified by any of the chromatographic means known in the art, including, but not limited to, high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including, but not limited to, normal and reverse phase and ionic resins. In some embodiments, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0321] During any of the processes for the preparation of the compounds provided herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is further discussed in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 4 th This can be achieved by conventional protecting groups, as described in standard works such as "Protective Groups for the Synthesis of Novel Compounds," ed., Wiley, New York 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0322] Exemplary chemicals useful in the methods of the embodiments will now be described by reference to the illustrative synthetic schemes herein for their general preparation and the specific examples below. To obtain the various compounds herein, those skilled in the art will recognize that starting materials can be appropriately selected to obtain the desired product, such that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0323] Although the methods of the present disclosure generally provide a particular enantiomer or diastereomer as the desired product, the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is derived without indicating the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or diastereomerically pure.

[0324] Representative syntheses of compounds of the present disclosure are described in the following schemes and specific examples below. [ka] Scheme 1 shows a general synthesis of compounds, starting from the reaction of intermediate I-1a with carboxylic acid S1a in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) to give S1c. Alternatively, reaction of intermediate I-1a with an anhydride S1b in the presence of a base (e.g., DMAP) gives S1c. Removal of the acetonide group under acidic conditions (e.g., HCl) gives final compounds of type S1d. [ka]

[0325] Scheme 2 shows a general synthesis of compounds, starting with the reaction of intermediate I-1a with 1,1-dimethoxy-N,N-dimethylmethanamine to give amidine-protected base S2a. Coupling of S2a with carboxylic acid S2b in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) can give S2d. Alternatively, reaction of S2a with anhydride S2c in the presence of a base (e.g., DMAP) gives S2d. Removal of the acetonide and amidine groups under acidic conditions (e.g., HCl) gives final compounds of type S2e. [ka]

[0326] Scheme 3 shows a general synthesis of compounds, starting with the reaction of intermediate I-1a with a silyl protecting group reagent (e.g., TBSCl) under basic conditions (e.g., EtN) to give S3a. Coupling of S3a with carboxylic acid S3b in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) gives S3d. Alternatively, reaction of S3a with anhydride S3c in the presence of a base (e.g., DMAP) gives S3d. Removal of the TBS protecting group (e.g., TBAF) and acetonide group with fluoride under acidic conditions (e.g., HCl) gives final compounds of type S3e. [ka]

[0327] Scheme 4 shows a general synthesis of compounds, beginning with the reaction of compound 0 with a silyl protecting group reagent (e.g., TBSCl) under basic conditions (e.g., EtN) to give S4a. Reaction of S4a with another equivalent of a silyl protecting group reagent (e.g., TBSCl) under basic conditions (e.g., EtN) gives a mixture of bis-silyl protected intermediates S4b and S4c. Coupling of S4b with carboxylic acid S4d in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) gives S4f. Alternatively, reaction of S4b with anhydride S4e in the presence of a base (e.g., DMAP) gives S4f. Removal of the TBS protecting group with a fluoride (e.g., TBAF) gives final compounds of type S4g. Further coupling of S4c with carboxylic acid S4h in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) gives S4j. Alternatively, reaction of S4c with an anhydride S4i in the presence of a base (e.g., DMAP) gives S4j. Removal of the TBS protecting group with a fluoride (e.g., TBAF) gives final compounds of type S4k. [ka]

[0328] Scheme 5 shows a general synthesis of compounds, starting from the reaction of intermediate S1c with carboxylic acid S5a in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) to give S5c. Alternatively, reaction of S1c with an anhydride S5b in the presence of a base (e.g., DMAP) gives S5c. Removal of the acetonide group under acidic conditions (e.g., HCl) gives final compounds of type S5d. [ka]

[0329] Scheme 6 shows a general synthesis of compounds, starting with the reaction of intermediate S1d with a silyl-protecting group reagent (e.g., TBSCl) under basic conditions (e.g., EtN) to give a mixture of silyl-protected intermediates S6a and S6b. Coupling of S6a with carboxylic acid S6c in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) gives S6e. Alternatively, reaction of S6a with anhydride S6d in the presence of a base (e.g., DMAP) gives S6e. Removal of the TBS protecting group with a fluoride (e.g., TBAF) gives final compounds of type S6f. Coupling of S6f with either carboxylic acid S6g in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) or anhydride S6h in the presence of a base (e.g., DMAP) gives final compounds of type S6i. Coupling of S6i with either the carboxylic acid S6j in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) or the anhydride S6k in the presence of a base (e.g., DMAP) gives final compounds of type S6l. Furthermore, coupling of S6b with the carboxylic acid S6m in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) gives S6o. Alternatively, reaction of S6b with the anhydride S6n in the presence of a base (e.g., DMAP) gives S6o. Removal of the TBS protecting group with a fluoride (e.g., TBAF) gives final compounds of type S6p. Coupling of S6p with either the carboxylic acid S6q in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) or the anhydride S6r in the presence of a base (e.g., DMAP) gives final compounds of type S6s. Coupling of S6s with either the carboxylic acid S6t in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) or with the anhydride S6u in the presence of a base (e.g., DMAP) gives final compounds of type S6v. [ka]

[0330] Scheme 7 shows the general synthesis of compounds, starting from the reaction of S1d with CDI to give final compounds of type S7a. Coupling of S7a with either a carboxylic acid S7b in the presence of a coupling agent (e.g., EDCI) and a base (e.g., DMAP) or with an anhydride S7d in the presence of a base (e.g., DMAP) gives final compounds of type S7e. [ka]

[0331] Scheme 8 shows a general synthesis of compounds starting from the reaction of S3a with chloromethyl ester S8a in the presence of iodide ion (e.g., KI) to give intermediate S8b. Cleavage of the TBS protecting group in the presence of fluoride (e.g., TBAF) followed by acetonide removal under acidic conditions (e.g., HCl) gives compounds of type S8c. [ka]

[0332] Scheme 9 shows a general synthesis of compounds beginning with the reaction of S1d with chloromethyl phosphate S9a in the presence of iodide ion (e.g., NaI) to give intermediate S9b. Cleavage of the TBS protecting group in the presence of fluoride (e.g., TBAF) followed by benzyl removal using H2 gas and Pd / C gives compounds of type S9c. [ka]

[0333] Scheme 10 shows a general synthesis of compounds beginning with the reaction of S4a with chloromethyl phosphate S10a in the presence of iodide ion (e.g., NaI) to give intermediate S10b. Cleavage of the TBS protecting group in the presence of fluoride (e.g., TBAF) followed by benzyl removal using H gas and Pd / C gives compound S10c. [ka]

[0334] Scheme 11 shows a general synthesis of compounds, beginning with the reaction of compound 0 with a silyl protecting group reagent (e.g., TBSCl) under basic conditions (e.g., EtN) to give intermediate S11a. Reaction of S11a with CDI gives the cyclic carbonate, followed by removal of TBS in the presence of a fluoride (e.g., TBAF) to give final compound S11b. [Example]

[0335] A. Abbreviation Certain abbreviations and acronyms are used in describing the experimental details. While most of these will be understood by those skilled in the art, Table 12 contains a list of many of these abbreviations and acronyms. [Table 12] B. Intermediates Intermediate I-1a: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ka]

[0336] Intermediate I-26 (18.87 mmol) was taken up in THF (100 mL). A 1.0 M solution of TBAF in THF (28.31 mmol) was added in one portion at ambient temperature. Stirring was allowed for 10 minutes at ambient temperature. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water and the organics were removed under reduced pressure. The crude material was partitioned between EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and dried over sodium sulfate. The solids were filtered off and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (120 g column, 0% to 10% CHOH in CHCl) to give intermediate I-1a. LC / MS: R = 0.76 min, MS m / z = 332.14 [M+1]; LC system: Thermo Accela 1250 UHPLC; MS system: Thermo LCQ Fleet; Column: Kinetex 2.6μ XB-C18 100A, 50 × 3.00 mm; Solvent: Acetonitrile (with 0.1% formic acid), water (with 0.1% formic acid). Gradient: 2 to 100% ACN from 0 to 2.4 min, 100% ACN from 2.4 to 2.80 min, 100% ACN from 2.8 to 2.85 min, 2% ACN from 2.85 to 3.0 min, at 1.8 mL / min. 1 H NMR(400MHz,DMSO-d6)δ 7.87-7.80(m,3H),6.85(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),5.74(t,J=5.8Hz,1H),5.52(d,J=4.2Hz,1H ),5.24(dd,J=6.8,4.2Hz,1H),4.92(d,J=6.8Hz,1H),3.65(dd,J=6.1,1.7Hz,2H),1.61(s,3H),1.33(s,3H). Intermediate I-1: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl benzoate [ka]

[0337] To a mixture of intermediate I-1a (1.51 mmol) and benzoic acid (2.26 mmol) in DMF (5 mL) was added DMAP (1.51 mmol) followed by EDCI-HCl (2.26 mmol). The resulting mixture was stirred at room temperature for 2 h, added with MeOH (0.5 mL), concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give intermediate I-1. 1 H NMR(400MHz,acetonitrile-d3)δ 8.12-8.01(m,2H),7.84(s,1H),7.69(m,1H),7.61-7.42(m,2H),6.80(d,J=4.5Hz,1H),6.75(d,J=4.5Hz,1H),6.27(s,2H),5.70(d,J=3.4Hz) MS m / z[M+1]=436. Intermediate I-2 and Intermediate I-3: Intermediate I-2 ((3aS,4R,6S,6aS)-4-cyano-6-(4-(2-ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-ethylbutanoate and Intermediate I-3 ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-ethylbutanoate [ka]

[0338] To a mixture of intermediate I-1a (0.362 mmol) and 2-ethylbutanoic acid (0.543 mmol) in DMF (2 mL) was added DMAP (0.543 mmol) followed by EDCI-HCl (0.543 mmol). The resulting mixture was stirred at room temperature for 2 h, added with MeOH (0.5 mL), concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-2 and intermediate I-3.

[0339] Intermediate I-2: 1 H NMR(400MHz,acetonitrile-d3)δ 8.92(s,1H),8.22(s,1H),7.22(d,J=4.7Hz,1H),6.99(d,J=4.7Hz,1H),5.7 5(d,J=3.4Hz,1H),5.34(dd,J=6.6,3.4Hz,1H),5.07(d,J=6.6Hz,1H),4.51 (d,J=11.7Hz,1H),4.38(d,J=11.7Hz,1H),2.62(m,1H),2.28(m,1H),1.79- 1.48(m,11H),1.38(s,3H),0.97(t,J=7.4Hz,6H),0.88(q,J=7.6Hz,6H).MS m / z[M+1]=528.

[0340] Intermediate I-3: 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.81(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.26(s,2H),5.67(d,J=3.5Hz,1H),5.33(dd,J=6.6,3.5Hz,1H),5.06(d,J= MS m / z[M+1]=430. Intermediate I-4: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl pivalate [ka]

[0341] To a mixture of intermediate I-1a (0.637 mmol) and pivalic acid (0.955 mmol) in DMF (2 mL) was added DMAP (0.955 mmol) followed by EDCI-HCl (0.955 mmol). The resulting mixture was stirred at room temperature for 3 h, added with MeOH (0.5 mL), concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-4. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.26(s,2H),5.67(d,J=3.5Hz,1H),5.32(dd,J=6.7,3.5Hz MS m / z[M+1]=416. Intermediate I-5: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(tert-butoxycarbonyl)-L-valinate [ka]

[0342] To a mixture of intermediate I-1a (0.634 mmol) and L-Boc-alanine (0.951 mmol) in DMF (2 mL) was added DMAP (0.951 mmol) followed by EDCI-HCl (0.951 mmol). The resulting mixture was stirred at room temperature for 1 h, added with MeOH (0.5 mL), concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give intermediate I-5. 1 H NMR(400MHz,acetonitrile-d3)δ 7.92(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.27(s,2H),5.6 7(d,J=3.5Hz,1H),5.55(d,J=8.9Hz,1H),5.33(dd,J=6.6,3.5Hz,1H),5.08( d,J=6.6Hz,1H),4.48(d,J=2.1Hz,2H),4.10(m,1H),2.17-2.02(m,1H),1.72 (s,3H),1.44-1.24(m,12H),0.92(d,J=6.9Hz,3H),0.86(d,J=6.8Hz,3H).MS m / z[M+1]=531. Intermediate I-6: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3,3-dimethylbutanoate [ka]

[0343] To a mixture of intermediate I-1a (0.356 mmol) and 3,3-dimethylbutanoic acid (0.534 mmol) in DMF (2 mL) was added DMAP (0.534 mmol) followed by EDCI-HCl (0.534 mmol). The resulting mixture was stirred at room temperature for 2 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-6. 1H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.6Hz,1H),6.77(d,J=4.5Hz,1H),6.26(s,2H),5.67(d,J=3.5Hz,1H),5.33(dd,J=6.6,3.5Hz,1H),5.06(d, MS m / z[M+1]=430. Intermediate I-7: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4-methylbenzoate [ka]

[0344] To a mixture of intermediate I-1a (0.326 mmol) and 4-methylbenzoic acid (0.453 mmol) in DMF (2 mL) was added DMAP (0.489 mmol) followed by EDCI-HCl (0.489 mmol). The resulting mixture was stirred at room temperature for 2 h, water (1 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate I-7. 1 H NMR(400MHz,acetonitrile-d3)δ 7.99-7.89(m,2H),7.85(s,1H),7.39-7.32(m,2H),6.80(d,J=4.5Hz,1H),6.75(d,J=4.5Hz,1H),6.25(s,2H),5.69(d,J=3.5Hz,1H),5.3 6(dd,J=6.7,3.5Hz,1H),5.21(d,J=6.7Hz,1H),4.73(d,J=11.6Hz,1H),4.59(d,J=11.7Hz,1H),2.44(s,3H),1.74(s,3H),1.41(s,3H).MS m / z[M+1]=450. Intermediate I-8: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 1-methylcyclopropane-1-carboxylate [ka]

[0345] To a mixture of intermediate I-1a (0.323 mmol) and 1-methylcyclopropanecarboxylic acid (0.420 mmol) in DMF (2 mL) was added DMAP (51 mg, 0.420 mmol) followed by EDCI-HCl (81 mg, 0.420 mmol). The resulting mixture was stirred at room temperature for 4 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-8. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.27(s,2H),5.66(d,J=3.4Hz,1H),5.31(dd,J=6.6,3.5Hz,1H),5.06(d MS m / z[M+1]=414. Intermediate I-9: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-cyclobutyl acetate [ka]

[0346] To a mixture of intermediate I-1a (0.664 mmol) and 2-cyclobutylacetic acid (0.863 mmol) in DMF (4 mL) was added DMAP (0.863 mmol) followed by EDCI-HCl (0.863 mmol). The resulting mixture was stirred at room temperature for 1.5 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-9. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.27(s,2H),5.66( d,J=3.5Hz,1H),5.32(dd,J=6.6,3.5Hz,1H),5.05(d,J=6.6Hz,1H),4.47(d,J= 11.7Hz,1H),4.32(d,J=11.7Hz,1H),2.71-2.57(m,1H),2.48(d,J=7.6Hz,2H), 2.23-2.05(m,4H),1.94-1.80(m,1H),1.75-1.64(m,4H),1.43-1.36(m,3H).MS m / z[M+1]=428. Intermediate I-10: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3,3-dimethylcyclobutane-1-carboxylate [ka]

[0347] To a mixture of intermediate I-1a (0.326 mmol) and 3,3-dimethylcyclobutanecarboxylic acid (0.424 mmol) in DMF (2 mL) was added DMAP (0.424 mmol) followed by EDCI-HCl (0.424 mmol). The resulting mixture was stirred at room temperature for 3.5 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-10. 1H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.78(m,2H),6.44(s,2H),5.67(d,J=3.5Hz,1H),5.31(dd,J=6.6,3.4Hz,1H),5.06(d,J=6.6Hz,1H),4.51(d,J= MS m / z[M+1]=442. Intermediate I-11 and Intermediate I-12: ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((tert-butyldimethylsilyl)oxy)-2-cyano-3-hydroxytetrahydrofuran-2-yl)methyl benzoate and ((2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-((tert-butyldimethylsilyl)oxy)-2-cyano-4-hydroxytetrahydrofuran-2-yl)methyl benzoate [ka]

[0348] To a mixture of compound 2 (1.11 mmol) and TBSCl (3.84 mmol) in THF (5 mL) was added imidazole (4.38 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h, and the reaction was quenched by the addition of methanol (1 mL). After dilution with EtOAc, it was washed with water, dried, concentrated in vacuo, and purified on silica gel (20% to 100% EtOAc in hexanes) to give intermediates I-11 and I-12.

[0349] Intermediate I-11: 1H NMR(400MHz,acetonitrile-d3)δ 8.08-8.02(m,2H),7.81(s,1H),7.68(m,1H),7.55(m,2H),6.77-6.71(m,2H),6.24(s,2H),5.50(d,J=4.2Hz, 1H),4.86-4.78(m,2H),4.66-4.59(m,2H),3.76(d,J=7.8Hz,1H),0.91(s,9H),0.04(s,3H),-0.04(s,3H).MS m / z[M+1]=510.

[0350] Intermediate I-12: 1 H NMR(400MHz,acetonitrile-d3)δ 8.05-7.96(m,2H),7.85(s,1H),7.71-7.64(m,1H),7.58-7.50(m,2H),6.77-6.68(m,2H),6.23(s,2H),5.52(d,J=5.3Hz,1H),4. 80-4.72(m,2H),4.68(q,J=5.2Hz,1H),4.54(d,J=11.9Hz,1H),3.45(d,J=5.2Hz,1H),1.03(s,9H),0.24(s,3H),0.23(s,3H).MS m / z[M+1]=510. Intermediate I-13 and Intermediate I-14 (Mixture): ((2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-((tert-butyldimethylsilyl)oxy)-2-cyano-4-(isobutyryloxy)tetrahydrofuran-2-yl)methyl benzoate and ((2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-((tert-butyldimethylsilyl)oxy)-2-cyano-3-(isobutyryloxy)tetrahydrofuran-2-yl)methyl benzoate [ka]

[0351] To a mixture of intermediate I-12 (0.135 mmol) and isobutyric acid (0.016 mL, 0.176 mmol) in DMF (1 mL) was added DMAP (0.203 mmol) followed by EDCI-HCl (0.203 mmol). The resulting mixture was stirred at room temperature for 2 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-13 and intermediate I-14 as a mixture.

[0352] Mixture of Intermediate I-13 and Intermediate I-14: 1 H NMR(400MHz,acetonitrile-d3)δ 8.08-8.03(m,1H),7.99-7.91(m,1H),7.82(s,0.5H),7.78(s,0.5H),7.67 (m,1H),7.52(m,2H),6.78(s,1H),6.73(s,1H),6.51(bs,2H),5.81(dd,J= 5.5,2.7Hz,0.5H),5.65(d,J=5.3Hz,0.5H),5.59(d,J=2.7Hz,0.5H),5.52 (d,J=5.5Hz,0.5H),5.19(d,J=5.5Hz,0.5H),5.06(t,J=5.5Hz,0.5H),4.91 (d,J=12.1Hz,0.5H),4.86(d,J=11.9Hz,0.5H),4.69(d,J=11.8Hz,0.5H), 4.52(d,J=12.1Hz,0.5H),2.70(dq,J=26.1,7.0Hz,0.5H),2.54(h,J=7.0H z,0.5H),1.30-1.20(m,3H),1.16(d,J=6.9Hz,3H),0.98(s,4.5H),0.82(s ,4.5H),0.22(s,1.5H),0.17(s,1.5H),-0.05(s,1.5H),-0.19(s,1.5H).MS m / z[M+1]=580. Intermediate I-15: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate [ka]

[0353] To a solution of intermediate I-1a (2.1 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.23 mmol, 0.11 equiv.) in THF (7.0 mL) was added isobutyric anhydride (0.34 mL, 2.1 mmol, 1.0 equiv.) dropwise at room temperature. The solution was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel (0% to 100% EtOAc in DCM) to give intermediate I-15. 1 H NMR(400MHz, methanol-d4)δ 7.84(s,1H),6.86(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),5.63(d,J=3.1Hz,1H),5.32(dd,J=6.6,3.2Hz,1H),5.10(d,J=6. MS m / z[M+1]=402.1. Intermediate I-16: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3-methylbutanoate [ka]

[0354] To a solution of intermediate I-1a (0.45 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.11 mmol, 0.25 equiv.) in THF (2.0 mL) was added isovaleric anhydride (0.10 mL, 0.50 mmol, 1.1 equiv.) dropwise at room temperature. The solution was stirred for 30 min. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel (0% to 100% EtOAc in DCM) to give intermediate I-16. 1H NMR(400MHz, methanol-d4)δ 7.84(s,1H),6.86(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),5.63(d,J=3.2Hz,1H),5.33(dd,J=6.6,3.2Hz,1H),5.10(d,J=6.6Hz,1H), 4.49(d,J=11.5Hz,1H),4.36(d,J=11.5Hz,1H),2.28-2.24(m,2H),2.13-2.02(m,1H),1.71(s,3H),1.39(s,3H),0.98-0.92(m,6H).MS m / z[M+1]=416.1. Intermediate I-17: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate [ka]

[0355] To a solution of intermediate I-1a (0.44 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.19 mmol, 0.42 equiv.) in THF (2.0 mL) was added acetic anhydride (0.47 mmol, 1.1 equiv.) dropwise at room temperature. The solution was stirred for 20 minutes. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel (0% to 100% EtOAc in DCM) to give intermediate I-17. 1 H NMR(400MHz, methanol-d4)δ 7.83(s,1H),6.85(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),5.62(d,J=3.2Hz,1H),5.32(dd,J=6.6,3.2Hz,1H),5 .10(d,J=6.6Hz,1H),4.49(d,J=11.5Hz,1H),4.35(d,J=11.5Hz,1H),2.10(s,3H),1.71(s,3H),1.39(s,3H).MS m / z[M+1]=374.1. Intermediate I-18: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl propionate [ka]

[0356] To a solution of intermediate I-1a (0.45 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.14 mmol, 0.31 equiv.) in THF (2.0 mL) was added propionic anhydride (65 μL, 0.50 mmol, 1.1 equiv.) dropwise at room temperature. The solution was stirred for 1 h. The reaction mixture was concentrated in vacuo, and the crude material was purified on silica gel (0% to 100% EtOAc in DCM) to give intermediate I-18. MS m / z [M+1] = 388.2. Intermediate I-19: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl cyclopentanecarboxylate [ka]

[0357] To a solution of intermediate I-1a (0.46 mmol, 1.0 equiv.) in DMF (2.0 mL) was added cyclopentanecarboxylic acid (55 μL, 0.51 mmol, 1.1 equiv.), followed by DIAD (0.09 mL, 0.46 mmol, 1.0 equiv.) and 4-dimethylaminopyridine (0.46 mmol, 1.0 equiv.). The solution was stirred at room temperature for 30 min, and then DIC (0.09 mL, 0.55 mmol, 1.2 equiv.) was added. The solution was stirred for an additional 6 h before being quenched with water (50 mL) and extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0% to 10% MeOH in DCM) to give intermediate I-19. MS m / z [M+1] = 428.1. Intermediate I-20: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylcyclohexanecarboxylate [ka]

[0358] To a solution of intermediate I-1a (0.48 mmol, 1.0 equiv) in DMF (2.0 mL) was added cyclohexanecarboxylic acid (65 μL, 0.53 mmol, 1.1 equiv) and DIC (0.09 mL, 0.58 mmol, 1.2 equiv), followed by 4-dimethylaminopyridine (0.48 mmol, 1.0 equiv). The solution was stirred overnight at room temperature. The reaction was quenched with water (50 mL), and the aqueous layer was extracted with EtOAc (2 × 50 mL). The organic layers were combined, dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (0% to 20% MeOH in DCM) to give intermediate I-20. MS m / z [M+1] = 442.1. Intermediate I-21: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl cyclobutanecarboxylate [ka]

[0359] To a solution of intermediate I-1a (0.39 mmol) and cyclobutanecarboxylic acid (0.47 mmol) in DMF (2 mL), N,N'-diisopropylcarbodiimide (0.47 mmol) and then 4-dimethylaminopyridine (0.39 mmol) were added dropwise and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate, washed once with water, washed once with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure (temperature maintained below 30 °C). The crude product was dissolved in 5% MeOH / DCM and loaded onto a 40 g silica gel column. elution was performed with hexane for 2 minutes, DCM for 1 minute, and 0% to 100% EtOAc / DCM for 18 minutes. Pure fractions were combined and concentrated to give intermediate I-21. 1H NMR (400 MHz, methanol-d4) δ 7.86(s,1H),6.88(d,J=4.5Hz,1H),6.79(d,J=4.5Hz,1H),5.64(d,J=3.1Hz,1H),5.3 4(dd,J=6.6,3.2Hz,1H),5.12(d,J=6.6Hz,1H),4.45(dd,J=66.7,11.5Hz,2H),4.12( q,J=7.1Hz,1H),3.80(p,J=6.5Hz,2H,DIPEA salt),3.26(p,J=8.4Hz,1H),2.37-2.18(m, 5H),1.99-1.86(m,1H),1.73(s,3H),1.41(s,3H),1.12(d,J=6.5Hz,12H,DIPEA salt).MS m / z[M+1]=414.05. Intermediate I-22: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl cyclopropanecarboxylate [ka]

[0360] To a solution of intermediate I-1a (0.45 mmol) and DMAP (0.068 mmol) in THF (4.5 mL) was added cyclopropanecarbonyl cyclopropanecarboxylate (0.45 mmol) at 0 °C and stirred at 0 °C for 1 h. The reaction mixture was warmed to room temperature and directly loaded onto a 40 g silica gel column and eluted with hexane for 3 min, DCM for 1 min, and 0% to 100% EtOAc / DCM for 18 min. Pure fractions were combined and concentrated to give intermediate I-22. MS m / z [M+1] = 400.03. Intermediate I-23: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl butyrate [ka]

[0361] To a solution of intermediate I-1a (0.45 mmol) and DMAP (0.068 mmol) in THF (4.5 mL) was added butanoyl butanoate (0.45 mmol) dropwise (5 min) at 0 °C and stirred at 0 °C for 1 h. The reaction mixture was warmed to room temperature and directly loaded onto a 40 g silica gel column and eluted with hexane for 3 min, DCM for 1 min, and 0% to 100% EtOAc / DCM for 18 min. Pure fractions were combined and concentrated to give intermediate I-23. MS m / z [M+1] = 402.07. Intermediate I-24: Synthesis of ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-(1-methylcyclobutyl)acetate [ka]

[0362] To a mixture of intermediate I-1a (0.302 mmol) and 2-(1-methylcyclobutyl)acetic acid (0.453 mmol) in ACN (2 mL) was added DMAP (0.453 mmol) followed by EDCI-HCl (0.453 mmol). The resulting mixture was stirred at room temperature for 1 h, added with methanol (0.5 mL), concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-24. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.78(dd,J=4.5,0.8Hz,1H),6.39(s,2H),5.67(d,J=3.4Hz,1H),5.36-5.27(m,1H),5.06(d,J=6.6Hz, MS m / z[M+1]=441.9. Synthesis of Intermediate I-25: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl spiro[3.3]heptane-2-carboxylate [ka]

[0363] To a mixture of intermediate I-1a (0.302 mmol) and spiro[3.3]heptane-2-carboxylic acid (0.453 mmol) in ACN (2 mL) was added DMAP (0.453 mmol) followed by EDCI-HCl (0.453 mmol). The resulting mixture was stirred at room temperature for 2 h, water (0.5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-25. 1H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.79(m,2H),6.38(s,2H),5.66(d,J=3.5Hz,1H),5.31(dd,J=6.7,3.5Hz,1H),5.05(d,J=6.6Hz,1H),4.49(d,J=11.7Hz,1H),4. 32(d,J=11.7Hz,1H),3.10-2.90(m,1H),2.22(m,4H),2.09-2.00(m,2H),1.97-1.88(m,2H),1.85-1.74(m,2H),1.71(s,3H),1.39(s,3H).MS m / z[M+1]=453.8. Intermediate I-26: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [ka]

[0364] Intermediate I-26 was prepared according to WO 2015 / 069939. For example, WO 2015 / 069939, paragraphs 127-138, provide a process for preparing this compound (identified as compound 14k in WO 2015 / 069939).

[0365] Intermediate I-27: (7-((3aS,4S,6R,6aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4-iminopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl isobutyrate [ka]

[0366] To a mixture of intermediate I-26 (0.180 mmol, 80% purity) and KI (0.898 mmol) in HMPA (1 mL) was added chloromethyl isobutyrate (0.449 mmol). The resulting mixture was stirred at room temperature for 15 h, diluted with EtOAc (30 mL), washed with brine (10 mL × 3), dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-27. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91-7.66(m,2H),6.82(d,J=4.3Hz,1H),6.52(d,J=4.3Hz,1H),5.86(s,2H),5.47(d,J=3.7Hz,1H),5.18(dd,J=3.88,6.66Hz,1H), 4.92(d,J=6.6Hz,1H),4.02-3.78(m,2H),2.59(m,1H),1.69(s,3H),1.39(s,3H),1.14(d,J=7.0Hz,6H),0.92(s,9H),0.09(s,6H).MS m / z[M+1]=545.9. Intermediate I-28: ((3aS,4R,6S,6aS)-4-cyano-6-(4-(3,3-dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3,3-dimethylbutanoate [ka]

[0367] To a mixture of intermediate I-1a (2.32 mmol) and 3,3-dimethylbutanoic acid (0.36 mL, 2.79 mmol) in ACN (15 mL) was added DMAP (2.79 mmol) followed by EDCI-HCl (2.79 mmol). The resulting mixture was stirred at room temperature for 1 h, water (5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate I-28. 1H NMR (400 MHz, acetonitrile-d3) δ 8.80 (s, 1H), 8.22 (s, 1H), 7.21 (dd, J = 4.7, 0.9 Hz, 1H), 6.99 (d, J = 4.7 Hz, 1H), 5.75 (d, J = 3.4 Hz, 1H), 5.34 (ddd, J = 6.6, 3.4, 1.0 Hz, 1H), 5.07 (d, J = 6.6 Hz, 1H), 4.49-4.41 (m, 1H), 4.38-4.30 (m, 1H), 2.52 (s, 2H), 2.27 (s, 2H), 1.72 (s, 3H), 1.40 (s, 3H), 1.13 (s, 9H), 1.02 (s, 9H). MS m / z [M+1] = 528.0. Intermediate I-29: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 1-methylcyclobutane-1-carboxylate [ka]

[0368] To a mixture of intermediate I-1a (0.302 mmol) and 1-methylcyclobutane-1-carboxylic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-29. 1 H NMR(400MHz,acetonitrile-d3)δ 7.92(s,1H),6.78(m,2H),6.37(s,2H),5.68(d,J=3.4Hz,1H),5.32(dd,J=6.6,3.5Hz,1H),5.08(d,J=6.7Hz,1H),4.53(d,J =11.6Hz,1H),4.36(d,J=11.6Hz,1H),2.60-2.35(m,2H),1.98(m,2H),1.92-1.80(m,2H),1.71(s,3H),1.43-1.34(m,6H).MS m / z[M+1]=428.2. Intermediate I-30: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3,3-dimethylpentanoate [ka]

[0369] To a mixture of intermediate I-1a (0.302 mmol) and 3,3-dimethylpentanoic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate I-30. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.31(s,2H),5.67(d,J=3.5Hz,1H),5.33(dd,J=6.6,3.5Hz,1H),5.06(d,J=6.6H) MS m / z[M+1]=444.3. Intermediate I-31: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 3-fluoro-2,2-dimethylpropanoate [ka]

[0370] To a mixture of intermediate I-1a (0.302 mmol) and 3-fluoro-2,2-dimethyl-propanoic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-31. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.91 (s, 1H), 7.47-7.36 (m, 2H), 6.96 (s, 2H), 5.63 (m, 1H), 5.24 (m, 1H), 5.00 (m, 1H), 4.53-4.44 (m, 2H), 4.41-4.25 (m, 2H), 1.72 (s, 3H), 1.37 (s, 3H), 1.30-1.17 (m, 6H). MS m / z [M+1] = 434.3. Intermediate I-32: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (R)-5-oxotetrahydrofuran-2-carboxylate [ka]

[0371] To a mixture of intermediate I-1a (0.302 mmol) and (2R)-5-oxotetrahydrofuran-2-carboxylic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 15 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-32. 1H NMR(400MHz,acetonitrile-d3)δ 7.92(s,1H),6.81(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.34(s,2H),5.69(d,J=3.3Hz,1H),5.33(dd,J=6.6,3.3Hz,1H),5.11(d,J= MS m / z[M+1]=444.2. Intermediate I-33: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2,2-dimethylbutanoate [ka] To a mixture of intermediate I-1a (0.302 mmol) and 2,2-dimethylbutanoic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-33. 1 H NMR(400MHz, methanol-d4)δ 7.85(s,1H),6.85(d,J=4.5Hz,1H),6.78(d,J=4.5Hz,1H),5.65(d,J=3.2H z,1H),5.34(ddd,J=6.7,3.3,1.1Hz,1H),5.08(d,J=6.6Hz,1H),4.47(dd, J=11.5,1.1Hz,1H),4.36(dd,J=11.5,1.1Hz,1H),1.72(s,3H),1.65-1.52 (m,2H),1.40(s,3H),1.19-1.17(m,3H),1.15(s,3H),0.89-0.74(m,3H).MS m / z[M+1]=430.0. Intermediate I-34: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 4,4-dimethylpentanoate [ka]

[0372] To a mixture of intermediate I-1a (0.453 mmol) and 4,4-dimethylpentanoic acid (0.543 mmol) in ACN (2 mL) was added DMAP (0.543 mmol) followed by EDCI-HCl (0.543 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-34. 1 H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.40(s,2H),5.67(d,J=3.5Hz,1H),5.32(dd,J=6.6,3.5Hz,1H),5.07(d,J=6. MS m / z[M+1]=444.0. Intermediate I-35: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (R)-2-methylbutanoate [ka]

[0373] To a mixture of intermediate I-1a (0.302 mmol) and (R)-2-methylbutanoic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate I-35. 1 H NMR(400MHz,acetonitrile-d3)δ 7.92(s,1H),6.80(d,J=4.5Hz,1H),6.77(d,J=4.5Hz,1H),6.35(s,2H),5.67(d,J= 3.4Hz,1H),5.32(ddd,J=6.7,3.4,0.8Hz,1H),5.07(d,J=6.6Hz,1H),4.52(dd,J=1 1.7,0.8Hz,1H),4.34(dd,J=11.7,0.8Hz,1H),2.45(m,1H),1.76-1.60(m,4H),1.5 1(m,1H),1.39(s,3H),1.14(dd,J=6.9,0.8Hz,3H),0.91(dd,J=7.9,7.1Hz,3H).MS m / z[M+1]=416.1. Intermediate I-36: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 2-phenylacetate [ka]

[0374] To a mixture of intermediate I-1a (0.302 mmol) and 2-phenylacetic acid (0.362 mmol) in ACN (2 mL) was added DMAP (0.362 mmol) followed by EDCI-HCl (0.362 mmol). The resulting mixture was stirred at room temperature for 5 h, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate I-36. 1H NMR(400MHz,acetonitrile-d3)δ 7.91(s,1H),7.38-7.19(m,5H),6.80-6.74(m,2H),6.32(s,2H),5.66(d,J=3.6Hz,1H),5.28(dd,J=6.6,3.6Hz,1H ),5.05(d,J=6.6Hz,1H),4.53(d,J=11.7Hz,1H),4.38(d,J=11.7Hz,1H),3.72(s,2H),1.72(s,3H),1.39(s,3H).MS m / z[M+1]=450.0. Intermediate I-37 and Intermediate I-38: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (Intermediate I-37), and ((3aS,4R,6S,6aS)-6-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (Intermediate I-38). [ka]

[0375] To a solution of intermediate I-1a (1.5 mmol) and 4-dimethylaminopyridine (0.17 mmol) in THF (8.0 mL) was added acetic anhydride (0.29 mL, 3 mmol) dropwise at 0 °C. The solution was stirred at 0 °C for 30 min and at room temperature for 30 min. The reaction mixture was concentrated in vacuo, dissolved in DCM, loaded onto a 40 g silica gel column, and eluted with hexane for 3 min, DCM for 1 min, and 0% to 100% EtOAc / DCM for 16 min to give intermediate I-37 (MS m / z [M+1] = 374.0) and intermediate I-38 (MS m / z [M+1] = 416.0).

[0376] Intermediate I-39 and Intermediate I-40: ((3aS,4R,6S,6aS)-4-cyano-6-(4-isobutylamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (Intermediate I-39), and ((3aS,4R,6S,6aS)-6-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (Intermediate I-40). [ka]

[0377] ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl acetate (120 mg, 0.32 mmol) and ((3aS,4R,6S,6aS)-6-(4-acetamidopyrrolo[2,1-f To a mixture of [3,4-d][1,3]dioxol-4-yl]methyl acetate (150 mg, 0.36 mmol), DMAP (0.07 mmol) and THF, was added isobutyric anhydride (0.11 mL, 0.64 mmol) dropwise and stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (0% to 100% EtOAc in DCM) to give intermediates I-39 and I-40.

[0378] Intermediate I-39.1H NMR (400MHz, acetonitrile-d3)δ 8.90(s,1H),8.21(s,1H),7.22(d,J=4.7Hz,1H),6.99(d,J=4.7Hz,1H),5.74(d,J=3.3Hz,1H),5.33(dd,J=6.6,3.4Hz,1H),5 .09(d,J=6.6Hz,1H),4.57-4.30(m,2H),3.04-2.94(m,1H),2.08(s,3H),1.73(s,3H),1.40(s,3H),1.24(d,J=6.8Hz,6H),MS m / z[M+1]=444.1. Intermediate I-40.1H NMR (400MHz, acetonitrile-d3)δ 8.85(s,1H),8.22(s,1H),7.17(d,J=4.7Hz,1H),6.98(d,J=4.7Hz,1H),5.74(d,J=3.4Hz,1H),5.33(dd,J=6.6 MS m / z[M+1]=416.1. C. Compound Example 0. Compound 0 (2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile [ka]

[0379] Compound 0 was prepared according to WO 2015 / 069939. For example, WO 2015 / 069939, chapters 43-55 provide a process for preparing this compound (identified as Compound 1 in WO 2015 / 069939). Example 1: Compound 1 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate [ka]

[0380] To a solution of intermediate I-15 (1.9 mmol, 1.0 equiv) in ACN (10.0 mL) was added concentrated HCl (0.80 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 55 min, then diluted with EtOAc (50 mL) and quenched with saturated NaHCO solution (50 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (50 mL). The organic fractions were combined, washed with brine (50 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 30% MeOH in DCM) to give compound 1. 1 H NMR(400MHz, methanol-d4)δ 7.80(s,1H),6.86(d,J=4.5Hz,1H),6.73(d,J=4.5Hz,1H),5.48(d,J=4.8Hz,1H),4.66-4.61(m,1H),4.54 (d,J=11.8Hz,1H),4.45(d,J=5.6Hz,1H),4.35(d,J=11.7Hz,1H),2.67-2.54(m,1H),1.18-1.13(m,6H).MS m / z[M+1]=362.1. Example 2: Compound 2 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl benzoate [ka]

[0381] To a solution of intermediate I-1 (1.49 mmol) in ACN (3 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 2. 1H NMR(400MHz,acetonitrile-d3)δ 8.11-7.92(m,2H),7.84(s,1H),7.75-7.63(m,1H),7.63-7.44(m,2H),6.74(s,2H),6.21(s,2H),5.50(d,J=4.7 Hz,1H),4.77(d,J=11.8Hz,1H),4.67(m,1H),4.64-4.53(m,2H),4.25(d,J=6.5Hz,1H),3.97(d,J=4.9Hz,1H).MS m / z[M+1]=396. Example 3: Compound 3 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3-methylbutanoate [ka]

[0382] To a solution of intermediate I-16 (0.33 mmol, 1.0 equiv) in ACN (5.0 mL) was added concentrated HCl (0.14 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 1 hour and 20 minutes, then diluted with EtOAc (30 mL) and quenched with a 1:1 solution of water and saturated NaHCO (30 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (30 mL). The organic fractions were combined, washed with 1:1 water:brine (20 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 20% MeOH in DCM) to give compound 3. 1 H NMR(400MHz,DMSO-d6)δ 7.86(s,1H),7.76(br s,2H),6.86(d,J=4.6Hz,1H),6.73(d,J=4.4Hz,1H),6.10(d,J=5.9Hz,1H),5.49(d,J=5.4Hz,1H),5.38(d,J= MS m / z[M+1]=376.2. Example 4: Compound 4 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl acetate [ka]

[0383] To a solution of intermediate I-17 (0.40 mmol, 1.0 equiv) in ACN (5.0 mL) was added concentrated HCl (0.17 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 1 h, then diluted with EtOAc (30 mL) and quenched with a 1:1 solution of water:saturated NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (30 mL). The organic fractions were combined, washed with 1:1 water:brine (20 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 20% MeOH in DCM) to give compound 4. 1 H NMR(400MHz,DMSO-d6)δ 7.86(s,1H),7.76(br s,2H),6.86(d,J=4.5Hz,1H),6.73(d,J=4.5Hz,1H),6.11(d,J=6.0Hz,1H),5.49(d,J=5 .5Hz,1H),5.38(d,J=5.5Hz,1H),4.50-4.43(m,2H),4.31-4.18(m,2H),2.06(s,3H).MS m / z[M+1]=334.2. Example 5: Compound 5 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylpropionate [ka]

[0384] To a solution of intermediate I-18 (0.34 mmol, 1.0 equiv) in ACN (5.0 mL) was added concentrated HCl acid (0.14 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 4 hours and 45 minutes, then diluted with EtOAc (30 mL) and quenched with a 1:1 solution of water:saturated NaHCO (30 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (30 mL). The organic fractions were combined, washed with 1:1 water:brine (30 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 20% MeOH in DCM) to give compound 5. 1 H NMR(400MHz, methanol-d4)δ 7.80(s,1H),6.86(d,J=4.5Hz,1H),6.72(d,J=4.5Hz,1H),5.49(d,J=4.7Hz,1H),4.65-4.60(m,1H),4.55 (d,J=11.8Hz,1H),4.45(d,J=5.6Hz,1H),4.35(d,J=11.7Hz,1H),2.46-2.31(m,2H),1.14-1.08(m,3H).MS m / z[M+1]=348.2. Example 6: Compound 6 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl butyrate [ka]

[0385] To a well-stirred mixture of intermediate I-23 (0.34 mmol) in CH3CN (2.0 mL) was added concentrated HCl (100 μL, 1.2 mmol) dropwise (2 min) at room temperature and stirred for 4 h. The reaction mixture was diluted with EtOAc followed by saturated sodium bicarbonate. (Continued dilution with EtOAc (100 mL) and NaHCO3 (50 mL) until the solids dissolved and a clear solution was formed.) The aqueous layer was extracted with EtOAc (50 mL × 2), and the organic layer was separated, washed once with brine solution (70 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (maintaining the temperature below 30 °C). The crude product was dissolved in 10% MeOH / DCM and loaded onto a 40 g silica gel column. eluted with hexane for 3 min, DCM for 1 min, and 0% to 25% MeOH / DCM for 18 min. Pure fractions were combined and concentrated to give compound 6. 1H NMR (400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.50(d,J=4.7Hz,1H),4.65(t,J=5.1Hz,1H),4.57(d,J=11.8Hz,1H) ),4.47(d,J=5.6Hz,1H),4.37(d,J=11.8Hz,1H),2.36(td,J=7.3,3.0Hz,2H),1.65(h,J=7.3Hz,2H),0.95(t,J=7.4Hz,3H).MS m / z[M+1]=362.17. Example 7: Compound 7 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclopropanecarboxylate [ka]

[0386] To a well-stirred mixture of intermediate I-22 (0.34 mmol) in CH3CN (2.5 mL) was added concentrated HCl (140 μL, 1.7 mmol) dropwise (2 min) at room temperature and stirred for 70 min. The reaction mixture was diluted with EtOAc followed by saturated sodium bicarbonate (continuously dilute with EtOAc (100 mL) and NaHCO3 (50 mL) until the solids dissolved and a clear solution was formed). The aqueous layer was extracted with EtOAc (100 mL × 2), and the organic layer was separated, washed once with brine solution (70 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (temperature maintained below 30 °C). The crude product was dissolved in 15% MeOH / DCM and loaded onto a 40 g silica gel column. eluted with hexane for 3 min, DCM for 1 min, and 0% to 25% MeOH / DCM for 20 min. Pure fractions were combined and concentrated to give compound 7. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.75(d,J=4.5Hz,1H),5.51(d,J=4.7Hz,1H),4.64(t,J=5.2Hz,1H),4.57(d,J=1 MS m / z[M+1]=360.02. Example 8: Compound 8 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclobutanecarboxylate [ka]

[0387] To a well-stirred mixture of intermediate I-21 (0.31 mmol) in CH3CN (3 mL) was added concentrated HCl (130 μL, 1.6 mmol) dropwise (2 min) at room temperature. The reaction mixture went from an opaque solid to a clear solution within minutes and was stirred for 2 h. The reaction mixture was diluted with EtOAc, followed by saturated sodium bicarbonate. (Continued dilution with EtOAc (50 mL) and NaHCO3 (40 mL) until the solid dissolved and a clear solution was formed.) The aqueous layer was extracted with EtOAc (50 mL × 2), and the organic layer was separated, washed once with brine solution (70 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure (maintaining the temperature below 30 °C). The crude product was dissolved in 10% MeOH / DCM and loaded onto a 40 g silica gel column. eluted with hexane for 3 min, DCM for 1 min, and 0% to 25% MeOH / DCM for 15 min. Pure fractions were combined and concentrated to give compound 8. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.50(d,J=4.8Hz,1H),4.64(t,J=5.2Hz,1H),4.57(d,J=11. MS m / z[M+1]=374.11. Example 9: Compound 9: ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-ethylbutanoate [ka]

[0388] To a solution of intermediate I-3 (0.263 mmol) in ACN (1 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 9. 1 H NMR(400MHz,acetonitrile-d3)δ 7.89(s,1H),6.79(d,J=4.6Hz,1H),6.76(d,J=4.6Hz,1H),6.36(s,2H),5.48(d,J=5.0Hz,1H),4.63(t,J=5.4Hz,1H), 4.52(d,J=11.9Hz,1H),4.45(d,J=5.8Hz,1H),4.36(d,J=11.9Hz,1H),2.29(m,1H),1.68-1.47(m,4H),0.88(m,6H).MS m / z[M+1]=390. Example 10: Compound 10 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl pivalate [ka]

[0389] To a solution of intermediate I-4 (0.481 mmol) in ACN (4 mL) and THF (2 mL) was added cHCl (0.7 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-10% MeOH in DCM) to give compound 10. 1H NMR(400MHz,DMSO-d6)δ 7.87(s,1H),7.72(s,2H),6.88(d,J=4.5Hz,1H),6.74(d,J=4.4Hz,1H),6.07(m,1H),5.48(m,1H),5. 41(d,J=5.6Hz,1H),4.55-4.39(m,2H),4.30(t,J=5.7Hz,1H),4.25(d,J=11.8Hz,1H),1.18(s,9H).MS m / z[M+1]=376. Example 11: Compound 11 ((2R,3S,4R,5S)-2-cyano-5-(4-(2-ethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-ethylbutanoate [ka]

[0390] To a solution of intermediate I-2 (0.0417 mmol) in ACN (1 mL) was added cHCl (0.2 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 11. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),8.34(s,1H),7.24(d,J=4.7Hz,1H),7.04(d,J=4.7Hz,1H),5.51(d,J=5.4Hz,1H),4.59-4.35(m,2H),4.35-4.14(m,2H) ),2.78(td,J=8.7,4.4Hz,1H),2.24(tt,J=8.1,5.7Hz,1H),1.72-1.40(m,8H),0.90(t,J=7.4Hz,6H),0.81(td,J=7.4,4.6Hz,6H).MS m / z[M+1]=488. Example 12: Compound 12 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl L-valinate [ka]

[0391] To a solution of intermediate I-5 (0.477 mmol) in ACN (2 mL) was added cHCl (0.3 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and lyophilized with ACN to give the crude product, which was dissolved in water (5 mL) and purified by preparative HPLC (10% to 50% ACN (containing 0.1% TFA) in water (containing 0.1% TFA)) to give compound 12 as a TFA salt. 1 H NMR(400MHz, methanol-d4)δ 8.08(s,1H),7.43(d,J=4.7Hz,1H),6.99(d,J=4.7Hz,1H),5.58(d,J=4.8Hz,1H),4.82(s,1H) ,4.61-4.50(m,2H),4.40(d,J=5.5Hz,1H),4.07(d,J=4.3Hz,1H),2.34(m,1H),1.08(m,6H).MS m / z[M+1]=391. Example 13: Compound 13 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3,3-dimethylbutanoate [ka]

[0392] To a solution of intermediate I-6 (0.270 mmol) in ACN (1 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 13. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.51(d,J=4.8Hz,1H),4.67(t,J=5.2Hz,1H ),4.51(d,J=11.8Hz,1H),4.46(d,J=5.5Hz,1H),4.39(d,J=11.8Hz,1H),2.25(m,2H),1.02(s,9H).MS m / z[M+1]=390. Example 14: Compound 14 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 4-methylbenzoate [ka]

[0393] To a solution of intermediate I-7 (0.267 mmol) in ACN (1 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 14. 1H NMR(400MHz, methanol-d4)δ 7.96-7.87(m,2H),7.73(s,1H),7.31(d,J=8.0Hz,2H),6.82(d,J=4.5Hz,1H),6.71(d,J=4.5Hz,1H),5.53 (d,J=4.6Hz,1H),4.80(d,J=11.8Hz,1H),4.71(dd,J=5.6,4.6Hz,1H),4.65-4.55(m,2H),2.43(s,3H).MS m / z[M+1]=410. Example 15: Compound 15 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 1-methylcyclopropane-1-carboxylate [ka]

[0394] To a solution of intermediate I-8 (0.235 mmol) in ACN (2 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 15. 1 H NMR(400MHz, methanol-d4)δ 7.82(d,J=0.9Hz,1H),6.88(dd,J=4.5,0.9Hz,1H),6.73(d,J=4.5Hz,1H),5.49(d,J=4.8Hz,1H),4.65(td,J=5.2,4.8,1.0Hz,1 H),4.52(dd,J=11.7,0.9Hz,1H),4.45(d,J=5.6Hz,1H),4.35(dd,J=11.8,0.9Hz,1H),1.31(s,3H),1.27(m,2H),0.76(m,2H).MS m / z[M+1]=374. Example 16: Compound 16 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-cyclobutyl acetate [ka]

[0395] To a solution of intermediate I-9 (0.503 mmol) in ACN (4 mL) was added cHCl (2 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 10% MeOH in DCM) to give compound 16. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.50(d,J=4.7Hz,1H),4.66(t,J=5.1Hz,1H),4.54(d,J=11.8Hz,1 H),4.47(d,J=5.5Hz,1H),4.35(d,J=11.8Hz,1H),2.66(m,1H),2.47(m,2H),2.11(m,2H),1.95-1.79(m,2H),1.71(m,2H).MS m / z[M+1]=388. Example 17: Compound 17 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3,3-dimethylcyclobutane-1-carboxylate [ka]

[0396] To a solution of intermediate I-10 (0.256 mmol) in ACN (2 mL) was added cHCl (1 mL) at room temperature. The mixture was stirred for 1 h, diluted with EtOAc, and aqueous NaHCO3 was slowly added. After stirring for 5 min, the phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give compound 17. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.51(d,J=4.7Hz,1H),4.64(t,J=5.1Hz,1H),4.57(d,J=11.7Hz) MS m / z[M+1]=402. Example 18: Compound 18 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl cyclopentanecarboxylate [ka]

[0397] To a solution of intermediate I-19 (0.30 mmol, 1.0 equiv) in ACN (5.0 mL) was added concentrated HCl (0.12 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 1 h, then diluted with EtOAc (30 mL) and quenched with saturated NaHCO (30 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (30 mL). The organic fractions were combined, washed with 1:1 water:brine (20 mL), dried over NaSO, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0%-20% EtOAc in hexanes, followed by 0-20% MeOH in DCM) to give compound 18. 1H NMR(400MHz, methanol-d4)δ 7.80(s,1H),6.86(d,J=4.5Hz,1H),6.72(d,J=4.5Hz,1H),5.49(d,J=4.8Hz,1H),4.66-4.61(m,1H),4.54(d,J=11. MS m / z[M+1]=388.1. Example 19: Compound 19 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclohexanecarboxylate [ka]

[0398] To a solution of intermediate I-20 (0.39 mmol, 1.0 equiv) in ACN (5.0 mL) was added concentrated HCl (0.16 mL, 12 M, 5.0 equiv) at room temperature. The reaction mixture was stirred for 8 h, then diluted with EtOAc (30 mL) and quenched with a 1:1 solution of water:saturated NaHCO3 (30 mL). The layers were separated, and the aqueous layer was extracted once more with EtOAc (30 mL). The organic fractions were combined, washed with 1:1 water:brine (20 mL), dried over Na2SO4, filtered, concentrated in vacuo, and then purified by silica gel chromatography (0% to 15% MeOH in DCM) to give compound 19. 1 H NMR(400MHz, methanol-d4)δ 7.80(s,1H),6.86(d,J=4.5Hz,1H),6.72(d,J=4.5Hz,1H),5.48(d,J=4.6Hz,1H),4.67-4.62(m,1H),4.53( MS m / z[M+1]=402.1. Example 20 and Example 21: Compound 20 (2R,3S,4S,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) and Compound 21 (2R,3S,4S,5S)-2-cyano-5-(4-isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((isobutyryloxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate). [ka]

[0399] To a solution of compound 0 (0.34 mmol) and DMAP (0.069 mmol) in THF (3 mL), 2-methylpropanoyl 2-methylpropanoate (0.11 µL, 0.69 mmol) was added dropwise at 0 °C and stirred at 0 °C for 30 min. The reaction mixture was warmed to room temperature and directly loaded onto a 12 silica gel cartridge. A 40 g silica gel column was used, eluting with hexane for 3 min, DCM for 1 min, and 0% to 100% EtOAc / DCM for 18 min. Pure fractions were combined and concentrated to give compounds 20 and 21.

[0400] Compound 20:1H NMR (400MHz, acetonitrile-d3)δ 7.92(s,1H),6.79(q,J=4.6Hz,2H),6.38(s,2H),5.94-5.80(m,2H),5.68(d,J=3.8Hz,1H), 4.48(dd,J=68.6,12.0Hz,2H),2.65(ddq,J=35.6,14.1,7.0Hz,3H),1.26-1.10(m,18H).MS m / z[M+1]=502.08.

[0401] Compound 21:1H NMR (400MHz, acetonitrile-d3)δ 8.83(s,1H),8.22(s,1H),7.22(d,J=4.8Hz,1H),6.98(d,J=4.7Hz,1H),5.88-5.80(m,2H),5.76(d MS m / z[M+1]=572.11. Example 22: Compound 22 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3-hydroxy-4-(isobutyryloxy)tetrahydrofuran-2-yl)methyl benzoate [ka]

[0402] To a mixture of intermediate I-13 and intermediate I-14 (0.0811 mmol) in THF (1 mL) was added TBAF (0.24 mL) at room temperature, stirred for 20 min, diluted with EtOAc, washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give compound 22. 1 H NMR (400 MHz, acetonitrile-d3) δ 8.02-7.98(m,2H),7.81(s,1H),7.70-7.64(m,1H),7.52(m,2H),6.75(d,J=4.5H z,1H),6.72(d,J=4.6Hz,1H),6.33(s,2H),5.72(dd,J=5.9,3.7Hz,1H),5.64(d, J=3.7Hz,1H),4.99(d,J=5.9Hz,1H),4.84(d,J=12.0Hz,1H),4.61(d,J=12.0Hz, 1H),4.46(bs,1H),2.69(m,1H),1.23(d,J=7.0Hz,3H),1.20(d,J=7.0Hz,3H).MS m / z[M+1]=466. Example 23: Compound 23 ((2R,3S,4R,5S)-2-cyano-3,4-dihydroxy-5-(4-isobutylamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl acetate [ka]

[0403] To a well-stirred mixture of intermediate I-39 (0.25 mmol) in CH3CN (4.0 mL) was added concentrated HCl (100 μL) dropwise (2 min) at 0 °C. The reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc, followed by saturated sodium bicarbonate. Dilution with EtOAc (30 mL) and NaHCO3 solution (30 mL) continued until the solids dissolved to form a clear solution. The aqueous layer was extracted with EtOAc (50 mL × 2), and the organic layer was separated, washed once with brine solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in 10% MeOH / DCM and loaded onto a 40 g silica gel column. eluted with hexane for 3 min, DCM for 1 min, and 0–25% MeOH / DCM for 18 min. Pure fractions were combined and concentrated to give compound 23. 1H NMR (400MHz, acetonitrile-d3)δ 8.80(s,1H),8.20(s,1H),7.21(d,J=4.7Hz,1H),6.94(d,J=4.7Hz,1H),5.57(d,J=4.6Hz,1H),4.62-4.459(m,1H),4.53(d,J=11.9Hz, MS m / z[M+1]=404.0. Example 24: Compound 24 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 1-methylcyclobutane-1-carboxylate [ka]

[0404] To a solution of intermediate I-29 (0.257 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 24. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.51(d,J=4.8Hz,1H),4.66(dd,J=5.6,4.8Hz,1H),4.57(d MS m / z[M+1]=388.2. Example 25: Compound 25 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl (R)-5-oxotetrahydrofuran-2-carboxylate [ka]

[0405] To a solution of intermediate I-32 (0.226 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 25. 1 H NMR(400MHz, methanol-d4)δ 7.83(s,1H),6.87(d,J=4.5Hz,1H),6.76(d,J=4.5Hz,1H),5.52(d,J=4.5Hz,1H),5.15-5.09(m,1H),4.76( MS m / z[M+1]=404.0. Example 26: Compound 26 ((2R,3S,4R,5S)-2-cyano-5-(4-(3,3-dimethylbutanamido)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3,3-dimethylbutanoate [ka]

[0406] To a solution of intermediate I-28 (0.0512 mmol) in ACN (1 mL) was added 25% HCl (0.1 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 26. 1H NMR(400MHz, methanol-d4)δ 8.21(s,1H),7.20(d,J=4.7Hz,1H),6.98(d,J=4.7Hz,1H),5.60(d,J=4.8Hz,1H),4.66(t,J=5.2Hz,1H), 4.51(d,J=11.8Hz,1H),4.46-4.36(m,2H),2.51(s,2H),2.33-2.18(m,2H),1.14(s,9H),1.02(s,9H).MS m / z[M+1]=487.9. Example 27: Compound 27 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3,3-dimethylpentanoate [ka]

[0407] To a solution of intermediate I-30 (0.248 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 27. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.54-5.44(m,1H),4.72-4.61(m,1H),4.50(d,J=11.8Hz,1H ),4.46(d,J=5.5Hz,1H),4.39(d,J=11.8Hz,1H),2.30-2.15(m,2H),1.35(m,2H),0.97(s,6H),0.85(t,J=7.5Hz,3H).MS m / z[M+1]=404.3. Example 28: Compound 28 (2R,3S,4S,5S)-2-(acetoxymethyl)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyanotetrahydrofuran-3,4-diyl diacetate [ka]

[0408] To a mixture of compound 0 (0.604 mmol) and acetic acid (0.17 mL, 2.79 mmol) in DMF (2 mL) was added DMAP (2.79 mmol) followed by EDCI-HCl (302 mmol). The resulting mixture was stirred at room temperature for 1 h, water (5 mL) was added, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give intermediate 28. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.93 (s, 1H), 6.88-6.70 (m, 2H), 6.33 (s, 2H), 5.85-5.79 (m, 2H), 5.71-5.65 (m, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 2.06 (s, 3H). MS m / z [M+1] = 418.2. Example 29: Compound 29 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 3-fluoro-2,2-dimethylpropanoate [ka]

[0409] To a solution of intermediate I-31 (0.254 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 29. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.6Hz,1H),5.51(d,J=4.9Hz,1H),4.70-4.64(m,1H),4.57(d ,J=11.7Hz,1H),4.48(s,1H),4.46(d,J=5.7Hz,1H),4.43(d,J=11.7Hz,1H),4.36(s,1H),1.27-1.21(m,6H). 19 F NMR (376 MHz, methanol-d4) δ 17.31. MS m / z [M+1] = 394.3. Example 30: Compound 30 and Compound 34, N-(7-((2S,3R,4S,5R)-5-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)isobutyramide (Compound 30), and (7-((2S,3R,4S,5R)-5-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-iminopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl isobutyrate (Compound 34) [ka]

[0410] To a solution of intermediate I-27 (0.123 mmol) in ACN (1 mL) was added 25% HCl (1.0 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give Compound 30 and Compound 34.

[0411] Compound 30: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.79 (s, 1H), 8.19 (s, 1H), 7.20 (d, J = 4.7 Hz, 1H), 6.96 (d, J = 4.7 Hz, 1H), 5.50 (d, J = 5.7 Hz, 1H), 4.65-4.54 (m, 1H), 4.42 (d, J = 5.6 Hz, 1H), 4.15 (s, 1H), 3.97-3.73 (m, 4H), 2.99 (m, 1H), 1.24 (d, J = 6.8 Hz, 6H). MS m / z [M+1] = 362.0.

[0412] Compound 34: 1 H NMR (400 MHz, acetonitrile-d3) δ 7.76 (s, 1H), 6.83 (d, J = 4.3 Hz, 1H), 6.51 (d, J = 4.3 Hz, 1H), 5.85 (s, 2H), 5.24 (d, J = 6.0 Hz, 1H), 4.52-4.43 (m, 1H), 4.35 (d, J = 5.7 Hz, 1H), 4.12 (s, 1H), 3.96-3.60 (m, 4H), 2.59 (m, 1H), 1.14 (d, J = 7.0 Hz, 6H). MS m / z [M+1] = 391.9. Example 32: Compound 32 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl spiro[3.3]heptane-2-carboxylate [ka]

[0413] To a solution of intermediate I-25 (0.221 mmol) in ACN (2 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (30 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give compound 32. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.73(d,J=4.5Hz,1H),5.63-5.45(m,1H),4.66-4.62(m,1H),4.56(d,J=11.8Hz,1H),4.45(d,J=5.5 Hz,1H),4.36(d,J=11.8Hz,1H),3.03(p,J=8.43Hz,1H),2.02-2.02(m,4H),2.10-2.01(m,2H),2.00-1.86(m,2H),1.86-1.73(m,2H).MS m / z[M+1]=413.9. Example 33: Compound 33 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2-(1-methylcyclobutyl)acetate [ka]

[0414] To a solution of intermediate I-24 (0.256 mmol) in ACN (2 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (30 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 33. 1H NMR(400MHz, methanol-d4)δ 7.81(s,1H),6.86(d,J=4.5Hz,1H),6.73(d,J=4.5Hz,1H),5.52(d,J=4.8Hz,1H),4.73-4.59(m,1H),4.53(d,J=1 MS m / z[M+1]=401.9. Example 34: Compound 34 (7-((2S,3R,4S,5R)-5-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-iminopyrrolo[2,1-f][1,2,4]triazin-3(4H)-yl)methyl isobutyrate [ka]

[0415] A method for preparing compound 34 and its associated characterization data is described in Example 30 above. Example 35: Compound 35 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 2,2-dimethylbutanoate [ka]

[0416] To a solution of intermediate I-33 (0.275 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give compound 35. 1H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.88(d,J=4.5Hz,1H),6.75(d,J=4.5Hz,1H),5.50(d,J=4.9Hz,1H),4.67(dd,J=5.6,4.9Hz,1H),4.50( MS m / z[M+1]=390.0. Example 36: Compound 36 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl 4,4-dimethylpentanoate [ka]

[0417] To a solution of intermediate I-34 (0.361 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give compound 36. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.52(d,J=4.6Hz,1H),4.65(dd,J=5.5,4.6Hz,1H),4.5 6(d,J=11.8Hz,1H),4.49(d,J=5.5Hz,1H),4.37(d,J=11.7Hz,1H),2.34(m,2H),1.61-1.50(m,2H),0.90(s,9H).MS m / z[M+1]=404.0. Example 37: Compound 37 ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl (R)-2-methylbutanoate [ka]

[0418] To a solution of intermediate I-35 (0.193 mmol) in ACN (1 mL) was added 25% HCl (0.2 mL) at room temperature. The mixture was stirred for 2 h, diluted with EtOAc (20 mL), and aqueous NaHCO3 (10 mL) was slowly added. The mixture was stirred for 10 min, the phases were separated, and the aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (0% to 5% MeOH in DCM) to give compound 37. 1 H NMR(400MHz, methanol-d4)δ 7.82(s,1H),6.87(d,J=4.5Hz,1H),6.74(d,J=4.5Hz,1H),5.62-5.34(m,1H),4.66(dd,J=5.6,4.8Hz,1H),4.55(d,J=11.7Hz,1H), 4.4...

Claims

1. Structure: 【Chemistry 164】 or a pharmaceutically acceptable salt thereof.

2. Structure: 【Chemistry 176】 or a pharmaceutically acceptable salt thereof.

3. Structure: 【Chemistry 178】 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

5. 10. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

6. A composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for treating or preventing a viral infection in a human in need thereof.

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