Phospholipid compounds and methods for their preparation and use

Abstract

A phospholipid compound for the treatment of a viral infection, a method of using said compound alone or in combination with an additional agent, and a pharmaceutical formulation of said compound are disclosed.

Description

Technology Field

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 234,515 filed August 18, 2021 and U.S. Provisional Application No. 63 / 313,633 filed February 24, 2022, all of which are incorporated herein by reference in their entirety.

[0003] Sequence list

[0004] This application includes a sequence listing submitted as an electronic document, the entirety of which is incorporated herein by reference. Background Technology

[0005] Viral infections, for example, Paramyxoviruses ( Paramyxoviridae ), Pneumoviridae ( Pneumoviridae ), Picornaviridae ( Picornaviridae ), Flaviviridae( Flaviviridae ), Filovirus family ( Filoviridae ) and orthomyxoviruses ( Orthomyxovirus Compounds, pharmaceutical preparations, and methods for treating infections are required. Embodiments of the present invention can address these and other requirements.

[0006] A compound of Formula I or a pharmaceutically acceptable salt thereof is disclosed herein:

[0007] [Chemical Formula I]

[0008]

[0009] In the above formula,

[0010] R 1 C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 Ns; where R 1 is R 1A and -NR 13A R 14AIt is arbitrarily replaced with 1, 2, or 3 units independently selected from;

[0011] Here, each R 1A is independently a 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or N and O;

[0012] Each R 13A is independently H or C1-C3 alkyl;

[0013] Each R 14A is independently H or C1-C3 alkyl;

[0014] R 2 is H or C1-C3 alkyl;

[0015] R 3 is a C1-C3 alkyl;

[0016] Each R 4 is independently bonded (bond), H, halo, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, and

[0017] Each R 5 is independently combined or H,

[0018] Here, 2 or more adjacent (CR 4 R 5 ) are arbitrarily connected through double bonds;

[0019] R 6 is H or -C(O)C1-C6 alkyl;

[0020] R 7 is H or -C(O)C1-C6 alkyl;

[0021] m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21;

[0022] L is -O-, -(CR 12A R 12B ) n-, -O-(CR 12A R 12B ) n -, -(CR 12A R 12B ) n -O- or -(CR 12A R 12B ) n -O-(CR 12A R 12B ) n -is;

[0023] Here,

[0024] Each R 12A is independently H or C1-C6 alkyl;

[0025] Each R 12B is independently H or C1-C6 alkyl;

[0026] n is 1 or 2 and;

[0027] Q is bonded or phenylene;

[0028] T is bonded or -O- and;

[0029] X is a bond or C1-C3 alkylene;

[0030] Z is -O-, -O-(C1-C6)-alkylene or NR 15 -(C1-C6)-alkylene and;

[0031] Here, R 15 It is H or C1-C3 alkyl.

[0032] In addition, compounds of sub-formulas of chemical formula I, such as chemical formulas Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, and XIIIb, are disclosed in this specification.

[0033] A pharmaceutical formulation comprising a pharmaceutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient is disclosed herein.

[0034] Additionally, a method for treating or preventing a viral infection in a subject is disclosed in this specification, comprising the step of administering a compound disclosed in this specification or a pharmaceutically acceptable salt thereof to a subject who requires treatment or prevention of a viral infection.

[0035] Additionally, a method for treating or preventing a viral infection in a human being who requires treatment or prevention of a viral infection is disclosed in this specification, comprising the step of administering a compound disclosed in this specification or a pharmaceutically acceptable salt thereof to said human being.

[0036] The present invention provides a method for manufacturing a medicine for treating or preventing a viral infection in a subject requiring treatment or prevention of a viral infection, characterized by using a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0037] The present invention provides a method for manufacturing a medicine for treating or preventing a viral infection in a human requiring treatment or prevention of a viral infection, characterized by using a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0038] The present invention provides the use of the compound disclosed herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for treating or preventing a viral infection in humans who require treatment or prevention of a viral infection. Specific details for implementing the invention

[0039] I. outline

[0040] The present invention generally relates to methods and compounds for treating or preventing viral infections, e.g., Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, and Orthomyxovirus infections. The following description presents exemplary methods, parameters, etc. However, it should be recognized that such description is provided as an explanation of exemplary embodiments and is not intended to limit the scope of the invention.

[0041] II. definition

[0042] The following words, phrases, and symbols used in this specification are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0043] A dash (“-”) not between two letters or symbols is used to indicate the attachment point for a substituent. For example, -CONH2 is attached through a carbon atom. The dashes before or after chemical groups are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in the structure indicates the attachment point of the group. Unless chemically or structurally required, the order in which chemical groups are listed or named does not indicate or imply directionality.

[0044] A meandering line in a chemical group as shown below, for example It indicates an attachment point, that is, it indicates a broken connection where the device is connected to another described device.

[0045] As used herein, “compound of the invention” may mean a compound of any of formulas I through XIIIb or a pharmaceutically acceptable salt thereof. Similarly, the phrase “compound of formula (number)” means a compound of said formula and a pharmaceutically acceptable salt thereof.

[0046] Prefix "C u -C v " indicates that the following group has u to v carbon atoms. For example, "C1-C8alkyl" indicates that the alkyl group has 1 to 8 carbon atoms.

[0047] "Alkyl" indicates an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group consists of 1 to 20 carbon atoms (i.e., C1-C 20 It may have alkyl), 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), and 1-propyl ( n -Pr, n -Profile, -CH2CH2CH3), 2-Profile( 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)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), but are not limited thereto. Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0048] "Alkylene" refers to unbranched and branched divalent saturated hydrocarbon chains. As used herein, alkylenes have 1 to 20 carbon atoms (i.e., C 1-20 alkylene), 1 to 12 carbon atoms (i.e., C 1-12 alkylene), 1 to 8 carbon atoms (i.e., C 1-8 alkylene), 1 to 6 carbon atoms (i.e., C 1-6 alkylene), 1 to 4 carbon atoms (i.e., C 1-4 alkylene), 1 to 3 carbon atoms (i.e., C 1-3 alkylene), or one to two carbon atoms (i.e., C 1-2It has an alkylene). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Where an alkyl residue having a specific number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); "Prop" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0049] "Alkenyl" refers to an unbranched or branched hydrocarbon chain comprising two or more carbon atoms and one or more carbon-carbon double bonds. As used herein, alkenyls comprise 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 It can have an alkenyl group. The alkenyl group can have any number of carbon atoms, e.g., C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20or may include within that range. The alkenyl group may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. The alkenyl group may be substituted or unsubstituted.

[0050] "Alkoxy" refers to a group having the chemical formula ―O-alkyl, wherein the alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group consists of 1 to 20 carbon atoms (i.e., C1-C 20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 It may have an alkoxy group, one to eight carbon atoms (i.e., C1-C8 alkoxy), one to six carbon atoms (i.e., C1-C6 alkoxy), or one to three carbon atoms (i.e., 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), etc. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy group may be substituted or unsubstituted.

[0051] "Haloalkyl" is an alkyl group in which one or more hydrogen atoms of the alkyl group are substituted with halogen atoms as defined above. The alkyl portion of the haloalkyl group consists of 1 to 20 carbon atoms (i.e., C1-C 20haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 It may have haloalkyl, 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 haloalkyl), or 1 to 3 carbon atoms (i.e., C1-C3 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0052] "Halo" or "halogen" as used in this specification refers to fluoro(-F), chloro(-Cl), bromo(-Br), and iodo(-I).

[0053] "Haloalkoxy" is an alkoxy group as defined above in which one or more hydrogen atoms of the alkoxy group are substituted with halogen atoms. The alkoxy portion of the haloalkoxy group consists of 1 to 20 carbon atoms (i.e., C1-C 20 haloalkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 It may have a haloalkoxy, one to eight carbon atoms (i.e., C1-C8 haloalkoxy), one to six carbon atoms (i.e., C1-C6 haloalkoxy), or one to three carbon atoms (i.e., C1-C3 haloalkoxy). Examples of suitable haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, -OCFH2, -OCH2CF3, etc.

[0054] "Hydroxy" refers to -OH.

[0055] "Aryl" refers to an aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, etc.

[0056] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single or multiple ring, including fused, cross-linked, and spiro-ring systems. As used herein, cycloalkyls have 3 to 20 cyclic carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 It has a cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include fused ring systems having one aromatic ring and one non-aromatic ring, but not a fully aromatic ring system, and include a partially unsaturated ring system having one or more double bonds.

[0057] "Heteroaryl" refers to an aromatic group comprising an aromatic tautomer or resonance structure having one or more cyclic heteroatoms, having a single ring, multiple rings, or multiple fused rings, having at least one heteroatom in the ring, namely, independently selected from nitrogen, oxygen, and sulfur, wherein nitrogen or sulfur can be oxidized. Accordingly, the term includes a ring having one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. The term includes a ring having one or more cyclic C(O) groups. As used herein, heteroaryls comprise 5 to 20 ring atoms (i.e., 5 to 20 heteroaryls), 5 to 12 ring atoms (i.e., 5 to 12 heteroaryls), or 5 to 10 ring atoms (i.e., 5 to 10 heteroaryls), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(1H)-one, pyridazine-3(2H)-one, pyrimidin-4(3H)-one, quinoline-2(1H)-one, pyrimidinyl, furinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryls do not comprise or overlap with aryls as defined above.

[0058] "Heterocycle" or "heterocyclile" refers to a saturated or unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocyclile may be single-ring or polycyclic, wherein the polycyclic may be fused, cross-linked, or spiro. The heterocyclils used herein have 3 to 20 ring atoms (i.e., 3 to 20-membered heterocyclils), 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclils), 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclils), 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclils), 4 to 12 ring carbon atoms (i.e., 4 to 12-membered heterocyclils), 4 to 8 ring atoms (i.e., 4 to 8-membered heterocyclils), or 4 to 6 ring atoms (i.e., 4 to 6-membered heterocyclils). Examples of heterocyclil groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanil, dioxolanil, azetidinyl, and morpholinil.

[0059] With respect to specific parts of the compounds disclosed herein, the term “optionally substituted” (e.g., optionally substituted aryl group) refers to a part in which all substituents are hydrogen, or a part in which one or more hydrogens of said part may be substituted with the listed substituents.

[0060] 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, compositions, dosage forms, and other substances useful for preparing pharmaceutical formulations suitable for human pharmaceutical use.

[0061] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A pharmaceutically acceptable salt is a non-toxic salt in the free base form of a compound having the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound containing basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting said compound with an inorganic acid or an organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphate, dihydrogen-phosphate, metaphosphate, pyrophosphate, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrate, caproate, heptanoate, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioate, hexine-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, and methoxybenzoates. Includes phthalates, sulfonates, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is available in the literature [Remington: The Science and Practice of Pharmacy, 21 st It is found in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0062] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + Salts derived from (where X is a C1-C4 alkyl) are included. Base addition salts, such as sodium or potassium salts, are also included.

[0063] Compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which one to n hydrogen atoms attached to a carbon atom may be replaced with a deuterium atom or D, are also provided, wherein 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 may increase metabolic resistance and thus may be useful in increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. For example, refer to the literature [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 a starting material in which one or more hydrogen atoms are replaced by deuterium. The compounds disclosed in this specification may be deuterated at various positions including, but not limited to, the following positions:

[0064]

[0065] Examples of isotopes that can be introduced into the disclosed compound also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, each 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 125 I is included. Positron-emitting isotopes, for example 11 C, 18 F, 15 O and 13 Substitution with N may be useful for positron emission tomography (PET) studies to investigate substrate acceptor occupancy. Isotope-labeled compounds of formulas I through XIIIb may be prepared by ordinary techniques generally known to those skilled in the art, or by methods similar to those described in the examples presented below, using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0066] The compounds of the embodiments disclosed herein or pharmaceutically acceptable salts thereof may comprise one or more asymmetric centers, and thus, in terms of absolute stereochemistry ( R )- or ( S Enantiomers, diastereomers, and other stereoisomers can be produced that can be defined as )-, or in the case of amino acids as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical activity (+) and (-), ( R )- and ( S)-, or (D)- and (L)- isomers may be prepared using chiral synthones or chiral reagents, or may be separated using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure prodrugs or the separation of racemic mixtures (or racemic mixtures of salts or derivatives) using, e.g., chiral high-pressure liquid chromatography (HPLC). Where a compound described herein contains an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, the compound is intended to contain both E geometric isomers and Z geometric isomers. Likewise, all tautomers are also intended to be included. Where a compound is represented by its chiral form, it is understood that embodiments encompass, but are not limited to, specific diastereomerically or enantiomerically abundant forms. Where chirality is not specified but is present, embodiments are understood to relate to forms that are diastereomerically or enantiomerically abundant in certain forms; or racemic or scalemic mixtures of such compound(s). As used herein, "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0067] The term "prevention" or "preventing" means any treatment of a disease or condition that prevents the occurrence of clinical symptoms of the disease or condition. The term "prevention" or "preventing" also includes the administration of a compound or composition according to the embodiments disclosed herein after the subject has been exposed to the virus but before the onset of symptoms of the disease and / or before the virus is detected in the blood, in order to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the embodiments disclosed herein to a mother before childbirth and to an infant within a few days of birth to prevent perinatal transmission of the virus from mother to infant.

[0068] "Racemic" refers to a mixture of enantiomers. Such a mixture may contain equal or unequal amounts of each enantiomer.

[0069] "Stereoisomers" and "stereoisomers" refer to compounds with different chiralities at one or more stereocenters. Stereoisomers include enantiomers and diastereomers. These compounds may exist as stereoisomers if they possess one or more asymmetric centers or double bonds with asymmetric substitutions, and thus may be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the foregoing description is intended to include mixtures as well as individual stereoisomers. Methods for measuring 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).

[0070] "Subject" or "patient" is to describe a vertebrate including humans, or dogs, cats, pocket pets, marmosets, horses, cattle, pigs, sheep, goats, elephants, giraffes, chickens, lions, monkeys, owls, rats, squirrels, lorises, and mice. "Pocket pets" refers to a group of vertebrates that can fit into a large coat pocket, such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0071] "Tautomer" refers to an alternative form of a compound with different proton positions, such as enol-keto and imine-enamin tautomers, or a tautomer of a heteroaryl group containing a ring atom attached to both the ring -NH- and ring =N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by those skilled in the art. Dashes preceding or following chemical groups are for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in a structure indicate the attachment points of the groups. Dashed lines indicate arbitrary bonds. Unless chemically or structurally required, no orientation is indicated or implied in the order in which chemical groups are listed or in the point where they are attached to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both may be connected in either direction. Similarly, for example, an "arylalkyl" group may 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 Prefixes such as ) indicate that the following group has u to v carbon atoms. For example, "C 1-6Both "alkyl" and "C1-C6alkyl" indicate that the alkyl group has one to six carbon atoms. Likewise, the term "x- to y-membered" ring (where x and y are numerical ranges), e.g. "three- to twelve-membered heterocyclil" refers to a ring containing x to y (e.g., three to twelve) atoms, in which up to 80% may be heteroatoms, e.g., N, O, S, and the remaining atoms are carbons.

[0073] Unless otherwise specified, the carbon atoms of compounds of formulas I through XIIIb are intended to be tetravalent. In some chemical structural representations, where a sufficient number of variables are not attached to a carbon atom to produce tetravalence, the remaining carbon substituents required to provide tetravalence must be assumed to be hydrogen.

[0074] The terms “treating” and “treating” as used herein are intended to mean administering a compound or composition according to the embodiments disclosed herein to alleviate or eliminate symptoms of a viral infection and / or to reduce the viral load of a subject.

[0075] As used herein, the term “therapeutic effective dose” refers to the amount of a compound disclosed herein present in a formulation described herein that is necessary to provide a desired level of drug in the secretions and tissues of the airways and lungs of a subject to be treated, or alternatively, in the bloodstream, which is intended to obtain the expected physiological response or desired biological effect when such formulation is administered by a selected route of administration. The precise amount will depend on a number of factors, e.g., the specific compound disclosed herein, the specific activity of the formulation, the delivery device used, the physical properties of the formulation, and its intended use, as well as subject considerations, e.g., the severity of the disease state, subject cooperation, etc., and can be readily determined by a person skilled in the art based on the information provided herein. The terms “therapeutic effective dose” or “effective dose” also refer to an amount that removes or reduces the viral load and / or viral reservoir of a subject.

[0076] As used herein, the term "adjacent carbon" refers to consecutive carbon atoms directly bonded to each other. For example, In this case, 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. Similarly, In this case, 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.

[0077] As used herein, "solvent" refers to the result of the interaction between a solvent and a compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0078] As used herein, "prodrug" refers to a derivative of a drug that is converted into a parent drug via certain chemical or enzymatic pathways when administered to the human body.

[0079] As used herein, "pharmaceuticalally acceptable carriers" or "pharmaceuticalally acceptable excipients" include, but are not limited to, all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retardants, and combinations thereof. The use of pharmaceutically acceptable carriers and pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Their use in therapeutic formulations is considered except where any conventional medium or formulation is incompatible with the active ingredient. A co-active ingredient may also be incorporated into the formulation. The carrier(s) must be "acceptable" in the sense that they are compatible with other components of the formulation and are physiologically harmless to the recipient.

[0080] III. compound

[0081] A compound of Formula I or a pharmaceutically acceptable salt thereof is provided herein:

[0082] [Chemical Formula I]

[0083]

[0084] In the above formula,

[0085] R 1 C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 Ns; where R 1 is R 1A and -NR 13A R 14A It is arbitrarily replaced with 1, 2, or 3 units independently selected from;

[0086] Here, each R 1Ais independently a 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or N and O;

[0087] Each R 13A is independently H or C1-C3 alkyl;

[0088] Each R 14A is independently H or C1-C3 alkyl;

[0089] R 2 is H or C1-C3 alkyl;

[0090] R 3 is a C1-C3 alkyl;

[0091] Each R 4 is independently bonded, H, halo, C1-C3 alkyl, C1-C3 haloalkyl or C3-C6 cycloalkyl, and

[0092] Each R 5 is independently combined or H,

[0093] Here, 2 or more adjacent (CR 4 R 5 ) are arbitrarily connected through double bonds;

[0094] R 6 is H or -C(O)C1-C6 alkyl;

[0095] R 7 is H or -C(O)C1-C6 alkyl;

[0096] m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21;

[0097] L is -O-, -(CR 12A R 12B ) n -, -O(CR 12A R 12B ) n -, -(CR 12A R 12B ) n-O- or -(CR 12A R 12B ) n -O-(CR 12A R 12B ) n -is;

[0098] Here,

[0099] Each R 12A is independently H or C1-C6 alkyl;

[0100] Each R 12B is independently H or C1-C6 alkyl;

[0101] n is 1 or 2 and;

[0102] Q is bonded or phenylene;

[0103] T is bonded or -O- and;

[0104] X is a bond or C1-C3 alkylene;

[0105] Z is -O-, -O-(C1-C6)-alkylene or NR 15 -(C1-C6)-alkylene and;

[0106] Here, R 15 It is H or C1-C3 alkyl.

[0107] In some embodiments, R 1 This C6-C 10 Arilgo, R 2 is H, and R 3 ga is methyl, and each R 4 is H, and each R 5 is H, and L is -O- or -O(CR 12A R 12B ) n - and, if X is -CH2-, T is -O-, and Q is bonded, then R 1 1 to 3 R 1A It is substituted with a group. In some embodiments, the compounds disclosed herein and pharmaceutically acceptable salts thereof do not include the following compounds and pharmaceutically acceptable salts thereof:

[0108] .

[0109] R 1 C3-C 10 Cycloalkyl, C6-C 10 It may be an aryl, or a 5- to 10-membered heteroaryl containing one or two Ns. R 1 is R 1A and -NR 13A R 14A It is optionally replaced with one, two, or three groups independently selected from. In some embodiments, R 1 is not substituted. In some embodiments, R 1 is R 1A and -NR 13A R 14A It is replaced with one group selected from. In some embodiments, R 1 1 R 1A It is replaced by. In some embodiments, R 1 is 1 -NR 13A R 14A It is replaced by. In some embodiments, R 1 is R 1A and -NR 13A R 14A It is replaced by two groups independently selected from. In some embodiments, R 1 is R 1A It is replaced by two groups independently selected from. In some embodiments, R 1 -NR 13A R 14A It is replaced by two groups independently selected from. In some embodiments, R 1 is R 1A and -NR 13A R 14A It is replaced by three groups independently selected from. In some embodiments, R 1 is R 1A It is replaced by three groups independently selected from. In some embodiments, R 1 -NR 13A R 14AIt is replaced by three groups independently selected from. In some embodiments, R 1 1 R 1A and 1 -NR 13A R 14A It is replaced by. In some embodiments, R 1 1 R 1A and 2 -NR 13A R 14A It is replaced by. In some embodiments, R 1 2 R 1A and 1 -NR 13A R 14A It is replaced by. In some embodiments, R 1 1, 2, or 3 Rs 1A It is replaced with, where each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is replaced with, where each R 1A is independently selected from 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is replaced with, where each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 11, 2, or 3 Rs 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 One R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl 1A It is replaced by. In some embodiments, R 1 2 R 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 3 Rs 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 The cycloalkyl, aryl, or heteroaryl is two R's selected from halo and cyano. 1A It is replaced by. In some embodiments, R 1 The cycloalkyl, aryl, or heteroaryl is two R's selected from chloro and cyano 1A It is replaced by. In some embodiments, R 1 The cycloalkyl, aryl, or heteroaryl is two R groups selected from fluoro and cyano. 1A It is replaced with.

[0110] In some embodiments, R 1 C3-C 10 (For example, C3-C4, C3-C5, C3-C6, C3-C7, C3-C8, C3-C9, C4-C5, C4-C6, C4-C7, C4-C8, C4-C9, C4-C 10 , C5-C6, C5-C7, C5-C8, C5-C9, C5-C 10, C6-C7, C6-C8, C6-C9, C6-C 10 , C7-C8, C7-C9, C7-C 10 , C8-C9, C8-C 10 or C9-C 10 ) is a cycloalkyl. In some embodiments, R 1 is C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, C8-cycloalkyl, C9-cycloalkyl or C 10 It is a cycloalkyl. In some embodiments, C3-C 10 The cycloalkyl group is saturated. In some embodiments, C3-C 10 The cycloalkyl group is partially saturated. In some embodiments, C3-C 10 Cycloalkyl has a single ring (i.e., the cycloalkyl is a monocyclic cycloalkyl). In some embodiments, C3-C 10 Cycloalkyl groups have multiple rings (e.g., 2, 3, 4, 5, or 6 rings). In some embodiments, C3-C 10 Cycloalkyls have multiple rings including fused rings, cross-linked rings, spiro rings, or combinations thereof. In some embodiments, C3-C 10 The cycloalkyl group has two fused rings. In some embodiments, C3-C 10 The cycloalkyl comprises a partially unsaturated ring system containing one or more (e.g., 1, 2, 3, or 4) double bonds. In some embodiments, C3-C 10 Cycloalkyls include fused ring systems having one aromatic ring and one non-aromatic ring. C3-C 10 Cycloalkyl does not contain a fully aromatic ring system. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0111] C3-C10 Cycloalkyl is R 1A and -NR 13A R 14A It is optionally substituted with one, two, or three groups independently selected from. In some embodiments, C3-C 10 The cycloalkyl group is not substituted. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R 14A It is replaced with one group selected from. In some embodiments, C3-C 10 Cycloalkyl has one R 1A It is replaced by. In some embodiments, C3-C 10 Cycloalkyl has one -NR 13A R 14A It is replaced by. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R 14A It is replaced with two groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is R 1A It is replaced with two groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is -NR 13A R 14A It is replaced with two groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R 14A It is replaced with three groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is R 1A It is replaced with three groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is -NR 13A R 14A It is replaced with three groups independently selected from. In some embodiments, C3-C 10The cycloalkyl is unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, unsubstituted cycloheptyl, or unsubstituted cyclooctyl. In some embodiments, C3-C 10 Cycloalkyl is R 1A and -NR 13A R 14A It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl substituted with one, two, or three groups independently selected from. In some embodiments, C3-C 10 Cycloalkyl is R 1A It is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl substituted with one, two, or three groups independently selected from.

[0112] In some embodiments, R 1 1, 2, or 3 Rs 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1Ais independently selected from 5 to 10-membered (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered) heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 One R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl. In some embodiments, R 1 2 R 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1Ais independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 3 Rs 1A C3-C substituted with 10 (e.g., C3, C4, C5, C6, C7, C8, C9, C 10 ) is a cycloalkyl, where each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0113] In some embodiments, R 1 C6-C 10 It is Aril. In some embodiments, R 1 C6-aryl (e.g., phenyl) or C 10 It is an aryl (e.g., naphthyl). In some embodiments, R 1 It is phenyl. In some embodiments, C6-C 10 The aryl is phenyl. In some embodiments, C6-C 10 Aril is Naphthyl.

[0114] R 1 C6-C 10 Aril is R 1A and -NR 13A R 14A It is optionally substituted with one, two, or three groups independently selected from. In some embodiments, C6-C 10 The aryl group is not substituted. In some embodiments, C6-C 10 Aril is R 1A and -NR 13A R 14A It is replaced with one group selected from. In some embodiments, C6-C 10 Aril is 1 R 1A It is replaced by. In some embodiments, C6-C 10 Aryl is 1 -NR 13A R 14A It is replaced by. In some embodiments, C6-C 10 Aril is R1A and -NR 13A R 14A It is replaced with two groups independently selected from. In some embodiments, C6-C 10 Aril is R 1A It is replaced with two groups independently selected from. In some embodiments, C6-C 10 Aril is -NR 13A R 14A It is replaced with two groups independently selected from. In some embodiments, C6-C 10 Aril is R 1A and -NR 13A R 14A It is replaced with three groups independently selected from. In some embodiments, C6-C 10 Aril is R 1A It is replaced with three groups independently selected from. In some embodiments, C6-C 10 Aril is -NR 13A R 14A It is replaced by three groups independently selected from. In some embodiments, R 1 unsubstituted C6-aryl (e.g., phenyl) or unsubstituted C 10 It is an aryl (e.g., naphthyl). In some embodiments, R 1 is R 1A and -NR 13A R 14A A C6-aryl (e.g., phenyl) or C substituted with one, two, or three groups independently selected from 10 It is an aryl (e.g., naphthyl). In some embodiments, C6-C 10 The aryl is an unsubstituted phenyl. In some embodiments, C6-C 10 Aril is R 1A and -NR 13A R 14A It is a phenyl substituted with one or two groups independently selected from. In some embodiments, C6-C 10 Aril is R 1AIt is a phenyl substituted with one or two groups independently selected from. In some embodiments, C6-C 10 Aril is 1 R 1A and 1 -NR 13A R 14A It is a phenyl substituted with . In some embodiments, C6-C 10 Aril is 1 R 1A and 2 -NR 13A R 14A It is a phenyl substituted with . In some embodiments, C6-C 10 Aril has 2 Rs 1A and 1 -NR 13A R 14A It is a phenyl substituted with .

[0115] In some embodiments, R 1 1, 2, or 3 Rs 1A C6-C substituted with 10 It is Aril, and here, each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C6-C substituted with 10 It is Aril, and here, each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C6-C substituted with 10 It is Aril, and here, each R 1Ais independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A C6-C substituted with 10 It is Aril, and here, each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 One R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl 1A C6-C substituted with 10 It is Aril. In some embodiments, R 1 2 R 1A C6-C substituted with 10 It is Aril, and here, each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 3 Rs 1A C6-C substituted with 10 It is Aril, and here, each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0116] In some embodiments, R 1It is a 5- to 10-membered heteroaryl containing one or two Ns. In some embodiments, the 5- to 10-membered heteroaryl contains one N. In some embodiments, the 5- to 10-membered heteroaryl contains two Ns. In some embodiments, the 5- to 10-membered heteroaryl has one ring (i.e., the 5- to 10-membered heteroaryl is a monocyclic heteroaryl). In some embodiments, the 5- to 10-membered heteroaryl has two or more rings (e.g., two rings, three rings, or four rings). In some embodiments, the 5- to 10-membered heteroaryl contains two fused rings. In some embodiments, the 5- to 10-membered heteroaryl is pyridinyl. In some embodiments, the 5- to 10-membered heteroaryl is pyrimidinyl.

[0117] R 1 is R 1A and -NR 13A R 14A It may be a 5- to 10-membered heteroaryl comprising one or two Ns, optionally substituted with one, two, or three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl comprising one or two Ns is not substituted. In some embodiments, the 5- to 10-membered heteroaryl comprising one or two Ns is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, a 5- to 10-membered (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered) heteroaryl containing one or two Ns has one R 1A It is substituted with. In some embodiments, a 5- to 10-membered heteroaryl containing one or two Ns is substituted with one -NR 13A R 14A It is substituted with. In some embodiments, the 5- to 10-membered heteroaryl containing one or two Ns is R 1A and -NR13A R 14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl comprising one or two Ns is R 1A It is substituted with two groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one or two Ns is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl comprising one or two Ns is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl comprising one or two Ns is R 1A It is substituted with three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one or two Ns is -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl comprising one or two Ns is R 1A It is substituted with one or two groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl comprising one or two Ns is substituted with one R 1A and 1 -NR 13A R 14A It is substituted with. In some embodiments, a 5- to 10-membered heteroaryl containing one or two Ns has one R 1A and 2 -NR 13A R 14A It is substituted with. In some embodiments, a 5- to 10-membered heteroaryl containing one or two Ns has two Rs 1A and 1 -NR 13AR 14A It is replaced with.

[0118] In some embodiments, R 1 1, 2, or 3 Rs 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A is independently selected from 5 to 10-membered (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered) heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1One R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl 1A It is a 5- to 10-membered heteroaryl comprising one or two Ns substituted with . In some embodiments, R 1 2 R 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 3 Rs 1A It is a 5- to 10-membered heteroaryl comprising 1 or 2 Ns substituted with , wherein each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0119] R 1 is R 1A and -NR 13A R 14A It may be a 5- to 10-membered heteroaryl containing one N, optionally substituted with one, two, or three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one N is not substituted. In some embodiments, the 5- to 10-membered heteroaryl containing one N is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, a 5- to 10-membered heteroaryl containing one N is substituted with one R 1A It is substituted with. In some embodiments, a 5- to 10-membered heteroaryl containing one N is substituted with one -NR 13A R 14A It is substituted with. In some embodiments, the 5- to 10-membered heteroaryl containing one N is R 1A and -NR 13A R14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl containing one N is R 1A It is substituted with two groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one N is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl containing one N is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl containing one N is R 1A It is substituted with three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one N is -NR 13A R 14A It is replaced by three independently selected units.

[0120] R 1 is R 1A and -NR 13A R 14A It may be a 5- to 10-membered heteroaryl containing two Ns, optionally substituted with one, two, or three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing one N is not substituted. In some embodiments, the 5- to 10-membered heteroaryl containing two Ns is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, a 5- to 10-membered heteroaryl containing two Ns is substituted with one R 1A It is substituted with. In some embodiments, a 5- to 10-membered heteroaryl containing two Ns is substituted with one -NR 13A R 14AIt is substituted with. In some embodiments, the 5- to 10-membered heteroaryl containing two Ns is R 1A and -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl containing two Ns is R 1A It is substituted with two groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing two Ns is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, a 5- to 10-membered heteroaryl containing two Ns is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing two Ns is R 1A It is substituted with three groups independently selected from. In some embodiments, the 5- to 10-membered heteroaryl containing two Ns is -NR 13A R 14A It is replaced by three independently selected units.

[0121] In some embodiments, the 5- to 10-membered heteroaryl is pyridinyl. Pyridinyl is R 1A and -NR 13A R 14A It is optionally substituted with one, two, or three groups independently selected from. In some embodiments, pyridinyl is not substituted. In some embodiments, pyridinyl is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, pyridinyl is one R 1A It is substituted with . In some embodiments, pyridinyl is one -NR 13A R 14A It is substituted with. In some embodiments, pyridinyl is R1A and -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridinyl is R 1A It is substituted with two groups independently selected from. In some embodiments, pyridinyl is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridinyl is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridinyl is R 1A It is substituted with three groups independently selected from. In some embodiments, pyridinyl is -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridinyl is one R 1A and 1 -NR 13A R 14A It is substituted with. In some embodiments, pyridinyl has one R 1A and 2 -NR 13A R 14A It is substituted with. In some embodiments, pyridinyl has two Rs. 1A and 1 -NR 13A R 14A It is replaced with.

[0122] In some embodiments, R 1 1, 2, or 3 Rs 1A It is a pyridinyl substituted with , where each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridinyl has one, two, or three R atoms. 1AIt is replaced with, where each R 1A is independently selected from 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) heteroaryls comprising 1, 2, or 3 heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridinyl has 1, 2, or 3 R atoms. 1A It is replaced with, where each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridinyl has one, two, or three R atoms. 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridinyl is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1A It is substituted with. In some embodiments, pyridinyl has two Rs. 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridinyl has three R groups. 1A It is replaced with, where each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0123] In some embodiments, the 5- to 10-membered heteroaryl is pyridin-2-yl. Pyridin-2-yl is R 1A and -NR 13A R 14AIt is optionally substituted with one, two, or three groups independently selected from. In some embodiments, pyridine-2-yl is not substituted. In some embodiments, pyridine-2-yl is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, pyridine-2-yl is one R 1A It is replaced with . In some embodiments, pyridine-2-yl is one -NR 13A R 14A It is replaced by. In some embodiments, pyridine-2-yl is R 1A and -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridine-2-yl is R 1A It is substituted with two groups independently selected from. In some embodiments, pyridine-2-yl is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridine-2-yl is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridine-2-yl is R 1A It is substituted with three groups independently selected from. In some embodiments, pyridine-2-yl is -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridine-2-yl is one R 1A and 1 -NR 13A R 14A It is replaced with. In some embodiments, pyridine-2-yl is one R 1A and 2 -NR 13A R 14A It is replaced with. In some embodiments, pyridine-2-yl consists of two Rs. 1A and 1 -NR13A R 14A It is replaced with.

[0124] In some embodiments, R 1 1, 2, or 3 Rs 1A It is pyridine-2-yl substituted with , where each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridine-2-yl has one, two, or three R atoms. 1A It is replaced with, where each R 1A is independently selected from 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) heteroaryls comprising 1, 2, or 3 heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridine-2-yl has 1, 2, or 3 R atoms. 1A It is replaced with, where each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, pyridine-2-yl has one, two, or three R atoms. 1A It is replaced with, where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridine-2-yl is one R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. 1A It is replaced with. In some embodiments, pyridine-2-yl consists of two Rs. 1A It is replaced with, where each R 1Ais independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, pyridine-2-yl is 3 R 1A It is replaced with, where each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0125] In some embodiments, the 5- to 10-membered heteroaryl is pyridin-3-yl. Pyridin-3-yl is R 1A and -NR 13A R 14A It is optionally substituted with one, two, or three groups independently selected from. In some embodiments, pyridine-3-yl is not substituted. In some embodiments, pyridine-3-yl is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, pyridine-3-yl is one R 1A It is replaced by . In some embodiments, pyridine-3-yl is one -NR 13A R 14A It is replaced by. In some embodiments, pyridine-3-yl is R 1A and -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridine-3-yl is R 1A It is substituted with two groups independently selected from. In some embodiments, pyridine-3-yl is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyridine-3-yl is R 1A and -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridine-3-yl is R 1A It is substituted with three groups independently selected from. In some embodiments, pyridine-3-yl is -NR13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyridine-3-yl is one R 1A and 1 -NR 13A R 14A It is replaced with. In some embodiments, pyridine-3-yl is one R 1A and 2 -NR 13A R 14A It is replaced with. In some embodiments, pyridine-3-yl consists of two Rs. 1A and 1 -NR 13A R 14A It is replaced with.

[0126] In some embodiments, the 5- to 10-membered heteroaryl is pyrimidinyl. Pyrimidinyl is R 1A and -NR 13A R 14A It is optionally substituted with one, two, or three groups independently selected from. In some embodiments, pyrimidinyl is not substituted. In some embodiments, pyrimidinyl is R 1A and -NR 13A R 14A It is substituted with one group selected from. In some embodiments, pyrimidinyl is one R 1A It is substituted with . In some embodiments, pyrimidinyl is one -NR 13A R 14A It is substituted with. In some embodiments, pyrimidinyl is R 1A and -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyrimidinyl is R 1A It is substituted with two groups independently selected from. In some embodiments, pyrimidinyl is -NR 13A R 14A It is substituted with two groups independently selected from. In some embodiments, pyrimidinyl is R 1A and -NR 13AR 14A It is substituted with three groups independently selected from. In some embodiments, pyrimidinyl is R 1A It is substituted with three groups independently selected from. In some embodiments, pyrimidinyl is -NR 13A R 14A It is substituted with three groups independently selected from. In some embodiments, pyrimidinyl has one R 1A and 1 -NR 13A R 14A It is substituted with. In some embodiments, pyrimidinyl has one R 1A and 2 -NR 13A R 14A It is substituted with. In some embodiments, pyrimidinyl has two Rs. 1A and 1 -NR 13A R 14A It is replaced with.

[0127] In some embodiments, R 1 1, 2, or 3 Rs 1A It is a pyrimidinyl substituted with , where each R 1A is independently selected from pentagonal to tenagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is a pyrimidinyl substituted with , where each R 1A is independently selected from 5 to 10 (e.g., 5, 6, 7, 8, 9, or 10) heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1AIt is a pyrimidinyl substituted with , where each R 1A is independently selected from pentagonal to hexaagonal heteroaryls comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkoxy, C1-C3 haloalkoxy, and N and O. In some embodiments, R 1 1, 2, or 3 Rs 1A It is a pyrimidinyl substituted with , where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 One R selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl 1A It is a pyrimidinyl substituted with . In some embodiments, R 1 2 R 1A It is a pyrimidinyl substituted with , where each R 1A is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl. In some embodiments, R 1 3 Rs 1A It is a pyrimidinyl substituted with , where each R 1A It is independently selected from halo, cyano, methoxy, isopropoxy, triazolyl, and oxadiazolyl.

[0128] R 1 is R 1A and -NR 13A R 14A It is optionally replaced with one, two, or three groups independently selected from. In some embodiments, one or more R 1A is a halo. In some embodiments, one or more R 1A is a fluoro. In some embodiments, one or more R 1A is chloro. In some embodiments, one or more R 1Ais bromo. In some embodiments, halo is iodo. In some embodiments, one or more R 1A is cyano.

[0129] In some embodiments, one or more R 1A is a C1-C3 alkyl (e.g., methyl, ethyl, n - It is a profile, isopropyl.

[0130] In some embodiments, one or more R 1A is a C1-C3 alkoxy (e.g., methoxy, ethoxy, n - It is propoxy, isopropoxy).

[0131] In some embodiments, one or more R 1A is a C1-C3 haloalkoxy. In some embodiments, one or more R 1A is a C1-C3 fluoroalkoxy (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoro- n -propoxy, difluoro- n -Propoxy, Trifluoro- n -propoxy, tetrafluoro- n -Propoxy, Pentafluoro- n -Propoxy, Hexafluoro- n -Propoxy, Heptafluoro- n - is propoxy, fluoroisopropoxy, difluoroisopropoxy, trifluoroisopropoxy, tetrafluoroisopropoxy, heptafluoroisopropoxy, hexafluoroisopropoxy, or heptafluoroisopropoxy). In some embodiments, one or more R 1A is a C1-C3 chloroalkoxy (e.g., chloromethoxy, dichloromethoxy, trichloromethoxy, chloroethoxy, dichloroethoxy, trichloroethoxy, tetrachloroethoxy, pentachloroethoxy, chloro- n -Propoxy, Dichloro- n-Propoxy, Trichloro- n -Propoxy, Tetrachloro- n -Propoxy, Pentachloro- n -Propoxy, Hexachloro- n -Propoxy, Heptachloro- n - is propoxy, chloroisopropoxy, dichloroisopropoxy, trichloroisopropoxy, tetrachloroisopropoxy, heptachloroisopropoxy, hexachloroisopropoxy, or heptachloroisopropoxy). In some embodiments, one or more R 1A is a C1-C3 bromoalkoxy (e.g., bromomethoxy, dibromomethoxy, tribromomethoxy, bromoethoxy, dibromoethoxy, tribromoethoxy, tetrabromoethoxy, pentabromoethoxy, bromo- n -Profoxy, Dibromo- n -Propoxi, Tribromo- n -Propoxy, Tetrabromo- n -Propoxy, Pentabromo- n -Propoxy, Hexabromo- n -Propoxy, Heptabromo- n - is propoxy, bromoisopropoxy, dibromoisopropoxy, tribromoisopropoxy, tetrabromoisopropoxy, heptabromoisopropoxy, hexabromoisopropoxy, or heptabromoisopropoxy). In some embodiments, one or more R 1A is a C1-C3 iodoalkoxy (e.g., iodomethoxy, diiodomethoxy, triiodomethoxy, iodoethoxy, diiodoethoxy, triiodoethoxy, tetraiodoethoxy, pentaiodoethoxy, iodo- n -Propoxy, Daiyodo- n -Propoxy, Triiodo- n -Propoxy, Tetraiodo- n -Propoxy, Pentaiodine- n -Propoxy, Hexayoodo- n -Propoxy, Heptaiodo- n- It is propoxy, iodoisopropoxy, diiodoisopropoxy, triiodoisopropoxy, tetraiodoisopropoxy, heptaiodoisopropoxy, hexaiodoisopropoxy or heptaiodoisopropoxy).

[0132] In some embodiments, one or more R 1A is a pentagonal to tenagonal heteroaryl comprising one, two, or three heteroatoms selected from N and O. In some embodiments, one or more R 1A is a pentagonal to tenagonal heteroaryl comprising one, two, or three heteroatoms selected from N and O. In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl containing one N. In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl containing two Ns. In some embodiments, one or more Rs 1A is a pentagonal to tenagonal heteroaryl containing three Ns. In some embodiments, one or more Rs 1A is a 5- to 10-membered heteroaryl containing one O. In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl containing two O groups. In some embodiments, one or more R 1A is a pentagonal to tenagonal heteroaryl containing three oxygen groups. In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl comprising 1 N and 1 O. In some embodiments, one or more R 1A is a pentagonal to hexaagonal heteroaryl containing one N. In some embodiments, one or more R 1A is a pentagonal to hexaagonal heteroaryl containing two Ns. In some embodiments, one or more Rs 1Ais a pentagonal to hexaagonal heteroaryl containing three Ns. In some embodiments, one or more Rs 1A is a pentagonal to hexaagonal heteroaryl containing one O. In some embodiments, one or more R 1A is a pentagonal to hexaagonal heteroaryl comprising one N and one O. In some embodiments, one or more R 1A is a pentagonal to hexaagonal heteroaryl comprising two Ns and one O. In some embodiments, one or more Rs 1A is a 5- to 6-membered heteroaryl having one ring (i.e., 5- to 10-membered heteroaryls are monocyclic heteroaryls). In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl having two or more rings (e.g., two rings, three rings, or four rings). In some embodiments, one or more R 1A is a 5- to 10-membered heteroaryl comprising two fused rings. In some embodiments, the 5- to 10-membered heteroaryl is a triazolyl. In some embodiments, the 5- to 10-membered heteroaryl is an oxadiazolyl.

[0133] R 1 1, 2, or 3 NRs 13A R 14A It can be substituted as, where each R 13A is independently H or C1-C3 alkyl, and each R 14A is independently H or C1-C3 alkyl. In some embodiments, one or more R 13A is H. In some embodiments, one or more R 13A is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, two or more R 13A is H. In some embodiments, two or more R 13A is a C1-C3 alkyl (e.g., methyl, ethyl,n -propyl, isopropyl). In some embodiments, 3 R 13A is H. In some embodiments, 3 R 13A is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, one or more R 14A is H. In some embodiments, one or more R 14A is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, two or more R 14A is H. In some embodiments, two or more R 14A is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, 3 R 14A is H. In some embodiments, 3 R 14A is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, one or more NR 13A R 14A is R 13A is H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, two or more NRs 13A R 14A is R 13A is H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, three NRs 13A R 14A is R 13A is H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, one or more NR 13A R 14A is R 13Ais H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl), and one or more NR 13A R 14A is NH2. In some embodiments, one NR 13A R 14A is R 13A is H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl), and 2 NRs 13A R 14A is NH2. In some embodiments, two NRs 13A R 14A is R 13A is H, and R 14A ga C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl), and 1 NR 13A R 14A is NH2. In some embodiments, one or more NRs 13A R 14A is NH2. In some embodiments, two or more NRs 13A R 14A is NH2. In some embodiments, three NRs 13A R 14A is NH2.

[0134] In some embodiments, R 1 C3-C 10 Cycloalkyl, C6-C 10 It is an aryl, or a 5- to 10-membered heteroaryl containing 1, 2, or 3 Ns; where, R 1 The cycloalkyl and heteroaryls of R 1A and -NR 13A R 14A It is arbitrarily substituted with 1, 2, or 3 groups independently selected from, and the aryl is R 1A and -NR 13A R 14AIt is replaced with one, two, or three groups independently selected from. In some embodiments, R 1 is R 1A and -NR 13A R 14A It is a phenyl substituted with one, two, or three groups independently selected from. In some embodiments, R 1 1 R 1A It is a phenyl substituted with . In some embodiments, R 1 2 R 1A It is a phenyl substituted with . In some embodiments, R 1A is halo or cyano. In some embodiments, R 1A is chloro or cyano. In some embodiments, R 1A is a fluoro or cyano.

[0135] In some embodiments, R 1 is unsubstituted cyclohexyl; unsubstituted phenyl; phenyl substituted with one, two, or three substituents independently selected from cyano, halo, methoxy, isopropoxy, trifluoromethoxy, triazolyl, and oxadiazolyl; pyridinyl substituted with one, two, or three substituents independently selected from cyano and halo; or pyrimidinyl substituted with cyano. In some embodiments, R 1 is cyclohexyl, phenyl, phenyl substituted with cyano, phenyl substituted with cyano and fluoro, phenyl substituted with cyano and chloro, phenyl substituted with cyano and methoxy, phenyl substituted with cyano and isopropoxy, phenyl substituted with cyano and trifluoromethoxy, phenyl substituted with cyano and two methoxy, phenyl substituted with cyano and triazolyl, phenyl substituted with fluoro and oxadiazolyl, pyridinyl substituted with cyano, pyridinyl substituted with chloro, or pyrimidinyl substituted with cyano. In some embodiments, R 1 silver

[0136]

[0137]

[0138] or am.

[0139] In some embodiments, R 1 silver

[0140] or is. In some embodiments, R 1 silver am.

[0141] R 2 may be H or C1-C3 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is a C1-C3 alkyl (e.g., methyl, ethyl, n - It is a profile, isopropyl.

[0142] R 3 is a C1-C3 alkyl (e.g., methyl, ethyl, n - It can be a profile, isoprofile)

[0143] (CR 4 R 5 ) m In some embodiments, m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21. In some embodiments, m is 16. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19, and in some embodiments, m is 20. In some embodiments, m is 21. In some embodiments, (CR 4 R 5 ) m C 10 -C 21 It is an alkylenyl. In some embodiments, (CR 4 R 5 ) m Unsubstituted C 10 -C 21 It is an alkylenyl. In some embodiments, (CR 4 R 5 )m silver straight chain C 10 -C 21 It is an alkylenyl. In some embodiments, (CR 4 R 5 ) m Unsubstituted straight chain C 10 -C 21 It is an alkylenyl. In some embodiments, (CR 4 R 5 ) m Silver branched chain C 10 -C 21 It is an alkylenyl. In some embodiments, (CR 4 R 5 ) m C 10 -C 21 It is alkenylenyl. In some embodiments, (CR 4 R 5 ) m Unsubstituted C 10 -C 21 It is alkenylenyl. In some embodiments, (CR 4 R 5 ) m silver straight chain C 10 -C 21 It is alkenylenyl. In some embodiments, (CR 4 R 5 ) m Unsubstituted straight chain C 10 -C 21 It is alkenylenyl. In some embodiments, (CR 4 R 5 ) m Silver branched chain C 10 -C 21 It is alkenylenyl. In some embodiments, R 3 (CR 4 R 5 ) m C 11 -C 24 It is an alkyl. In some embodiments, R 3 (CR 4 R 5 ) m Unsubstituted C 11 -C 24 It is an alkyl. In some embodiments, R 3(CR 4 R 5 ) m is substituted C 11 -C 24 It is an alkyl. In some embodiments, R 3 (CR 4 R 5 ) m Silver branched chain C 11 -C 24 It is an alkyl. In some embodiments, R 3 (CR 4 R 5 ) m silver straight chain C 11 -C 24 It is an alkyl. In some embodiments, R 3 (CR 4 R 5 ) m Unsubstituted straight chain C 11 -C 24 It is an alkyl. In some embodiments, R 3 (CR 4 R 5 ) m It is octadecanil. In some embodiments, R 3 (CR 4 R 5 ) m It is nonadecanil. In some embodiments, R 3 (CR 4 R 5 ) m is eicosanyl. In some embodiments, R 3 (CR 4 R 5 ) m It is Heneicosanil.

[0144] Each R 4 may be independently bonded, H, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl. In some embodiments, one or more R 4 is a combination. In some embodiments, 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) Rs 4is H. In some embodiments, one or more R 4 is a halo (e.g., chloro, bromo, fluoro, or iodo). In some embodiments, one or more R 4 is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) R 4 is a C1-C3 alkyl (e.g., methyl, ethyl, n -propyl, isopropyl). In some embodiments, one or more R 4 is a C1-C3 haloalkyl (e.g., halomethyl, haloethyl, halo- n -propyl, haloisopropyl). In some embodiments, 10 to 21 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21) R 4 is a C1-C3 haloalkyl (e.g., methyl, ethyl, n -propyl, isopropyl). Exemplary C1-C3 haloalkyls are fluoromethyl, fluoroethyl, fluoro- n -propyl, fluoroisopropyl, chloromethyl, chloroethyl, chloro- n -propyl, chloroisopropyl, bromomethyl, bromoethyl, bromo- n -propyl, bromoisopropyl, iodomethyl, iodoethyl, iodo- n - Contains propyl or iodoisopropyl.

[0145] Each R 5 may be independently combined or H. In some embodiments, one or more R 5 is a combination. In some embodiments, a single R 5Only R 5 is H. In some embodiments, all R 5 is H.

[0146] In some embodiments, each R 4 and each R 5 is H. In some embodiments, two or more adjacent (CR 4 R 5 The ) groups are arbitrarily connected through double bonds. In some embodiments, (CR 4 R 5 ) m It has one double bond. In some embodiments, (CR 4 R 5 ) m It has one or more double bonds (e.g., 2, 3, 4, or 5 double bonds).

[0147] R 6 may be H or -C(O)C1-C6 alkyl. In some embodiments, R 6 is H. In some embodiments, R 6 -C(O)C1-C6 (e.g., -C(O)C1, -C(O)C2, -C(O)C3, -C(O)C4, -C(O)C5, -C(O)C6) alkyl, -C(O)methyl, -C(O)ethyl, -C(O)- n -propyl, -C(O)isopropyl, -C(O)- n -butyl, -C(O)isobutyl, -C(O)- s -butyl, -C(O)- t -butyl, -C(O)- n-pentyl, -C(O)-2-pentyl, -C(O)-3-pentyl, -C(O)-2-methyl-2-butyl, -C(O)-3-methyl-2-butyl, -C(O)-3-methyl-1-butyl, -C(O)-2-methyl-1-butyl, -C(O)-1-hexyl, -C(O)-2-hexyl, -C(O)-3-hexyl, -C(O)-2-methyl-2-pentyl, -C(O)-3-methyl-2-pentyl, -C(O)-4-methyl-2-pentyl, -C(O)-3-methyl-3-pentyl, -C(O)-2-methyl-3-pentyl, -C(O)-2,3-dimethyl-2-butyl or -C(O)-3,3-dimethyl-2-butyl.

[0148] R 7 can be H or -C(O)C1-C6 alkyl. In some embodiments, R 7 is H. In some embodiments, R 7 -C(O)C1-C6 (e.g., -C(O)C1, -C(O)C2, -C(O)C3, -C(O)C4, -C(O)C5, -C(O)C6) alkyl, -C(O)methyl, -C(O)ethyl, -C(O)- n -propyl, -C(O)isopropyl, -C(O)- n -butyl, -C(O)isobutyl, -C(O)- s -butyl, -C(O)- t -butyl, -C(O)- n -pentyl, -C(O)-2-pentyl, -C(O)-3-pentyl, -C(O)-2-methyl-2-butyl, -C(O)-3-methyl-2-butyl, -C(O)-3-methyl-1-butyl, -C(O)-2-methyl-1-butyl, -C(O)-1-hexyl, -C(O)-2-hexyl, -C(O)-3-hexyl, -C(O)-2-methyl-2-pentyl, -C(O)-3-methyl-2-pentyl, -C(O)-4-methyl-2-pentyl, -C(O)-3-methyl-3-pentyl, -C(O)-2-methyl-3-pentyl, -C(O)-2,3-dimethyl-2-butyl or -C(O)-3,3-dimethyl-2-butyl.

[0149] In some embodiments, R 6 and R 7 All are H. In some embodiments, R 6 is H, and R7 is -C(O)C1-C6 alkyl. In some embodiments, R 6 is H, and R 7 -C(O)methyl, -C(O)ethyl, -C(O)- n -propyl, -C(O)isopropyl, -C(O)- n -butyl, -C(O)isobutyl, -C(O)- s -butyl or -C(O)- t - It is butyl. In some embodiments, R 6 is -C(O)C1-C6 alkyl, and R 7 is H. In some embodiments, R 6 -C(O)methyl, -C(O)ethyl, -C(O)- n -propyl, -C(O)isopropyl, -C(O)- n -butyl, -C(O)isobutyl, -C(O)- s -butyl or -C(O)- t -butyl, R 7 is H. In some embodiments, R 6 and R 7 Each independently -C(O)methyl, -C(O)ethyl, -C(O)- n -propyl, -C(O)isopropyl, -C(O)- n -butyl, -C(O)isobutyl, -C(O)- s -butyl and -C(O)- t -Selected from butyl. In some embodiments, R 6 = R 7 is. In some embodiments, R 6 and R 7 All of them are -C(O)isopropyl.

[0150] L is -O-, -(CR 12A R 12B ) n -, -O-(CR 12A R 12B ) n -, -(CR 12A R 12B ) n -O- or -(CR 12A R12B ) n -O-(CR 12A R 12B ) n -It may be, where n is 1 or 2. In some embodiments, L is -O-. In some embodiments, L is -(CR 12A R 12B )- or -(CR 12A R 12B )-(CR 12A R 12B )-is. In some embodiments, L is -O-(CR 12A R 12B )- or -O-(CR 12A R 12B )(CR 12A R 12B )-is. In some embodiments, L is -(CR 12A R 12B )-O- or -(CR 12A R 12B )(CR 12A R 12B )-is. In some embodiments, L is -(CR 12A R 12B )-O-(CR 12A R 12B )- or -(CR 12A R 12B )(CR 12A R 12B )-O-(CR 12A R 12B )(CR 12A R 12B )-am.

[0151] Each R 12A is independently selected from H and C1-C6 alkyls. In some embodiments, one or more R 12A is H. In some embodiments, one or more R 12A is a C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl, methyl, ethyl, - n -Profile, Isoprofile, - 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.

[0152] Each R 12B is independently selected from H and C1-C6 alkyls. In some embodiments, one or more R 12B is H. In some embodiments, one or more R 12B is a C1-C6 (e.g., C1, C2, C3, C4, C5, or C6) alkyl, methyl, ethyl, - n -Profile, Isoprofile, - 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.

[0153] In some embodiments, R 12A = R 12B is. In some embodiments, each R 12A and each R 12B is H. In some embodiments, R 12A and R 12BEach is independently selected from C1-C6 alkyls. In some embodiments, L is -O-, -O-CH2-, -CH2-O-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, or -CH2-CH2-. In some embodiments, L is O. In some embodiments, L is -O-CH2- or -CH2-O-.

[0154] Q may be a bond or phenylene. In some embodiments, Q is a bond. In some embodiments, Q is phenylene. In some embodiments, Q is am.

[0155] T can be bonded or -O-. In some embodiments, T is bonded. In some embodiments, T is -O-.

[0156] X may be a bond or a C1-C3 alkylene. In some embodiments, X is a bond. In some embodiments, X is methylene, ethylene, n - It is propylene or isopropylene.

[0157] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is

[0158]

[0159]

[0160] or is. In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is or is. In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is is. In some embodiments, R 3 (CR 4 R5 ) m -QTX- is is. In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is is. In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is am.

[0161] In some embodiments, R 3 (CR 4 R 5 ) m -QTX- is

[0162] am.

[0163] Z is -O-, -O-(C1-C6)-alkylene or NR 15 It can be -(C1-C6)-alkylene, where R 15 is H or C1-C3 alkyl. In some embodiments, Z is -O-. In some embodiments, Z is -O-(C1-C6)-alkylene, where (C1-C6)-alkylene is methylene, ethylene, - n -Propylene, Isopropylene, - n -Butylene, Isobutylene, - s -Butylene, - t -Butylene, - n -pentylene, -2-pentylene, -3-pentylene, -2-methyl-2-butylene, -3-methyl-2-butylene, -3-methyl-1-butylene, -2-methyl-1-butylene, -1-hexylene, -2-hexylene, -3-hexylene, -2-methyl-2-pentylene, -3-methyl-2-pentylene, -4-methyl-2-pentylene, -3-methyl-3-pentylene, -2-methyl-3-pentylene, -2,3-dimethyl-2-butylene or -3,3-dimethyl-2-butylene.

[0164] In some embodiments, Z is NH-(C1-C6)-alkylene, N-methyl-(C1-C6)-alkylene, N-ethyl-(C1-C6)-alkylene, N-n -propyl-(C1-C6)-alkylene or N-isopropyl-(C1-C6)-alkylene, where (C1-C6)-alkylene is methylene, ethylene, - n -Propylene, Isopropylene, - n -Butylene, Isobutylene, - s -Butylene, - t -Butylene, - n -Pentylene, -2-Pentylene, -3-Pentylene, -2-Methyl-2-Butylene, -3-Methyl-2-Butylene, -3-Methyl-1-Butylene, -2-Methyl-1-Butylene, -1-Hexylene, -2-Hexylene, -3-Hexylene, -2-Methyl-2-Pentylene, -3-Methyl-2-Pentylene, -4-Methyl-2-Pentylene, -3-Methyl-3-Pentylene, -2-Methyl-3-Pentylene, -2,3-Dimethyl-2-Butylene, or -3,3-Dimethyl-2-Butylene. In some embodiments, Z is -O-CH2-, -NH-CH2-, or -N(CH3)-CH2-.

[0165] In some embodiments, R 1 is cyclohexyl, phenyl, phenyl substituted with cyano, phenyl substituted with cyano and fluoro, phenyl substituted with cyano and chloro, phenyl substituted with cyano and methoxy, phenyl substituted with cyano and isopropoxy, phenyl substituted with cyano and trifluoromethoxy, phenyl substituted with cyano and two methoxy, phenyl substituted with cyano and triazolyl, phenyl substituted with fluoro and oxadiazolyl, pyridinyl substituted with cyano, pyridinyl substituted with chloro, or pyrimidinyl substituted with cyano; R 2 is H or methyl; R 3 is methyl, ethyl, or n-propyl; and each R 4 and R 5 is independently H or bonded; R 6 is H and; R 7is H; m is 11, 12, 13, 14, 15, 16, 17 or 18; L is -O-, -O-CH2-, -CH2-O-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O- or -CH2-CH2-; Q is bond or phenylene; T is bond or -O-; X is bond, -CH2-, -CH2-CH2- or -CH(CH3)-; Z is -O-CH2-, -NH-CH2- or -N(CH3)-CH2-.

[0166] In some embodiments, R 1 is unsubstituted cyclohexyl; unsubstituted phenyl; phenyl substituted with one, two, or three substituents independently selected from cyano, halo, methoxy, isopropoxy, trifluoromethoxy, triazolyl, and oxadiazolyl; pyridinyl substituted with one, two, or three substituents independently selected from cyano and halo; or pyrimidinyl substituted with cyano; and R 2 is H or methyl; R 3 is methyl, ethyl or n - It is a profile; each R 4 and R 5 is independently H or bonded; R 6 is H and; R 7 is H; m is 11, 12, 13, 14, 15, 16, 17 or 18; L is -O-, -O-CH2-, -CH2-O-, -CH2-O-CH2-, -O-CH2-CH2-, -CH2-CH2-O- or -CH2-CH2-; Q is bond or phenylene; T is bond or -O-; X is bond, -CH2-, -CH2-CH2- or -CH(CH3)-; and Z is -O-CH2-, -NH-CH2- or -N(CH3)-CH2-. In some embodiments, R 1 -L is am.

[0167] Those skilled in the art will know of the method disclosed in this specification (e.g., R 1Each and every embodiment of ) is the remaining device (e.g., R 2 , R 3 , R 4 , R 5 , R 6 It is known that, in combination with each of the other embodiments, a compound of the complete formula (I) or any formula described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer (each of which falls within the scope of the present invention) can be produced.

[0168] In some embodiments, the compound of Formula I and the pharmaceutically acceptable salt comprises the compound of Table 1 and the pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I and the pharmaceutically acceptable salt comprises the compound of Table 1A and the pharmaceutically acceptable salt thereof. Tables 1 and 1A provide some of the compounds disclosed in the present invention along with their compound numbers and corresponding structures.

[0169] [Table 1]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] [Table 1A]

[0178]

[0179]

[0180] In some embodiments, the compound of formula I has formula Ia:

[0181] [Chemical Formula Ia]

[0182] .

[0183] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, T, X, Z, L and m) applies to chemical formula Ia.

[0184] In some embodiments, the compound of formula Ia and the pharmaceutically acceptable salt include the compound of Table 2 and the pharmaceutically acceptable salt thereof.

[0185] [Table 2]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193] In some embodiments, the compound of formula I has formula Ib:

[0194] [Chemical Formula Ib]

[0195] .

[0196] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7The description of , Q, T, X, Z, L and m) applies to Formula Ib. In some embodiments, compounds of Formula Ib and pharmaceutically acceptable salts include the compounds of Table 3 and their pharmaceutically acceptable salts.

[0197] [Table 3]

[0198]

[0199]

[0200] In some embodiments, the compound of formula I has formula II:

[0201] [Chemical Formula II]

[0202] .

[0203] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7 The description of , L and m) applies to Formula II. In some embodiments, the compound of Formula II and pharmaceutically acceptable salts include the compound of Table 4 and its pharmaceutically acceptable salts.

[0204] [Table 4]

[0205]

[0206]

[0207]

[0208] In some embodiments, the compound of formula I has formula IIa:

[0209] [Chemical Formula IIa]

[0210] .

[0211] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7 The explanation for , L and m) applies to chemical formula IIa.

[0212] In some embodiments, the compound of formula IIa and the pharmaceutically acceptable salt include the compound of Table 5 and the pharmaceutically acceptable salt thereof.

[0213] [Table 5]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] In some embodiments, the compound of formula I has formula IIb:

[0220] [Chemical Formula IIb]

[0221] .

[0222] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7 The description of , L and m) applies to Formula IIb. In some embodiments, the compounds of Formula IIb and pharmaceutically acceptable salts include the compounds of Table 6 and their pharmaceutically acceptable salts.

[0223] [Table 6]

[0224]

[0225] In some embodiments, the compound of formula I has formula III:

[0226] [Chemical Formula III]

[0227] .

[0228] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7 The explanation for , m and n) applies to Chemical Formula III.

[0229] In some embodiments, the compound of Formula III and the pharmaceutically acceptable salt include the compound of Table 7 and the pharmaceutically acceptable salt thereof.

[0230] [Table 7]

[0231]

[0232]

[0233]

[0234] In some embodiments, the compound of formula I has formula IIIa:

[0235] [Chemical Formula IIIa]

[0236] .

[0237] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7 The description of , m and n) applies to Formula IIIa. In some embodiments, the compound of Formula IIIa and the pharmaceutically acceptable salt include the compound of Table 8 and the pharmaceutically acceptable salt thereof.

[0238] [Table 8]

[0239]

[0240]

[0241] In some embodiments, the compound of formula I has formula IIIb:

[0242] [Chemical Formula IIIb]

[0243] .

[0244] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7The description of , m and n) applies to Formula IIIb. In some embodiments, the compound of Formula IIIb and the pharmaceutically acceptable salt include the compound of Table 9 and the pharmaceutically acceptable salt thereof.

[0245] [Table 9]

[0246]

[0247] In some embodiments, the compound of formula I has formula IV:

[0248] [Chemical Formula IV]

[0249] .

[0250] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7 The description of , L and m) applies to Formula IV. In some embodiments, the compound of Formula IV and pharmaceutically acceptable salts include the compound of Table 10 and its pharmaceutically acceptable salts.

[0251] [Table 10]

[0252]

[0253]

[0254]

[0255]

[0256] In some embodiments, the compound of formula I has formula IVa:

[0257] [Chemical Formula IVa]

[0258] .

[0259] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7The description of , L and m) applies to Formula IVa. In some embodiments, the compound of Formula IVa and the pharmaceutically acceptable salt include the compound of Table 11 and the pharmaceutically acceptable salt thereof.

[0260] [Table 11]

[0261]

[0262]

[0263]

[0264] In some embodiments, the compound of formula I has formula IVb:

[0265] [Chemical Formula IVb]

[0266] .

[0267] Substituents of chemical formula I (e.g., R 1 , R 6 , R 7 The description of , L and m) applies to Formula IVb. In some embodiments, the compound of Formula IVb and the pharmaceutically acceptable salt include the compound of Table 12 and the pharmaceutically acceptable salt thereof.

[0268] [Table 12]

[0269]

[0270] In some embodiments, the compound of formula I has formula V:

[0271] [Chemical Formula V]

[0272] .

[0273] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7 The description of , m and n) applies to Formula V. In some embodiments, the compounds of Formula V and pharmaceutically acceptable salts include the compounds of Table 13 and their pharmaceutically acceptable salts.

[0274] [Table 13]

[0275]

[0276]

[0277]

[0278] In some embodiments, the compound of formula I has formula Va:

[0279] [Chemical Formula Va]

[0280] .

[0281] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7 The description of , m and n) applies to the formula Va. In some embodiments, compounds of the formula Va and pharmaceutically acceptable salts include the compounds of Table 14 and their pharmaceutically acceptable salts.

[0282] [Table 14]

[0283]

[0284]

[0285] In some embodiments, the compound of formula I has formula Vb:

[0286] [Chemical Formula Vb]

[0287] .

[0288] Substituents of chemical formula I (e.g., R 1A , R 6 , R 7 The description of , m and n) applies to formula Vb. In some embodiments, compounds of formula Vb and pharmaceutically acceptable salts include the compounds of Table 15 and their pharmaceutically acceptable salts.

[0289] [Table 15]

[0290]

[0291] In some embodiments, the compound of formula I has formula VI:

[0292] [Chemical Formula VI]

[0293] .

[0294] Substituents of chemical formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, T, X, Z, L, m and n) applies to Formula VI. In some embodiments, the compounds and pharmaceutically acceptable salts of Formula VI include the compounds and pharmaceutically acceptable salts of Table 16.

[0295] [Table 16]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305] In some embodiments, the compound of formula I has formula VIa:

[0306] [Chemical Formula VIa]

[0307] .

[0308] Substituents of chemical formula I (e.g., R 1A , R2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, T, X, Z, L, m and n) applies to Formula VIa. In some embodiments, the compounds and pharmaceutically acceptable salts of Formula VIa include the compounds and pharmaceutically acceptable salts of Table 17.

[0309] [Table 17]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] In some embodiments, the compound of formula I has formula VIb:

[0317] [Chemical Formula VIb]

[0318] .

[0319] Substituents of chemical formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, T, X, Z, L, m and n) applies to the chemical formula VIb.

[0320] In some embodiments, the compound of formula VIb and the pharmaceutically acceptable salt include the compound of Table 18 and the pharmaceutically acceptable salt thereof.

[0321] [Table 18]

[0322]

[0323]

[0324] In some embodiments, the compound of formula I has formula VII:

[0325] [Chemical Formula VII]

[0326] .

[0327] Substituents of chemical formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, L, m and n) applies to Chemical Formula VII.

[0328] In some embodiments, the compound of Formula VII and the pharmaceutically acceptable salt comprises the compound of Table 19 and the pharmaceutically acceptable salt thereof.

[0329] [Table 19]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335] In some embodiments, the compound of formula I has formula VIIa:

[0336] [Chemical Formula VIIa]

[0337] .

[0338] Substituents of chemical formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7The description of , Q, X, L, m and n applies to Formula VIIa. In some embodiments, the compounds of Formula VIIa and pharmaceutically acceptable salts include the compounds of Table 20 and their pharmaceutically acceptable salts.

[0339] [Table 20]

[0340]

[0341]

[0342]

[0343]

[0344] In some embodiments, the compound of formula I has formula VIIb:

[0345] [Chemical Formula VIIb]

[0346] .

[0347] Substituents of chemical formula I (e.g., R 1A , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, L, m and n applies to Formula VIIb. In some embodiments, the compounds and pharmaceutically acceptable salts of Formula VIIb include the compounds and pharmaceutically acceptable salts of Table 21.

[0348] [Table 21]

[0349]

[0350] In some embodiments, the compound of formula I has formula VIIc:

[0351] [Chemical Formula VIIc]

[0352] .

[0353] Substituents of chemical formula I (e.g., R 1A , R2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, L, m and n) applies to Formula VIIc. In some embodiments, the compounds of Formula VIIc and pharmaceutically acceptable salts include the compounds of Table 22 and their pharmaceutically acceptable salts.

[0354] [Table 22]

[0355]

[0356] In some embodiments, the compound of formula I has formula VIII:

[0357] [Chemical Formula VIII]

[0358] .

[0359] Substituents of chemical formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, T, X, Z, L and m) applies to Chemical Formula VIII.

[0360] In some embodiments, the compound of Formula VIII and the pharmaceutically acceptable salt include the compound of Table 23 and the pharmaceutically acceptable salt thereof.

[0361] [Table 23]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] In some embodiments, the compound of formula I has formula VIIIa:

[0368] [Chemical Formula VIIIa]

[0369] .

[0370] Substituents of chemical formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, T, X, Z, L and m) applies to chemical formula VIIIa.

[0371] In some embodiments, the compound of formula VIIIa and the pharmaceutically acceptable salt comprises the compound of Table 24 and the pharmaceutically acceptable salt thereof.

[0372] [Table 24]

[0373]

[0374]

[0375]

[0376] In some embodiments, the compound of formula I has formula VIIIb:

[0377] [Chemical Formula VIIIb]

[0378] .

[0379] Substituents of chemical formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, T, X, Z, L and m) applies to chemical formula VIIIb.

[0380] In some embodiments, the compound of formula VIIIb and the pharmaceutically acceptable salt include the compound of Table 25 and the pharmaceutically acceptable salt thereof.

[0381] [Table 25]

[0382]

[0383] In some embodiments, the compound of formula I has formula VIIIc:

[0384] [Chemical Formula VIIIc]

[0385] .

[0386] Substituents of chemical formula I (e.g., R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, T, X, Z, L and m) applies to chemical formula VIIIc.

[0387] In some embodiments, the compound of formula VIIIc and the pharmaceutically acceptable salt include the compound of Table 26 and the pharmaceutically acceptable salt thereof.

[0388] [Table 26]

[0389]

[0390] In some embodiments, the compound of formula I has formula IX:

[0391] [Chemical Formula IX]

[0392] .

[0393] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, X, L and m) applies to Chemical Formula IX.

[0394] In some embodiments, the compound of Formula IX and the pharmaceutically acceptable salt include the compound of Table 27 and the pharmaceutically acceptable salt thereof.

[0395] [Table 27]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401] In some embodiments, the compound of formula I has formula IXa:

[0402] [Chemical Formula IXa]

[0403] .

[0404] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, X, L and m) applies to chemical formula IXa.

[0405] In some embodiments, the compound of formula IXa and the pharmaceutically acceptable salt include the compound of Table 28 and the pharmaceutically acceptable salt thereof.

[0406] [Table 28]

[0407]

[0408]

[0409]

[0410] In some embodiments, the compound of formula I has formula IXb:

[0411] [Chemical Formula IXb]

[0412] .

[0413] Substituents of chemical formula I (e.g., R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, X, L and m) applies to chemical formula IXb.

[0414] In some embodiments, the compound of formula IXb and the pharmaceutically acceptable salt include the compound of Table 29 and the pharmaceutically acceptable salt thereof.

[0415] [Table 29]

[0416]

[0417] In some embodiments, the compound of formula I has formula IXc:

[0418] [Chemical Formula IXc]

[0419] .

[0420] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q, X, L and m) applies to the chemical formula IXc.

[0421] In some embodiments, the compound of formula IXc and the pharmaceutically acceptable salt include the compound of Table 30 and the pharmaceutically acceptable salt thereof.

[0422] [Table 30]

[0423]

[0424] In some embodiments, the compound of formula I has formula X:

[0425] [Chemical Formula X]

[0426] .

[0427] Substituents of chemical formula I (e.g., R 1, R 2 , R 3 , R 4 , R 5 The description for and m) applies to Formula X. In some embodiments, the compound of Formula X and the pharmaceutically acceptable salt include the compound of Table 31 and the pharmaceutically acceptable salt thereof.

[0428] [Table 31]

[0429]

[0430]

[0431]

[0432]

[0433] In some embodiments, the compound of formula I has formula Xa:

[0434] [Chemical Formula Xa]

[0435] .

[0436] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 The explanation for and m) applies to the chemical formula Xa.

[0437] In some embodiments, the compound of formula Xa and the pharmaceutically acceptable salt include the compound of Table 32 and the pharmaceutically acceptable salt thereof.

[0438] [Table 32]

[0439]

[0440]

[0441]

[0442] In some embodiments, the compound of formula I has formula Xb:

[0443] [Chemical Formula Xb]

[0444] .

[0445] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 The explanation for and m) applies to the chemical formula Xb.

[0446] In some embodiments, the compound of formula Xb and the pharmaceutically acceptable salt include the compound of Table 33 and the pharmaceutically acceptable salt thereof.

[0447] [Table 33]

[0448]

[0449] In some embodiments, the compound of formula I has formula XI:

[0450] [Chemical Formula XI]

[0451] .

[0452] Substituents of chemical formula I (e.g., R 1 , R 3 , R 4 and R 5 The description of ) applies to Formula XI. In some embodiments, the compound of Formula XI and the pharmaceutically acceptable salt include the compound of Table 34 and the pharmaceutically acceptable salt thereof.

[0453] [Table 34]

[0454]

[0455]

[0456]

[0457]

[0458] In some embodiments, the compound of formula I has formula XIa:

[0459] [Chemical Formula XIa]

[0460] .

[0461] Substituents of chemical formula I (e.g., R 1 , R 3 , R 4 and R 5 The explanation for ) applies to the chemical formula XIa.

[0462] In some embodiments, the compound of formula XIa and the pharmaceutically acceptable salt include the compound of Table 35 and the pharmaceutically acceptable salt thereof.

[0463] [Table 35]

[0464]

[0465]

[0466] In some embodiments, the compound of formula I has formula XIb:

[0467] [Chemical Formula XIb]

[0468] .

[0469] Substituents of chemical formula I (e.g., R 1 , R 3 , R 4 and R 5 The explanation for ) applies to the chemical formula XIb.

[0470] In some embodiments, the compound of formula XIb and the pharmaceutically acceptable salt include the compound of Table 36 and the pharmaceutically acceptable salt thereof.

[0471] [Table 36]

[0472]

[0473] In some embodiments, the compound of formula I has formula XII:

[0474] [Chemical Formula XII]

[0475] ,

[0476] In the above equation, w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0477] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The explanation for , Q and L applies to Chemical Formula XII.

[0478] In some embodiments, the compound of formula XII and the pharmaceutically acceptable salt include the compound of Table 37 and the pharmaceutically acceptable salt thereof.

[0479] [Table 37]

[0480]

[0481] In some embodiments, the compound of formula I has formula XIIa:

[0482] [Chemical Formula XIIa]

[0483] ,

[0484] In the above equation, w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0485] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q and L applies to chemical formula XIIa.

[0486] In some embodiments, the compound of formula XIIa and the pharmaceutically acceptable salt comprises the compound of Table 37 and the pharmaceutically acceptable salt thereof.

[0487] In some embodiments, the compound of formula I has formula XIIb:

[0488] [Chemical Formula XIIb]

[0489] ,

[0490] In the above equation, w+v is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19.

[0491] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description for , Q and L applies to chemical formula XIIb.

[0492] In some embodiments, the compound of formula I has formula XIII:

[0493] [Chemical Formula XIII]

[0494] .

[0495] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, Z, L and m) applies to chemical formula XIII.

[0496] In some embodiments, the compound of formula XIII and the pharmaceutically acceptable salt include the compound of Table 38 and the pharmaceutically acceptable salt thereof.

[0497] [Table 38]

[0498]

[0499]

[0500]

[0501]

[0502] In some embodiments, the compound of formula I has formula XIIIa:

[0503] [Chemical Formula XIIIa]

[0504] .

[0505] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, Z, L and m) applies to Formula XIIIa. In some embodiments, the compounds of Formula XIIIa and pharmaceutically acceptable salts include the compounds of Table 39 and their pharmaceutically acceptable salts.

[0506] [Table 39]

[0507]

[0508]

[0509]

[0510] In some embodiments, the compound of formula I has formula XIIIb:

[0511] [Chemical Formula XIIIb]

[0512] .

[0513] Substituents of chemical formula I (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 The description of , Q, X, Z, L and m) applies to chemical formula XIIIb.

[0514] In some embodiments, the compound of formula XIIIb and the pharmaceutically acceptable salt include the compound of Table 40 and the pharmaceutically acceptable salt thereof.

[0515] [Table 40]

[0516]

[0517] Insofar as the in vivo metabolites of the compounds described herein are not novel and obvious compared to the prior art, such products are also included within the scope of the present invention. Such products may be generated, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compounds, primarily due to enzymatic processes. Accordingly, novel and non-obvious compounds are included that are generated by a method comprising the step of contacting a compound with a mammal for a period sufficient to produce its metabolites. Such products are typically radiolabeled (e.g., 14 C or 3 H) A compound is prepared and parenterally administered to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), given sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and is identified by isolating its transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated using antibodies capable of binding to epitopes surviving on the metabolites). The structure of the metabolites is determined in a conventional manner, for example, by MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as in conventional drug metabolism studies. Transformation products are useful for diagnostic assays for the therapeutic administration of the compound, even if they themselves do not possess HSV antiviral activity unless otherwise found in vivo.

[0518] Recipes and methods for determining the stability of a compound in surrogate gastrointestinal secretion are known. In this specification, a compound is defined as stable in the gastrointestinal tract if less than about 50 mol% of its protected groups are deprotected in surrogate gastric or gastric fluid upon incubation at 37°C for 1 hour. Simply put, the fact that a compound is stable in the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. While a prodrug will typically be stable in the digestive system, it may be substantially hydrolyzed into a parent drug in the lumen of the digestive tract, the 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 release a parent drug after overcoming biological barriers to oral delivery.

[0519] IV. Pharmaceutical preparations

[0520] In addition, pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of the present invention (e.g., a compound of formulas I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X, XI, XIa, XIb, XII, XIII, XIIIa, or XIIIb) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient are disclosed herein. In addition, pharmaceutical formulations comprising a pharmaceutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient are provided herein.

[0521] The compounds disclosed herein may be formulated with conventional carriers and excipients. Tablets may comprise, for example, excipients, flow promoters, fillers, binders, or combinations thereof. Aqueous formulations are prepared in a sterile form and, if intended to be delivered by means other than oral administration, will generally be isotonic. Exemplary excipients include, but are not limited to, those presented in the literature ["Handbook of Pharmaceutical Excipients" (1986)]. Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents (e.g., EDTA), carbohydrates (e.g., 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).

[0522] 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 may be presented, for example, as distinct units such as capsules, cases, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as liquid-in-water emulsions or liquid-in-oil emulsions. The active ingredient may also be administered, for example, as a bolus, an electric, or a paste.

[0523] Tablets may be manufactured by compression or molding using optionally one or more auxiliary components. Compression tablets may be manufactured by compressing an active ingredient in a free-flowing form, such as a powder or granule, mixed with optionally a binder, lubricant, inert diluent, preservative, surfactant, dispersant, or a combination thereof, using a suitable machine. Molded tablets may be manufactured by molding a mixture of powdered active ingredients moistened with an inert liquid diluent using a suitable machine. Tablets may optionally be coated or scored and optionally formulated to provide sustained or controlled release of the active ingredient.

[0524] For infections of the eyes or other external tissues (e.g., mouth and skin), the formulation may be applied as a topical ointment or cream containing active ingredient(s) in amounts of, for example, 0.075% to 20% w / w (containing active ingredient(s) in the range of 0.1% to 20% in increments of 0.1% w / w, 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 as an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base in some embodiments. Alternatively, the active ingredient may be formulated as a cream using an oil-in-water type cream base.

[0525] 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 polyhydric alcohols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. In some embodiments, the cream base may comprise, for example, a compound that promotes the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration promoters include, but are not limited to, dimethyl sulfoxide and related analogs. In some embodiments, the cream or emulsion does not contain water.

[0526] The oily phase of the emulsion may be composed of known components by known methods. In some embodiments, the oily phase consists solely of an emulsifier (also known as an emulgent). In some embodiments, the oily phase comprises a mixture of one or more emulsifiers and fats, oils, or combinations thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. Taken together, the emulsifier(s) may constitute a so-called emulsifying wax, with or without the stabilizer(s), and the wax together with oils and fats may constitute a so-called emulsifying ointment base that can form the oily dispersion phase of a cream formulation.

[0527] Tween is an emulsion and emulsion stabilizer suitable for use in formulations. ® 60, Twin ® 80, Span ® 80 may include, but is not limited to, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate, sodium lauryl sulfate and combinations thereof.

[0528] The selection of oils or fats suitable for the formulation may be based on achieving desired cosmetic properties. In some embodiments, the cream may be a non-greasy, stain-free, and washable product with an appropriate concentration to prevent leakage from a tube or other container. In some embodiments, esters may be included, for example, straight-chain or branched-chain, monobasic or dibasic alkyl esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, blends of branched-chain esters known as CRODAMOL® CAP, or combinations thereof. In some embodiments, high-melting point lipids may be included, such as white soft paraffin and / or liquid paraffin or other mineral oils.

[0529] In some embodiments, the compound disclosed herein is administered alone. In some embodiments, the compound disclosed herein is administered as a pharmaceutical preparation. In some embodiments, the pharmaceutical preparation is for veterinary use. In some embodiments, the pharmaceutical preparation is for human use. In some embodiments, the pharmaceutical preparation disclosed herein comprises one or more additional therapeutic agents.

[0530] The pharmaceutical formulations disclosed herein may be in any form suitable for the intended method of administration. The pharmaceutical formulations disclosed herein may be provided in a unit dosage form and may be manufactured by any method well known in the pharmaceutical field. Exemplary techniques and formulations can be found, for example, in the literature [Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA)]. Such methods may include the step of associating the compound disclosed herein with a carrier constituting one or more auxiliary components. Generally, the formulation may be manufactured by uniformly and closely binding the active ingredient with a liquid carrier, a fine solid carrier, or both, and then forming the product as needed.

[0531] When used for oral administration, for example, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. Oral formulations may be prepared according to any method known in the art for the preparation of pharmaceutical formulations, and such formulations may contain one or more agents including sweeteners, flavorings, colorings, and preservatives to provide a palatable formulation. Tablets containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the preparation of tablets are permitted. Such excipients may be, for example, inert diluents, such as calcium carbonate or sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrating agents, such as corn starch or alginate; binders, such as starch, gelatin, or acacia; and lubricants, such as magnesium stearate, stearic acid, or talc. The tablet may not be coated, or may be coated by known techniques, including microencapsulation, to provide sustained action over a longer period by delaying disintegration and adsorption in the gastrointestinal tract. For example, a time-delaying agent, such as glyceryl monostearate or glyceryl distearate, may be used alone or in combination with wax.

[0532] Preparations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, e.g., calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, e.g., peanut oil, liquid paraffin, or olive oil.

[0533] The aqueous suspension may contain an active substance mixed with an excipient suitable for the preparation of the aqueous suspension. The excipient may include, for example, a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, and a dispersant or wetting agent, such as a naturally occurring phosphatidide (e.g., lecithin), a condensation product of an alkylene oxide and a fatty acid (e.g., polyoxyethylene stearate), a condensation product of an ethylene oxide and a long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain, for example, one or more preservatives, e.g., ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents, one or more sweeteners (e.g., sucrose or saccharin), or a combination thereof. Further non-limiting examples of suspending agents include cyclodextrin. In some embodiments, the suspending agent is sulfobutyl ether beta-cyclodextrin (SEB-beta-CD), e.g., Captisol ® am.

[0534] Oily suspensions may be formulated by suspending an active ingredient in vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil, or a combination thereof), mineral oil, such as liquid paraffin, or a combination thereof. Oral suspensions may contain, for example, a thickener, such as beeswax, hard paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweeteners, such as those described above and / or flavoring agents, may be added to provide a palatable oral formulation. In some embodiments, the formulation disclosed herein is preserved by adding an antioxidant, such as ascorbic acid.

[0535] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water may provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, a preservative, and combinations thereof. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, e.g., sweeteners, flavoring agents, and coloring agents may also be present.

[0536] Pharmaceutical formulations may also be in the form of water-in-oil emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil; a mineral oil, such as liquid paraffin; or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as acacia gum and tragacanth gum; naturally occurring phosphatides, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated using sweeteners, for example, glycerol, sorbitol, or sucrose. These formulations may also contain, for example, emollients, preservatives, flavoring agents, coloring agents, or combinations thereof.

[0537] The pharmaceutical formulation may be in the form of a sterile injectable or intravenous formulation, such as a sterile aqueous or oleaginous suspension for injection. Such suspensions may be formulated according to known techniques using the appropriate dispersants or wetting agents and suspending agents mentioned above. The sterile injectable or intravenous formulation 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-butane-diol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, a sterile fixative oil may be used as a solvent or suspension medium. For this purpose, any bland fixative oil containing synthetic mono- or diglycerides may be used. Additionally, fatty acids such as oleic acid may likewise be used in the preparation of the injectable. Acceptable vehicles and solvents that may be used include, but are not limited to, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0538] The amount of active ingredient that can be combined with a carrier material to create a single-dose formulation will vary depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation for human oral administration may contain about 1 mg to about 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material that may vary from 5% to 95% (weight:weight) of the total formulation. Pharmaceutical formulations may be manufactured to provide an easily measurable amount for administration. For example, an aqueous solution for intravenous infusion may contain 3 μg to 500 μg of active ingredient per milliliter of solution to allow for an appropriate volume infusion to occur at a rate of 30 mL / hr.

[0539] Formulations suitable for topical administration to the eye also comprise ophthalmic preparations in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. In some embodiments, the compound disclosed herein is included in the pharmaceutical formulation disclosed herein at a concentration of 0.5% to 20% (e.g., 0.5% to 10%, 1.5% w / w).

[0540] Formulations suitable for topical administration into the mouth include: a lozenge comprising a flavoring base, typically an active ingredient among sucrose and acacia or tragacanth (i.e., compounds disclosed herein and / or additional therapeutic agents); a flavoring agent comprising an inert base, such as gelatin and glycerin, or an active ingredient among sucrose and acacia; and an oral rinse comprising an active ingredient in a suitable liquid carrier.

[0541] Preparations for rectal administration may be provided as suppositories containing a suitable base, for example, cocoa butter or salicylate.

[0542] Preparations suitable for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams, or sprays containing a carrier as known to be suitable in the art in addition to the active ingredient.

[0543] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents.

[0544] The formulations may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, e.g., distilled water for injection, immediately before use. Immediate injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the types described above. Preferred unit-dose formulations are those containing a daily dose or unit daily subdose of the active ingredient as mentioned above in this specification, or an appropriate fraction thereof.

[0545] In addition to the components specifically mentioned above, it should be understood that the formulation may include other agents conventional in the art with respect to the type of formulation, and, for example, those suitable for oral administration may include flavoring agents.

[0546] A veterinary preparation comprising the compound disclosed in this specification together with a veterinary carrier for this purpose is further provided.

[0547] The veterinary carrier is a substance useful for administering the preparation, and may otherwise be a solid, liquid, or gaseous substance that is inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary preparations may be administered orally, parenterally, or by any other desired route.

[0548] The compounds of the present invention are used to provide a release-controlled pharmaceutical formulation ("release-controlled formulation") containing one or more compounds of the present invention as an active ingredient, which can control and regulate the release of an active ingredient to enable less frequent administration or to improve the pharmacokinetics or toxicity profile of a given active ingredient.

[0549] The effective dose of the active ingredient will depend at least on the nature of the disease being treated, toxicity, whether the compound is being used prophylactically (at a lower dose) or for an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by a clinician using a conventional dose-increasing study. In some embodiments, it may be expected to be 0.0001 to 100 mg / kg (body weight) / day; e.g., 0.01 to 10 mg / kg (body weight) / day; 0.01 to 5 mg / kg (body weight) / day; or 0.05 to 0.5 mg / kg (body weight) / day. For example, a candidate daily dose for an adult weighing about 70 kg may be in the range of 1 mg to 1000 mg (e.g., 5 mg to 500 mg) and may take the form of a single or multiple doses.

[0550] V. Kit

[0551] Additionally, a kit comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof is provided herein. In some embodiments, the kit described herein may include instructions and / or a label for the use of the compound in the treatment of a disease or condition in a subject (e.g., human) requiring treatment of the disease or condition. In some embodiments, the disease or condition is a viral infection.

[0552] In some embodiments, the kit may also include one or more additional therapeutic agents used in combination with the compound disclosed herein in the treatment of a disease or condition in a subject (e.g., human) requiring treatment of the disease or condition, and / or instructions for the use of the additional therapeutic agents.

[0553] In some embodiments, the kit provided herein comprises individual dosing units of the compound described herein or its pharmaceutically acceptable salt, racemic, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. Examples of individual dosing units may include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each comprising a therapeutically effective amount of the corresponding compound or its pharmaceutically acceptable salt, racemic, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. In some embodiments, the kit may contain a single dosing unit, while in other embodiments, there are multiple dosing units, such as the number of dosing units required during a specified plan or period.

[0554] A product comprising a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; and a container is also provided. In some embodiments, the container of the product is a vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer.

[0555] VI. administration

[0556] One or more compounds of the present invention are administered by any route appropriate for the condition to be treated. Appropriate 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 noted that the route may vary, for example, depending on the condition of the recipient.

[0557] In the method of the present invention for treating a viral infection, the compound of the present invention may be administered at any time to a subject who may come into contact with the virus or who is already suffering from a viral infection. In some embodiments, the compound of the present invention may be administered prophylactically to a subject who is at risk of coming into contact with a subject suffering from a viral infection, e.g., a healthcare provider. In some embodiments, the administration of the compound of the present invention may be performed on a subject who has been tested as positive for a viral infection but has not yet shown symptoms of a viral infection. In the method of the present invention for treating a viral infection, the compound of the present invention may be administered at any time to a human who may come into contact with the virus or who is already suffering from a viral infection. In some embodiments, the compound of the present invention may be administered prophylactically to a human who is at risk of coming into contact with a human suffering from a viral infection, e.g., a healthcare provider. In some embodiments, the administration of the compound of the present invention may be performed on a human who has been tested as positive for a viral infection but has not yet shown symptoms of a viral infection. In some embodiments, the compound of the present invention may be administered to a human at the onset of symptoms of a viral infection.

[0558] In some embodiments, the method disclosed herein comprises event-inducing administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject.

[0559] As used herein, the terms “event induction” or “event induction administration” refer to the administration of any one of the compounds of Formulas I to XIIIb or a pharmaceutically acceptable salt thereof at (1) before an event in which the subject is exposed to the virus (or otherwise the subject’s risk of viral infection is increased) (e.g., at 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event); and / or (2) during an event in which the subject is exposed to the virus (or otherwise the subject’s risk of viral infection is increased) (or two or more repeated events); and / or (3) after an event in which the subject is exposed to the virus (or otherwise the subject’s risk of viral infection is increased) (or after the final event in a series of repeated events). In some embodiments, the event induction administration is performed before the subject’s exposure to the virus. In some embodiments, the event induction administration is performed after the subject’s exposure to the virus. In some embodiments, event-inducing administration is performed before the subject's exposure to the virus and after the subject's exposure to the virus.

[0560] In certain embodiments, the method disclosed herein comprises administration, for example, as a pre-exposure prophylaxis (PrEP) and / or a post-exposure prophylaxis (PEP), before and / or after an event that causes a subject (e.g., a human) to be exposed to the virus or otherwise increases the risk of the subject (e.g., a human) becoming infected with the virus. In some embodiments, the method disclosed herein comprises a pre-exposure prophylaxis (PrEP). In some embodiments, the method disclosed herein comprises a post-exposure prophylaxis (PEP).

[0561] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered prior to the exposure of the target to the virus.

[0562] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered before and after the target's exposure to the virus.

[0563] In some embodiments, the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered after the subject's exposure to the virus.

[0564] An example of an event-driven dosing regimen comprises administering the compound disclosed herein or a pharmaceutically acceptable salt thereof within 24 to 2 hours prior to viral exposure, administering the compound disclosed herein or a pharmaceutically acceptable salt thereof every 24 hours during the exposure period, additionally administering the compound disclosed herein or a pharmaceutically acceptable salt thereof after the last exposure, and finally administering the compound disclosed herein or a pharmaceutically acceptable salt thereof once after 24 hours.

[0565] Additional examples of event-inducing administration plans include administering any one of the compounds of formulas I to XIIIb or a pharmaceutically acceptable salt thereof within 24 hours prior to viral exposure, followed by daily administration during the exposure period, and finally administering approximately 24 hours after the last exposure (which may be an increased dose, e.g., double the dose).

[0566] 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 for an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by a clinician using a conventional dose-increasing study. It may be expected to be 0.0001 mg / kg to 100 mg / kg (body weight) / day (e.g., 0.01 mg / kg to 10 mg / kg (body weight) / day; 0.01 mg / kg to 5 mg / kg (body weight) / day; 0.05 mg / kg to 0.5 mg / kg (body weight) / day). In some embodiments, the daily candidate dose for an adult weighing about 70 kg is 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 may take the form of a single or multiple dose (e.g., a twice-daily dose, a three-daily dose). For example, the daily candidate dose for an adult weighing about 70 kg may be in the range of 1 mg to 1000 mg (e.g., 5 mg to 500 mg) and may take the form of a single or multiple dose.

[0567] Any suitable period for administering the compound of the present invention is considered. For example, administration may be performed for 1 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. Additionally, administration may be performed for 1 to 15 weeks, including 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks. Longer administration periods are also considered.

[0568] In some embodiments, the compound disclosed herein is administered once daily. In some embodiments, the compound disclosed herein is administered twice daily. In some embodiments, the compound disclosed herein is administered once every other day. In some embodiments, the compound disclosed herein is administered once a week. In some embodiments, the compound disclosed herein is administered twice a week.

[0569] In some embodiments, one or more compounds disclosed herein are administered once daily. The once-daily dose may be administered for as long as necessary, for example, 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 for a longer period. 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 for 1 day.

[0570] In some embodiments, one or more compounds disclosed herein are administered once daily for 6 to 12 days, for example, 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, for example, 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, for example, 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) of one or more compounds disclosed herein are administered once a day for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days.

[0571] In some embodiments, one or more compounds disclosed herein are administered twice daily. The twice-daily dose may be administered for as long as necessary, for example, 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 for a longer period. 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 for 1 day.

[0572] In some embodiments, one or more compounds disclosed herein are administered twice daily for 6 to 12 days, for example, 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 1000 mg of one or more compounds disclosed herein are administered twice daily for 5 to 12 days, for example, 5, 6, 7, 8, 9, 10, 11, or 12 days. In some embodiments, one or more compounds disclosed herein in an amount of 500 to 1500 mg (e.g., 500 to 1000 mg, 1000 to 1500 mg) are administered twice daily for 5 to 12 days, e.g., 5, 6, 7, 8, 9, 10, 11, or 12 days.

[0573] VII. How to use

[0574] The present invention also provides a method for treating or preventing a viral infection in a subject (e.g., a human) who requires treatment or prevention of a viral infection, comprising the step of administering a compound described herein to said subject.

[0575] In some embodiments, the present invention provides a method for treating a viral infection in a subject (e.g., a human) who requires treatment for a viral infection, comprising the step of administering a compound described herein to said subject.

[0576] In some embodiments, the present invention provides a method for treating or preventing a viral infection in a subject (e.g., a human) who requires treatment or prevention of a viral infection, comprising the step of administering a compound disclosed herein and at least one additional active therapeutic agent or prophylactic agent to said subject.

[0577] In some embodiments, the present invention provides a method for treating a viral infection in a subject (e.g., a human) who requires treatment for a viral infection, comprising the step of administering a compound disclosed herein and at least one additional active therapeutic agent to the subject.

[0578] In some embodiments, the present invention provides a method for inhibiting viral polymerase in a cell, comprising the step of contacting a virus-infected cell with a compound disclosed herein to inhibit viral polymerase.

[0579] In some embodiments, the present invention provides a method for inhibiting viral polymerase in a cell, comprising the step of contacting a virus-infected cell with a compound disclosed herein and one or more additional active therapeutic agents to inhibit viral polymerase.

[0580] In addition, uses of the compounds disclosed herein for use in treating or preventing viral infections in subjects requiring treatment or prevention of viral infections are provided herein. For example, uses of the compounds disclosed herein for use in treating viral infections in subjects requiring treatment of viral infections are provided herein.

[0581] A. Paramyxoviridae

[0582] In some embodiments, the viral infection is a paramyxoviridae virus infection. Thus, in some embodiments, the present invention provides a method for treating a paramyxoviridae infection in a subject (e.g., a human) who requires treatment for a paramyxoviridae infection, comprising the step of administering a compound disclosed herein to said subject. In some embodiments, the paramyxoviridae virus includes a BSL4 pathogen. The paramyxoviridae virus includes, but is not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza virus.

[0583] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a paramyxoviral virus infection in a subject (e.g., human) who requires treatment of said virus infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a paramyxoviral virus infection in a subject (e.g., human).

[0584] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a viral infection in a subject (e.g., human) requiring treatment for a paramyxovirus and viral infection.

[0585] B. Pneumoviridae

[0586] In some embodiments, the viral infection is a pneumoviridae virus infection. In some embodiments, the present invention provides a method for treating a pneumoviridae virus infection in a subject (e.g., a human) who requires treatment for a pneumoviridae virus infection, comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to said subject. 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.

[0587] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a viral infection in a subject (e.g., human) requiring treatment for a pneumoviral virus infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a pneumoviral virus infection in a subject (e.g., human). In some embodiments, the pneumoviral virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviral virus infection is a human metapneumovirus infection.

[0588] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a pneumoviral virus infection in a human requiring treatment of said virus infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a pneumoviral virus infection in a human. In some embodiments, the pneumoviral virus infection is a respiratory syncytial virus infection. In some embodiments, the pneumoviral virus infection is a human metapneumovirus infection.

[0589] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of a viral infection in a human requiring treatment for a pneumoviridae viral infection. In some embodiments, the pneumoviridae viral infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the pneumoviridae viral infection is a human metapneumovirus infection.

[0590] In certain embodiments, the present invention provides a method for treating RSV infection, comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) infected with respiratory syncytial virus. In some embodiments, the human has a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0591] In a specific embodiment, a method for inhibiting RSV replication is provided, comprising the step of administering a compound of the present invention or a pharmaceutically acceptable salt thereof to a target (e.g., a human).

[0592] In a specific embodiment, the present invention provides a method for reducing a viral load associated with RSV infection, the method comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) infected with RSV, wherein the therapeutically effective amount is sufficient to reduce the RSV viral load in the subject.

[0593] As more fully described herein, the compound of the present invention may be administered to a subject infected with RSV (e.g., human) together with one or more additional therapeutic agents. The additional therapeutic agents may be administered to the infected subject (e.g., human) simultaneously with the compound of the present invention, or before or after the administration of the compound of the present invention.

[0594] In certain embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is provided for use in treating or preventing RSV infection. In certain embodiments, a compound of the present invention (e.g., a compound of formulas I through XIIIb) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicine for treating or preventing RSV infection.

[0595] In some embodiments, a method for inhibiting RSV replication is provided, comprising the step of administering a compound disclosed herein by inhalation to a subject (e.g., a human) who requires inhibition of RSV replication.

[0596] In some embodiments, the present invention provides a method for reducing the viral load associated with RSV infection, comprising the step of administering a compound disclosed herein to a human infected with RSV.

[0597] C. Picornaviridae

[0598] In some embodiments, the viral infection is a picornaviridae virus infection. In some embodiments, the present invention provides a method for treating a picornaviridae virus infection in a human, comprising the step of administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject (e.g., a human) who requires treatment for a picornaviridae virus infection. A picornaviridae virus is an enterovirus that causes a heterogeneous group of infections including herpetic stomatitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic spinal polio-like syndrome, epidemic pleurisy (an acute, febrile, infectious disease that typically occurs as an epidemic), hand, foot, and mouth syndrome, 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).

[0599] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a viral infection in a subject (e.g., human) requiring treatment of a picornaviridae viral infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a picornaviridae viral infection in a subject (e.g., human). In some embodiments, the picornaviridae viral infection is a human rhinovirus infection.

[0600] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a viral infection in a subject (e.g., human) who requires treatment for a picornaviridae viral infection. In some embodiments, the picornaviridae viral infection is a human rhinovirus infection.

[0601] D. Flaviviridae

[0602] In some embodiments, the viral infection is a flaviviral virus infection. In some embodiments, the present invention provides a method for treating a flaviviral virus infection in a subject (e.g., a human) who requires treatment for a flaviviral virus infection, comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to said subject (e.g., a human). Representative flaviviral viruses include, but are not limited to, dengue fever, yellow fever, West Nile, Zika, Japanese encephalitis virus, tick-borne encephalitis virus (TBEV), and hepatitis C (HCV). In some embodiments, the flaviviral virus infection is a dengue virus infection. In some embodiments, the flaviviral virus infection is a yellow fever virus infection. In some embodiments, the flaviviral virus infection is a West Nile virus infection. In some embodiments, the flaviviral virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is tick-borne encephalitis virus (TBEV) infection. In some embodiments, the Flaviviridae virus infection is hepatitis C virus infection. In some embodiments, the Flaviviridae virus infection is bovine viral diarrhea (BVDV). In some embodiments, the Flaviviridae virus infection is swine fever virus (SFV).

[0603] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a viral infection in a subject (e.g., human) requiring treatment for a flaviviral virus infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a flaviviral virus infection in a subject (e.g., human). In some embodiments, the flaviviral virus infection is a dengue virus infection. In some embodiments, the flaviviral virus infection is a yellow fever virus infection. In some embodiments, the flaviviral virus infection is a West Nile virus infection. In some embodiments, the flaviviral virus infection is a Zika virus infection. In some embodiments, the flaviviral virus infection is a hepatitis C virus infection.

[0604] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a viral infection in humans requiring treatment for a flaviviral infection. In some embodiments, the flaviviral infection is a dengue virus infection. In some embodiments, the flaviviral infection is a yellow fever virus infection. In some embodiments, the flaviviral infection is a West Nile virus infection. In some embodiments, the flaviviral infection is a Zika virus infection. In some embodiments, the flaviviral infection is a hepatitis C virus infection.

[0605] E. Filovirus family

[0606] In some embodiments, the virus infection is a filoviroid virus infection. In some embodiments, the present invention provides a method for treating a filoviroid virus infection in a subject (e.g., human) who requires treatment for a filoviroid virus infection, comprising the step of administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to said subject (e.g., human). Representative filoviroid viruses include, but are not limited to, Ebola (variants Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg. In some embodiments, the filoviroid virus infection is an Ebola virus infection. In some embodiments, the filoviroid virus infection is a Marburg virus infection.

[0607] In some embodiments, the present invention provides a method for manufacturing a medicine for treating a viral infection in a human requiring treatment of a filoviral virus infection, characterized by using a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof in manufacturing a medicine for treating a filoviral virus infection in a human. In some embodiments, the filoviral virus infection is an Ebola virus infection.

[0608] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a virus infection in a subject (e.g., human) who requires treatment for a filovirological virus infection. In some embodiments, the filovirological virus infection is an Ebola virus infection. In some embodiments, the filovirological virus infection is a Marburg virus infection.

[0609] VIII. Combination therapy

[0610] The compounds described herein may also be used in combination with one or more additional therapeutic agents or prophylactic agents. Thus, a method for treating a viral infection in a subject requiring treatment for a viral infection is provided herein, comprising the step of administering a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents or prophylactic agents to the subject requiring treatment for a viral infection. In some embodiments, the method comprises the step of administering the compound disclosed herein and one or more additional therapeutic agents to the subject in a therapeutically effective amount. In some embodiments, the compound disclosed herein is combined with one or more other active therapeutic agents, wherein the combination is used to treat a viral infection in a subject requiring treatment for a viral infection. In some embodiments, the combination may be used to treat multiple distinct viral infections (e.g., RSV and HIV) in a single subject. In some embodiments, the compound disclosed herein is combined with one or more other active therapeutic agents to cover a wide range of respiratory viruses in a single treatment without requiring diagnosis.

[0611] In some embodiments, the combination may be used to treat the same virus (e.g., RSV) in a single target. 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 all of the above therapeutic agents.

[0612] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent may be used in the method described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, invasion inhibitors, non-cyclic guanosine analogs, non-cyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferon, immunostimulators, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0613] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU] and combinations thereof.

[0614] 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.

[0615] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is phospharnet or phosphonoacetate. In some embodiments, the additional therapeutic agent is phospharnet.

[0616] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agents are zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0617] 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.

[0618] 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, additional therapeutic agents are selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, paldaprevir, pedarevir, sobaprevir, deldeprevir, narlaprevir, and combinations thereof. In some embodiments, additional therapeutic agents are selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0619] 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.

[0620] In some embodiments, the additional therapeutic agent is an invasion 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 immunoglobulin, intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immune globulin [VZIG], and combinations thereof.

[0621] In some embodiments, the additional therapeutic agent is a non-cyclic guanosine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0622] In some embodiments, the additional therapeutic agent is a non-cyclic 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.

[0623] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, additional therapeutic agents are selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0624] 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, raninamivir 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, additional therapeutic agents are selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, raninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, additional therapeutic agents are selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, raninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0625] In some embodiments, the additional therapeutic agent is interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacone 1, interferon alpha 1b, interferon alpha 2a, interferon alpha 2b, pegylated interferon alphacone 1, pegylated interferon alpha 1b, pegylated interferon alpha 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alphacone 1, interferon alpha 1b, interferon alpha 2a, interferon alpha 2b, pegylated interferon alpha 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alpha-cone 1, pegylated interferon alpha 2a (PegIFNα-2a), pegylated interferon alpha-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0626] 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 an anti-mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of formivirsen, podophyllox, imiquimod, synecatekins, and combinations thereof.

[0627] In some embodiments, additional therapeutic agents are selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirin, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir and combinations thereof.

[0628] In some embodiments, the additional therapeutic agent is an RSV therapeutic agent. 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.

[0629] In some embodiments, the additional therapeutic agent is a picornavirus therapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-butionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is lupintrivir.

[0630] In some embodiments, the additional treatment is a malaria treatment. In some embodiments, the additional treatment is chloroquine.

[0631] In some embodiments, additional therapeutic agents are selected from the group consisting of hydroxychloroquine, chloroquine, artemeter, lumefantrin, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrin, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, pheroquine, artefenomel mesylate, ganaplaced, DSM-265, cypargamin, artemisone, and combinations thereof.

[0632] In some embodiments, the additional treatment is a coronavirus treatment. In some embodiments, the additional treatment is a COVID-19 (coronavirus disease 2019, a disease caused by the virus called SARS-CoV-2) treatment. In some embodiments, the additional treatment is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, lanfirnaase, nafamostat, LB-2, AM-1, anti-viropolin, remdesivir, VV116, GS-441524, GS-5245 and combinations thereof.

[0633] In some embodiments, additional therapeutic agents are Ebola virus therapeutic agents. For example, in some embodiments, additional therapeutic agents are ribavirin, palivizumab, motaviizumab, 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]pyrimidine-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, It is selected from the group consisting of FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenovirus vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus intrusion inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, additional therapeutic agents are ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0634] In some embodiments, the additional therapeutic agent is an HCV therapeutic agent. 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, ladalbuvir, 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, for instance, GS-9256, bedroprevir, voxilaprevir, and combinations thereof.

[0635] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0636] 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 alpha-hydroxycitropolone, amdoxovir, antroquinonol, beta-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elbusitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, virinapant, NJK14047, NOV-205 (molic acid, BAM-205), oligotide, mibotylate, ferron, 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, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, 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), International Patent Application Publication WO2015173164, WO2016023877, U.S. Patent Application Publication No. 2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), U.S. Patent Application Publication No. 2016237090A (Roche),Compounds disclosed in WO16107833A1 (Roche), WO16107832A1 (Roche), U.S. Patent Application Publication No. 2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), U.S. Patent Application Publication No. 2016220586A (Roche), and U.S. Patent Application Publication No. 2015031687A (Roche) are included, but not limited thereto. In some embodiments, an additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV 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, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), pilocyclovir, pradefovir, clevudine, ribavirin, and lamivudine (EPIVIR-HBV®). Phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234 are included, but not limited thereto. In some embodiments, an additional therapeutic agent is an HBV capsid inhibitor.

[0637] In some embodiments, the additional therapeutic agent is an HIV therapeutic agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, invasion inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, non-cyclic nucleoside phosphonate analogs, and combinations thereof.

[0638] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV invasion inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, genetic modifiers, gene editors (e.g., CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), and cell therapies (e.g., chimeric antigen receptor T-cells, CAR-T, and engineered T-cell receptors, TCR-T, T-cell pseudo-therapy).

[0639] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV combination agents, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV invasion (fusion) inhibitors, HIV maturation inhibitors, latent reversal agents, capsid inhibitors, immune-based therapeutic agents, PI3K inhibitors, HIV antibodies and bispecific antibodies, and “antibody-like” therapeutic proteins and combinations thereof.

[0640] In some embodiments, the additional treatment is an HIV combination. Examples of HIV combinations are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (Eviplera®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ®(Elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); Truvada ® (Tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (Tenofovir alafenamide and emtricitabine); ODEFSEY® (Tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (Tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); SYMTUZA ® (Darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; 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; doravirin, lamivudine, and tenofovir disoproxil fumarate; doravirin, lamivudine, and tenofovir disoproxil; Dapivirine + Levonorgestrel, Dolutegravir + Lamivudine, Dolutegravir + Emtricitabine + Tenofovir Alafenamide, 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, Includes, but not limited to, zidovudine and lamivudine.

[0641] In some embodiments, an additional therapeutic agent is an HIV capsid inhibitor (e.g., lenacafavir).

[0642] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and cobicistat. In some embodiments, additional therapeutic agents are selected from the group consisting of amprenavir, atazanavir, 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.

[0643] 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, additional therapeutic agents are bictegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeylquinic acid, derivatives of 3,5-dicaffeylquinic acid, aurine tricarboxylic acid, derivatives of aurine tricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tirfostine, derivatives of tirfostine, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, It is selected from the group consisting of NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbendisulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0644] In some embodiments, additional therapeutic agents are HIV intrusion inhibitors. For example, in some embodiments, additional therapeutic agents are selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Additional examples of HIV intrusion inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aflaviroc, 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).

[0645] 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 a non-cyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0646] In some embodiments, additional therapeutic agents are reverse transcriptase HIV nucleoside or nucleotide inhibitors. For example, additional therapeutic agents include adefovir, adefovir dipivoxil, azvudine, 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, allovudine, africitabine, sensabudine, didanosine, elbucitabine, festinavir, fosalvudine tydoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, It is selected from the group consisting of pozivudine tydoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461 and combinations thereof.

[0647] In some embodiments, the additional therapeutic agent is an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase. For example, the additional therapeutic agent is selected from the group consisting of dapivirine, delaviridine, delaviridine mesylate, doravirin, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilpivirine (VM-1500), and combinations thereof.

[0648] In some embodiments, the additional treatment 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 + FTC); Descovy® (Tenofovir alafenamide and emtricitabine); Odefsay® (Tenofovir alafenamide, emtricitabine and rilpivirine); Zenvoya® (Tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); Adefovir; Adefovir dipivoxil; cobicistat; emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; Triumeq ® (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); Epsicom ® (Rivexa ® ; Abacavir sulfate and lamivudine; ABC+3TC); Trizivir ®(Abacavir sulfate, 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; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; It is selected from saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0649] In some embodiments, additional therapeutic agents are selected from the group consisting of colistin, valubicin, icatibant, bepotastine, epirubicin, epoprostenol, bapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, flulifloxacin, bictegravir, nelfinavir, tegobuvir, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0650] In some embodiments, an additional therapeutic agent is a Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene number 695) inhibitor. For example, in some embodiments, additional therapeutic agents consist of (S)-6-amino-9-(1-(but-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spevrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatissen, and combinations thereof. It is selected from a group. In some embodiments, the additional treatment is selected from a group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional treatment is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional treatment is tirfostine A9 (A9).

[0651] In some embodiments, an additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, additional therapeutic agents are 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), room temperature11, MRTX-849(G12C) and KRAS(G12D)-selective inhibitory peptides (including KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2)), and combinations thereof.

[0652] 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.

[0653] 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, an attenuated live 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 the attenuated RSV live vaccine MEDI-559, the human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immunoglobulin, intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pediarix, Engerix-B, and Recomvivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavax and Varivax. In some embodiments, additional therapeutic agents are HPV vaccines, e.g., Cervarix, Gardasil 9, and Gardasil. In some embodiments, additional therapeutic agents are influenza virus vaccines. For example, (i) a monovalent vaccine for influenza A (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, additional therapeutic agents are human adenovirus vaccines (e.g., adenovirus type 4 and type 7 vaccines, live vaccines, oral).In some embodiments, additional therapeutic agents are rotavirus vaccines (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9, and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, additional therapeutic agents are hepatitis A virus vaccines (e.g., Havrix and Vaqta). In some embodiments, additional therapeutic agents are poliovirus vaccines (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, additional therapeutic agents are yellow fever virus vaccines (e.g., YF-Vax). In some embodiments, additional therapeutic agents are Japanese encephalitis virus vaccines (e.g., Ixiaro and JE-Vax). In some embodiments, additional therapeutic agents are measles vaccines (e.g., MMR II and ProQuad). In some embodiments, additional therapeutic agents are mumps vaccines (e.g., MMR II and ProQuad). In some embodiments, the additional treatment is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional treatment is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional treatment is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional treatment is a smallpox virus (variola) vaccine (ACAM2000). In some embodiments, the additional treatment is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional treatment is a SARS-COV-2 vaccine.

[0654] 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 Regeneron antibodies, Wuxi antibodies, Vir Biotechnology antibodies, antibodies targeting the SARS-CoV-2 spike protein, antibodies capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), 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 a PD-1 antibody.

[0655] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0656] 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.

[0657] In some embodiments, additional therapeutic agents are selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, arbidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib and combinations thereof.

[0658] In some embodiments, additional therapeutic agents are 6'-fluorinated aristeromycin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisocerine derivatives, neuroiminidase inhibitor analogs, pyritiovac derivatives, vananine and 5-hydroxychromone derivatives, SSYA10-001, griffitcin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thi-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, It is selected from the group consisting of recombinant interferon, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophylline inhibitor, K11777, camostat, K22, teicoplanin derivative, benzo-heterocyclic amine derivative N30, mycophenolic acid, silvesrol, and combinations thereof.

[0659] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for example, an antibody that binds to SARS or MERS. In some embodiments, the additional therapeutic agent is SARS-COV-2 It is a virus antibody.

[0660] The formulation of the present invention is also used in combination with other active ingredients. SARS-COV-2 In the case of treating viral infections, in some embodiments, other active agents are used for coronavirus infections, e.g., SARS-COV-2 It is active against viral infections. The compounds and formulations of the present invention are also intended for use in conjunction with general care provided to subjects with SARS-COV-2 virus infection, such general care including parenteral fluids (including dextrose saline and Ringer's lactate) and nutritional supplements, antibiotics (including metronidazole and cephalosporin antibiotics, e.g., ceftriaxone and cefuroxim) and / or antifungal prophylactic agents, fever and pain medications, antiemetics (e.g., metoclopramide) and / or antidiarrheal agents, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (e.g., ibuprofen or steroids), corticosteroids, e.g., methylprednisolone, immunomodulatory agents (e.g., interferon), and other small molecules or biological antivirals targeting SARS-COV-2 (e.g., lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, Neutralizing antibodies, etc., but not limited thereto), vaccines, pain medications, and medications for other common diseases in the target population, such as antimalarial agents (including artemeter and artesunate-lumefantrin combination therapy), tifoids (including quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or shigellosis antibiotics. In some embodiments, an additional therapeutic agent is dihydroartemisinin / piperaquine.

[0661] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapeutic agents are Toll-like receptor modulators, e.g., tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed cell-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 (MMF); ribavirin; polymeric 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, normperone, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103 are included. In some embodiments, additional therapeutic agents are fingolimod, leflunomide, or a combination thereof. In some embodiments, additional therapeutic agents are thalidomide.

[0662] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0663] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0664] 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.

[0665] In some embodiments, additional therapeutic agents are anti-inflammatory agents, such as pirfenidone.

[0666] 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 ( mycoplasma pneumoniae )), fluoroquinolones (e.g., ciprofloxacin and levofloxacin), tetracyclines (e.g., doxycycline and tetracycline), or combinations thereof.

[0667] In some embodiments, the compounds disclosed herein are used in combination with standard pneumonia treatment (see, for example, the literature [Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)]). Treatment for pneumonia generally involves curing the infection and preventing complications. Specific treatment will depend on several factors, including the type and severity of the pneumonia, the age of the subject, and their overall health status. Options include (i) antibiotics, (ii) cough medicines, and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, an additional therapeutic agent is a bromhexine anti-cough agent.

[0668] In some embodiments, the compound disclosed herein is used in combination with immunoglobulin from a cured COVID-19 subject. In some embodiments, the compound disclosed herein is used in combination with plasma transfusion. In some embodiments, the compound disclosed herein is used in combination with stem cells.

[0669] In some embodiments, additional therapeutic agents are TLR agonists. Examples of TLR agonists include, but are not limited to, besatolimod (GS-9620), GS-986, IR-103, repitolimod, 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, telatolimod, and RO-7020531.

[0670] In some embodiments, additional therapeutic agents are selected from the group consisting of bortezamide, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindol, clevidipine, atorvastatin, sinorazepam, clofazimine, fosaprepitant, and combinations thereof.

[0671] In some embodiments, additional therapeutic agents are carimycin, suramin, triazavirin, dipyridamol, bevacizumab, meplazumab, GD31 (ryzobium), NLRP inflammasome inhibitors, or α-ketoamines. In some embodiments, additional therapeutic agents are recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, additional therapeutic agents are viral macrophage inflammatory proteins (vMIP).

[0672] In some embodiments, the additional therapeutic agent is an anti-biroforin 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. Additional examples of additional therapeutic agents include those described in International Publications WO 2004112687, WO 2006135978, WO 2018145148, and WO 2009018609.

[0673] Additionally, any compound of the present invention may be combined with one or more additional active therapeutic agents in a single-dose form for simultaneous or sequential administration to a target. The combination therapy may be administered as simultaneous or sequential therapy. When administered sequentially, the combination may be administered in two or more doses.

[0674] The combined administration of the compound of the present invention and one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound of the present invention and one or more other active therapeutic agents such that both therapeutically effective amounts of the compound of the present invention and one or more other active therapeutic agents are present in the body of the subject.

[0675] Concomitant administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours after administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention may be administered within seconds or minutes after a unit dose of one or more other active therapeutic agents has been administered first. Alternatively, a unit dose of the compound of the present invention may be administered within seconds or minutes after a unit dose of one or more other therapeutic agents has been administered first. In some cases, it may be preferable to administer a unit dose of one or more other active therapeutic agents after a period of several hours (e.g., 1 to 12 hours) after administering a unit dose of the compound of the present invention first. In other cases, it may be preferable to administer a unit dose of the compound of the present invention after a period of several hours (e.g., 1 to 12 hours) after administering a unit dose of one or more other active therapeutic agents first.

[0676] Combination therapy can provide "synergy" and "synergistic effects," that is, the effect achieved when active ingredients are used together is greater than the sum of the effects obtained by using the compounds individually. Synergistic effects can be achieved when active ingredients are (1) co-formulated into a combination product and administered or delivered simultaneously; (2) delivered alternately or in parallel as separate products; or (3) by any other scheme. In the case of alternating therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, as separate tablets, pills, or capsules, or by different injections using separate syringes. Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., continuously, whereas in combination therapy, the effective dose of two or more active ingredients is administered together. Synergistic antiviral effects indicate that the antiviral effect is greater than the merely additive effect expected for the individual compounds of the combination product.

[0677] A. Pneumoviridae Combination therapy for the treatment of viral infections

[0678] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of pneumoviral virus infections specifically discussed in Section VIII.A. In some embodiments, the other active therapeutic agent is active against pneumoviral virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. As more fully described herein, the compounds of the present invention may be administered to a subject (e.g., human) infected with RSV in combination with one or more additional therapeutic agents. Additionally, in certain embodiments, when used to treat or prevent RSV, the compound of the present invention may be administered together with one or more additional therapeutic agents selected from the group consisting of (e.g., one, two, three, four, or more): RSV complex, RSV vaccine, RSV RNA polymerase inhibitor, immunomodulator, Toll-like receptor (TLR) modulator, interferon alpha receptor ligand, hyaluronidase inhibitor, respiratory fusion surface antigen inhibitor, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitor, cyclophylline inhibitor, RSV viral invasion inhibitor, antisense oligonucleotide targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulator, ribonucleotide reductase inhibitor, farnesoid X receptor agonist, RSV antibody, CCR2 chemokine antagonist, thymosin agonist, cytokine, nucleoprotein modulator, Retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, RSV replication inhibitors, arginase inhibitors, and other RSV drugs.

[0679] Non-limiting examples of these other active therapeutics 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 therapeutics, and combinations thereof. Non-limiting examples of active monoclonal antibodies and nanobody therapeutics include palivizumab, RSV-IGIV (RESPIGAM ® Includes ), MEDI-557 (motavizumab), MEDI8897 (nirsevimab), MK-1654, ALX-0171, A-60444 (aka 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, e.g., MDT-637, BMS-433771, AK-0529, RV-521 (cisunatovir), 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; lumistabine) and ALS-8112 (a variant of lumistabine); and viral replication inhibitors, such as EDP-938 and nitazoxanide; siRNA-based therapeutics, such as ALN-RSV01; and combinations thereof are included.

[0680] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI Delta M2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccines.

[0681] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include: sialydase modulators, e.g., DAS-181; RNA polymerase inhibitors, e.g., ALS-8112; and antibodies for the treatment of metapneumovirus infection, e.g., EV-046113.

[0682] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0683] B. Combination therapy for the treatment of picornavirus and viral infections

[0684] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of picornaviridae viral infections specifically discussed in Section VIII.B. In some embodiments, other active therapeutic agents are active against picornaviridae viral infections, particularly enterovirus infections. Non-limiting examples of these other active therapeutic agents are as follows: capsid binding inhibitors, e.g., pleconaryl, BTA-798 (bafendavir), and other compounds disclosed in U.S. Patent No. 7,078,403 (Wu, et al.) and U.S. Patent No. 7,166,604 (Watson); fusion sialydase proteins, e.g., DAS-181; capsid protein VP1 inhibitors, e.g., VVX-003 and AZN-001; viral protease inhibitors, e.g., CW-33; Phosphatidylinositol 4-kinase beta inhibitors, e.g., GSK-480 and GSK-533; anti-EV71 antibodies.

[0685] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of picornavirus and viral infections, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccine.

[0686] C. Combination therapy for the treatment of respiratory infections

[0687] The compounds disclosed herein and their pharmaceutically acceptable salts may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents specifically discussed in Section VIII.C. Most pneumoviral and picornaviral viral infections are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infection may be used in combination with the compounds provided herein. Additional agents may be administered orally or by direct inhalation. For example, other additional therapeutic agents used in combination with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0688] Glucocorticoids

[0689] Glucocorticoids, first introduced in 1950 as a treatment for asthma (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 undesirable and serious side effects, such as 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. Inhaled corticosteroids (ICS) have been developed to mitigate the serious adverse effects of oral steroids. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein include dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluorocortin-21-butylate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, and ciclesonide; Or these are pharmaceutically acceptable salts.

[0690] anti-inflammatory drugs

[0691] Other anti-inflammatory agents acting via anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents to be used in combination with the compounds provided herein for the treatment of viral respiratory infections. Applying "anti-inflammatory signaling modulators" (referred to herein as AISTM), such as phosphodiesterase inhibitors (e.g., specific to PDE-4, PDE-5, or PDE-7), transcription factor inhibitors (e.g., blockade of NFκB via IKK inhibition), or kinase inhibitors (e.g., blockade of P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to switching off inflammation because these small molecules target a limited number of common intracellular pathways—signaling pathways that are critical points for anti-inflammatory therapeutic interventions (see review by [PJ Barnes, 2006]).These non-limiting additional therapeutic agents include the following: 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-pyridine-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast); 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840); N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor oglemilast); N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indole-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid(3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazole-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenyl-propyl)-5-pyridine-4-yl-1H-imidazole-2-yl]-but-3-in-1-ol (P38 inhibitor RWJ-67657); 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of silomilast, PDE-4 inhibitor); (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholine-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor); and 4-(4-methyl-piperazine-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-yl-pyrimidine-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor).

[0692] β2-adrenergic receptor agonist bronchodilator

[0693] A combination of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol, albuterol, or salmeterol, together with the compounds provided in this specification is also suitable for use in the treatment of respiratory viral infections, but is not limited thereto.

[0694] Inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, and combinations of ICS are also used to treat both bronchoconstriction and inflammation (SYMBICORT® and ADVAIR®, respectively). Combinations comprising these ICS and β2-adrenergic receptor agonist combinations together with the compounds provided herein are also suitable for, but are not limited to, combinations useful for the treatment of respiratory viral infections.

[0695] Other examples of beta 2 adrenergic receptor agonists include, but are not limited to, vedoradrin, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, avedaterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0696] anticholinergics

[0697] For the treatment and prevention of pulmonary bronchoconstriction, anticholinergic agents may be potentially used 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, but are not limited to, the following: antagonists of muscarinic receptors (particularly those of the M3 subtype) that have shown therapeutic efficacy in humans in the modulation of cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidine-4-ylmethyl)-amide; 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate); 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin); 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (levattropate); 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 (buzeped); 7-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(oxytropium-N,N-diethylglycinate); 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophene-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(tiotropium-N,N-diethylglycinate); dimethylamino-acetic 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]oct-3-yl)-1-phenyl-prop-2-in-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophene-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (aclidinium-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-di-thiophene-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidine-4-yl ester; Lebefenacin, glycopyronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, and benzylochidium bromide.

[0698] mucolytic

[0699] The compounds provided herein may also be combined with mucolytics to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic is ambroxol. Similarly, the compounds may be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0700] Nebulized hypertonic saline is used to improve immediate and long-term clearance of small airways in patients with lung disease (Literature [Kuzik, J. Pediatrics[2007, 266]). Accordingly, the compounds provided herein may also be combined with nebulized hypertonic saline, particularly when a viral infection is exacerbated by bronchiolitis. The combination of the compounds provided herein and hypertonic saline may also include any additional formulations discussed above. In some embodiments, 3% hypertonic saline is used.

[0701] D. Combination therapy for the treatment of COPD

[0702] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of respiratory exacerbations of COPD specifically discussed in Section VIII.D. In some embodiments, other active therapeutic agents include other active therapeutic agents for COPD. Non-limiting examples of these other active therapeutic agents include the following: anti-IL5 antibodies, e.g., benralizumab, mepolizumab; dipeptidyl peptidase I (DPP1) inhibitors, e.g., AZD-7986 (INS-1007); DNA gyrase inhibitors / topoisomerase IV inhibitors, e.g., ciprofloxacin hydrochloride; MDR-associated protein 4 / phosphodiesterase (PDE) 3 and 4 inhibitors, e.g., RPL-554; CFTR stimulants, e.g., ivacaptor, QBW-251; MMP-9 / MMP-12 inhibitors, e.g., RBx-10017609; adenosine A1 receptor antagonists, e.g., PBF-680; GATA 3 transcription factor inhibitors, e.g., SB-010; muscarinic receptor modulators / nicotinic acetylcholine receptor agonists, e.g., ASM-024; MARCKS protein inhibitors, e.g., BIO-11006; kit tyrosine kinase / PDGF inhibitors, e.g., macitinib; phosphodiesterase (PDE) 4 inhibitors, e.g., roflumilast, CHF-6001; phosphoinositide-3 kinase delta inhibitors, e.g., nemiralisib; 5-lipoxygenase inhibitors, e.g., TA-270; muscarinic receptor antagonists / beta 2 adrenergic receptor agonists, e.g., vatepenterol succinate, AZD-887, ipratropium bromide; TRN-157; elastase inhibitor, e.g., erdosteine; metalloprotease-12 inhibitor, e.g., FP-025; interleukin-18 ligand inhibitor, e.g., tadekinig alfa; skeletal muscle troponin activator, e.g., CK-2127107; p38 MAP kinase inhibitor, e.g., acumapimod;IL-17 receptor modulators, e.g., CNTO-6785; CXCR2 chemokine antagonists, e.g., danilixin; leukocyte elastase inhibitors, e.g., POL-6014; epoxide hydrolase inhibitors, e.g., GSK-2256294; HNE inhibitors, e.g., CHF-6333; VIP agonists, e.g., aviftadil; phosphoinositide-3 kinase delta / gamma inhibitors, e.g., RV-1729; complement C3 inhibitors, e.g., APL-1; and G-protein coupled receptor-44 antagonists, e.g., AM-211.;

[0703] Other non-limiting examples of active therapeutic agents also include, but are not limited to, budesonide, adipocel, nitric oxide, PUR-1800, YLP-001, LT-4001, azithromycin, Gamunex, QBKPN, sodium pyruvate, MUL-1867, mannitol, MV-130, MEDI-3506, BI-443651, VR-096, OPK-0018, TEV-48107, doxophylline, TEV-46017, oligo-G-COPD-5 / 20, STEMPEUCEL®, ZP-051, and lysine acetylsalicylate.

[0704] In some embodiments, other active therapeutic agents may be vaccines active against COPD, including but not limited to MV-130 and GSK-2838497A.

[0705] E. Flaviviruses and combination therapy for the treatment of viral infections

[0706] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of flaviviral and viral infections specifically discussed in Section VIII.E. In some embodiments, the other active therapeutic agent is active against flaviviral and viral infections.

[0707] Non-limiting examples of other active therapeutic agents for the treatment of flaviviral and viral infections are as follows: host cell factor modulators, e.g. GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1 inhibitors, e.g. selgocivir; platelet-activating factor receptor (PAFR) antagonists, e.g. modipafant; cadherin-5 / factor Ia modulators, e.g. FX-06; NS4B inhibitors, e.g. JNJ-8359; viral RNA splicing modulators, e.g. ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0708] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of dengue, including but not limited to TETRAVAX-DV, DENGVAXIA®, DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue fever vaccine, quadrivalent DNA vaccine, rDEN2 delta30-7169; and DENV-1 PIV.

[0709] F. Combination therapy for the treatment of filovirus and viral infections

[0710] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of filoviral and viral infections specifically discussed in Section VIII.F. In some embodiments, other active therapeutic agents are active against filoviral and viral infections (e.g., Marburg virus, Ebola virus, Sudan virus, cueva virus infections). Non-limiting examples of these other active therapeutic agents include: MR186-YTE, remdesivir, ribavirin, palivizumab, motaviizumab, 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]pyrimidine-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 Monophosphate, T-705 Diphosphate, T-705 Triphosphate, FGI-106 (1-N,7-N-Bis[3-(dimethylamino)propyl]-3,9-Dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors, e.g., galidesivir, favipiravir (aka, T-705 or Avigan), JK-05; host cell factor modulators, e.g., GMV-006; cadherin-5 / factor Ia modulators, e.g., FX-06; and antibodies for the treatment of Ebola, e.g., INMAZEB (atoltivimab, maftivimab, and odesivimab), ZMapp, and mAb114 (EBANGA).

[0711] 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 grabbing 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).

[0712] In some embodiments, other active therapeutic agents may be vaccines for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo + Ad26-ZEBOV scheme, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combination 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.

[0713] The compounds provided herein may 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.

[0714] The compounds provided herein are also intended for use in conjunction with general care provided to subjects having filoviral and viral infections, such general care being parenteral fluids (including dextrose saline and Ringer's lactate) and nutritional supplements, antibiotics (including metronidazole and cephalosporin antibiotics, e.g., ceftriaxone and cefuroxim) and / or antifungal prophylactics, fever and pain medications, antiemetics (e.g., metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (e.g., ibuprofen), pain medications, and medications for other common diseases in the subject population, e.g., antimalarial agents (including artemeter and artesunate-lumefantrine combination therapy), and typoids (quinolone antibiotics, e.g., ciprofloxacin; macrolide antibiotics, e.g., azithromycin; cephalosporin antibiotics, e.g., ceftriaxone, or includes aminopenicillin, e.g. ampicillin) or sigelosis.

[0715] G. Combination therapy for influenza treatment

[0716] The compounds disclosed herein and pharmaceutically acceptable salts thereof may be used in combination with any active therapeutic agent discussed in Section VIII of this specification and / or other active therapeutic agents for the treatment of influenza virus infection specifically discussed in Section VIII.G. In some embodiments, the compounds provided herein are also used in combination with other active therapeutic agents for the treatment of influenza virus infection. The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In some embodiments, the compounds provided herein may also be combined with influenza therapeutic agents. In some embodiments, the compounds provided herein are used with influenza therapeutic agents when treating influenza virus. In some embodiments, the compounds provided herein are used with influenza therapeutic agents to treat a broader range 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 treatments 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, KYAH01-2019-121, raninamivir, 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 complex, ZSP-1273 and ZX-7101A Includes, but is not limited to.

[0717] IX. Compound preparation

[0718] In some embodiments, the present invention provides a method and an intermediate useful for preparing the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0719] The compounds disclosed herein may be purified by any means known in the art, including but not limited to chromatographic means such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, including but not limited to normal phases and reverse phases as well as ionic resins, may be used. In some embodiments, the disclosed compounds are purified via silica gel and / or alumina chromatography.

[0720] In any method of preparing the compounds provided herein, it may be necessary and / or desirable to protect the sensitive or reactive groups of any relevant molecule. This is based on standard references, e.g., literature [TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 4 th This can be achieved by a conventional protector as described in [ed., Wiley, New York 2006]. The protector can be removed at a convenient subsequent step using methods known in the art.

[0721] Exemplary chemical substances useful for the methods of the embodiments will now be described herein with reference to exemplary synthetic reaction schemes for their general production and the specific examples below. Those skilled in the art will recognize that, in order to obtain the various compounds of this specification, the desired product can be obtained by appropriately selecting starting materials such that the ultimately desired substituent is transferred through the reaction scheme, either protected or unprotected as needed. Alternatively, instead of the ultimately desired substituent, it may be necessary or desirable to use a suitable group that can be transferred through the reaction scheme and substituted with the desired substituent as needed. Furthermore, those skilled in the art will recognize that the transformations shown in the reaction scheme below can be carried out in any order suitable for the functionality of the specific pendant group.

[0722] The method of the present invention generally provides a specific enantiomer or diastereomer as a desired product, but the stereochemistry of the enantiomer or diastereomer is not determined in all cases. Where the stereochemistry of a specific stereocenter in the enantiomer or diastereomer is not determined, even if the compound may be substantially enantiomerically or diastereomerically pure, the compound is drawn without exhibiting any stereochemistry at that specific stereocenter.

[0723] Representative synthesis of the compounds of the present invention is described in the following reaction scheme and the following specific examples.

[0724] Reaction Schema 1

[0725]

[0726] Reaction Schematic 1 is alcohol S1a1 under basic conditions (e.g., KO t Epoxide having PG (e.g., Tr, TBDPS) under Bu or NaH S1b1 Add to alcohol S1cIt shows the general synthesis of a compound starting with obtaining. Alternatively, alcohol S1b2 alkyl halides under basic conditions (e.g., NaH). S1a2 After addition to (e.g., Br), remove acetonide under acidic conditions (e.g., HCl) and protect the primary alcohol under basic conditions (e.g., TBDPSCl, TEA), S1c Obtains. Basic conditions (e.g., KO t Halogenates under Bu or NaH S1d Reacts with a substitution reaction with (e.g., Br) and removes PG (e.g., HCl or TBAF) to produce an alcohol S1e Obtains alcohol S1e and nucleosides S1f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S1g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S1h The final compounds of (e.g., compounds 1, 3 to 10, 12 to 20, 22, 53, 55, 61, 63, 66, 67, 68, 73 and 75 of Table 1) are obtained.

[0727] Reaction Schema 2

[0728]

[0729] Reaction Schematic 2 is an alkyl Grignard S2a epoxide having PG (e.g., Tr, TBDPS) S2b Add to alcohol S2c Shows the general synthesis of a compound starting with obtaining. Basic conditions (e.g., KO t Halogenates under Bu) S2dReacts with a substitution reaction with (e.g., Br) and removes PG (e.g., HCl or TBAF) to produce an alcohol S2e Obtains alcohol S2e and nucleosides S2f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S2g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S2h The final compounds of (e.g., compounds 2, 11, 25 to 37, 56, 62, 70, 74 and 76 of Table 1) are obtained.

[0730] Reaction Schema 3

[0731]

[0732] Reaction Schematic 3 is alcohol S3a under basic conditions (e.g., KO t Epoxide having PG (e.g., Tr, TBDPS) under Bu) S3b Add to alcohol S3c Shows the general synthesis of a compound starting with obtaining. Basic conditions (e.g., KO t Halides under Bu) or Ullmann CO bonds (e.g., CuI, Cs2CO3, Me4Phen) S3d After a substitution reaction with (e.g., Br), PG (e.g., HCl or TBAF) is removed to obtain an alcohol S3e Obtains alcohol S3e and nucleosides S3f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine), S3gObtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S3h The final compounds of (e.g., compounds 21, 23, 24, 50, 59, 69, 71, 72, and 77 of Table 1) are obtained.

[0733] Reaction Schema 4

[0734]

[0735] Reaction Schematic 4 is an alkyl Grignard S4a1 under basic conditions (e.g., KO t Epoxide having PG (e.g., Tr, TBDPS) under Bu) S4b1 Add to alcohol S4c It shows the general synthesis of a compound starting with obtaining. Alternatively, terminal alkene S4a2 (Here, CR 4 R 5 After dihydroxylation of a group (not connected via a double bond), the alcohol is formed through the protection of a primary alcohol (e.g., TrCl or TBDPSCl). S4c Obtains. Basic conditions (e.g., KO t Halides under Bu) or Ullmann CO bonds (e.g., CuI, Cs2CO3, Me4Phen) S4d After a substitution reaction with (e.g., Br), PG (e.g., HCl or TBAF) is removed to obtain an alcohol S4e Obtains alcohol S4e and nucleosides S4f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S4g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S4hThe final compounds (e.g., compounds 38 to 40, 51 and 60 of Table 1) are obtained.

[0736] Reaction Schema 5

[0737]

[0738] Reaction Schematic 5 shows the reaction of alcohol under basic conditions (e.g., NaH). S5a halides of S5b Substitution reaction of , followed by cleavage of acetonide under acidic conditions (e.g., HCl) and protection of the alcohol (e.g., TBDPSCl) to form the alcohol S5c It shows the general synthesis of a compound starting with obtaining . alkyl halides under basic conditions (e.g., NaH). S5d After a substitution reaction with (e.g., Br), the protecting group (e.g., TBAF) is removed to form an alcohol S5e Obtains alcohol S5e and nucleosides S5f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S5g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S5h The final compounds (e.g., compounds 41 and 42 in Table 1) are obtained.

[0739] Reaction Schema 6

[0740]

[0741] Reaction Schematic 6 shows the reaction of alcohol under basic conditions (e.g., NaH) or Ullmann CO coupling (e.g., CuI, Cs2CO3, Me4Phen). S6a halides of S6bSubstitution reaction with (e.g., Br), followed by cleavage of the acetonide under acidic conditions (e.g., HCl) and protection of the alcohol (e.g., TBDPSCl) to form the alcohol S6c It shows the general synthesis of a compound starting with obtaining . alkyl halides under basic conditions (e.g., NaH). S6d After a substitution reaction with (e.g., Br), the protecting group (e.g., TBAF) is removed to form an alcohol S6e Obtains alcohol S6e and nucleosides S6f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S6g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S6h The final compounds (e.g., compounds 43 and 65 in Table 1) are obtained.

[0742] Reaction Schema 7

[0743]

[0744] Reaction Schematic 7 shows the reaction of alcohol under basic conditions (e.g., NaH). S7a alkyl halides S7b Substitution reaction of , followed by cleavage of acetonide under acidic conditions (e.g., HCl) and protection of the alcohol (e.g., TBDPSCl) to form the alcohol S7c It shows the general synthesis of compounds starting with obtaining . halides under basic conditions (e.g., NaH) or Ullmann CO bonds (e.g., CuI, Cs2CO3, Me4Phen). S7d After a substitution reaction with (e.g., Br), the protecting group (e.g., TBAF) is removed to form an alcohol S7e Obtains alcohol S7e and nucleosides S7fBy coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S7g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S7h The final compound (e.g., compound 44 in Table 1) is obtained.

[0745] Reaction Schema 8

[0746]

[0747] Reaction diagram 8 is an alcohol (e.g., S1e or S2e Tosylation of ), followed by substitution with sodium azide and treatment with triphenylphosphine, amine S8a It shows the general synthesis of a compound starting with obtaining amine S8a and nucleosides S8b By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S8c Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S8d The final compounds (e.g., compounds 45 and 46 in Table 1) are obtained.

[0748] Reaction Schema 9

[0749]

[0750] Reaction Schema 9 is amine S8a Sulfonylation of (e.g., X = O or CH2) (e.g., 2-nitrobenzenesulfonyl chloride), followed by the Mitsunobu reaction (e.g., MeOH, PPh3, DEAD) and desulfonylation (e.g., PhSH), amines S9aIt shows the general synthesis of a compound starting with obtaining amine S9a and nucleosides S9b By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S9c Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S9d The final compounds (e.g., compounds 57 and 58 in Table 1) are obtained.

[0751] Reaction Schema 10

[0752]

[0753] Reaction Schema 10 is Grignard S10a and S10b (e.g., through the coupling of [1,1-bis(diphenylphosphino)ferrocene]dichloronickel(II)) S10c Shows the general synthesis of a compound starting with obtaining . aryl halide S10c Metallization of (e.g., Mg; CuI) and epoxide having PG (e.g., Tr, TBDPS) S10d By adding to, alcohol S10e Obtains. Basic conditions (e.g., KO t Halogenates under Bu) S10f Reacts with a substitution reaction with (e.g., Br) and removes PG (e.g., HCl or TBAF) to produce an alcohol S10g Obtains alcohol S10g and nucleosides S10h By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S10i Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S10jThe final compound (e.g., compound 54 in Table 1) is obtained.

[0754] Reaction Schema 11

[0755]

[0756] Reaction Schema 11 is a primary alcohol S11a Through protection of (e.g., TrCl), S11b It shows the general synthesis of a compound starting with obtaining. Then, S11b Grignard using a metal catalyst (e.g., [1,1-bis(diphenylphosphino)ferrocene]-dichloronickel(II)) S11c By cross-coupling, S11d Obtains. Basic conditions (e.g., KO t Halogenates under Bu) S11e It undergoes a substitution reaction with (e.g., Br) and removes the protecting group under acidic conditions (e.g., HCl) to form an alcohol S11f Obtains alcohol S11f and nucleosides S11g By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S11h Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S11i The final compound (e.g., compound 47 in Table 1) is obtained.

[0757] Reaction Schema 12

[0758]

[0759] Reaction diagram 12 is alcohol S12b under acidic conditions (e.g., TsOH, MgSO4, Servi, S. J. Org. Chem. 1985 , 50 , 5865) under S12a Add to alcohol S12cIt shows the general synthesis of a compound starting with obtaining [the compound]. Under acidic conditions (e.g., TsOH) S12d alcohols formed by substitution reactions with and reduction of esters (e.g., LiAlH4). S12e Obtains alcohol S12e and nucleosides S12f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S12g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S12h The final compound (e.g., compound 64 in Table 1) is obtained.

[0760] Reaction Schema 13

[0761]

[0762] Reaction Schema 13 is alcohol S13a Through allylation of, followed by dihydroxylation (e.g., OsO4, NMNO) and cleavage of the vicinal diol (e.g., NaIO4), aldehyde S13b This shows the general synthesis of compounds starting with obtaining a Grignard reagent, by adding the reagent to an aldehyde to obtain a secondary alcohol, deoxygenating (e.g., Br2PPh3, Bu3SnH, AIBN, Bu4NF), and then removing a protecting group (e.g., TBAF). S13c Obtains alcohol S13c and nucleosides S13d By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S13e Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S13fObtain the final compound (e.g., compound 48 or compound 49 of Table 1).

[0763] Reaction Schema 14

[0764]

[0765] Reaction Schematic 14 shows malonate under basic conditions (e.g., NaH). S14b alkyl halides S14a Through a substitution reaction of , followed by the reduction of an ester (e.g., LiAlH4), S14c It shows the general synthesis of a compound starting with obtaining. Alcohol under basic conditions (e.g., NaH) S14c and alkyl halides (e.g., Br) S14d By a substitution reaction, S14e ...is obtained (Reference [Subba Reddy et al., Eur. J. Org. Chem 2013, 10, 1993-1999]). Alcohol S14e and nucleosides S14f By coupling to 2-Cl-phenylphosphorodichloridate under basic conditions (e.g., 1,2,4-triazole, TEA, NMI, CH3CN, pyridine, or THF), S14g Obtain. By removing 2-Cl-phenol (e.g., CsF, DMAP) and acetonide (e.g., HCl), type S14h The final compound (e.g., compound 52 in Table 1) is obtained.

[0766] Reaction Schema 15

[0767]

[0768] Reaction Schematic 15 illustrates the general synthesis of a compound starting with the cleavage of acetonide under acidic conditions (e.g., HCl) and leading to the esterification of 2'- and 3'-ribose alcohols and anhydrous reagents under basic conditions (e.g., DMAP). By removing 2-Cl-phenol (e.g., CsF, DMAP), type S15b The final compound is obtained.

[0769] Examples

[0770] A. abbreviation

[0771] Specific abbreviations and acronyms are used to describe experimental details. While most of these will be understood by those skilled in the art, Table 41 contains a list of many of these abbreviations and acronyms.

[0772] [Table 41]

[0773]

[0774] B. intermediate

[0775] Intermediate I-1: (S)-1-O-trityl-3-(heptadecyloxy)propane-1,2-diol

[0776]

[0777] Potassium tert-butoxide (18.7 mmol) and hexadecanol (8.42 mmol) were added to a solution of (S)-O-trityloxiran-2-ylmethanol (4.68 mmol) in DMF (40 mL). The resulting mixture was stirred at 100°C for 2 hours, cooled to room temperature, diluted with ether (300 mL), washed with brine (100 mL × 2), dried with sodium sulfate, and purified by silica gel column chromatography (0% to 20% EtOAc in hexane), Intermediate I-1 I obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.10 (m, 15H), 4.86 (d, J= 5.4 Hz, 1H), 3.76 (q, J = 5.4 Hz, 1H), 3.38 (m, 2H), 3.33 (s, 2H), 2.95 (m, 2H), 1.41 (m, 2H), 1.22 (d, J = 11.2 Hz, 28H), 0.89 - 0.79 (m, 3H).

[0778] Intermediate I-2: (R)-3-fluoro-5-(((1-(heptadecyloxy)-3-(trityloxy)propane-2-yl)oxy)methyl)benzonitrile

[0779]

[0780] in THF (8 mL) Intermediate I-1 Potassium tert-butoxide (3.04 mL, 1.0 M, 3.04 mmol) was added to a solution of (1.52 mmol). The mixture was stirred for 20 minutes, and 3-(bromomethyl)-5-fluorobenzonitrile (3.04 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours, diluted with water (50 mL), and extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine (50 mL), dried with Na2SO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0% to 10% EtOAc in hexane). Intermediate I-2 I obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.9 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.43 ― 7.16 (m, 15H), 4.68 (s, 2H), 3.77 ― 3.66 (m, 1H), 3.50 (m, 2H), 3.32 (m, 2H, hidden by solvent peak), 3.15 (dd, J = 10.1, 3.8 Hz, 1H), 3.07 (dd, J = 10.1, 5.7 Hz, 1H), 1.42 (s, 2H), 1.34 - 1.00 (m, 28H), 0.85 (t, J = 6.6 Hz, 3H).

[0781] Intermediate I-3: (S)-3-fluoro-5-(((1-(heptadecyloxy)-3-hydroxypropane-2-yl)oxy)methyl)benzonitrile

[0782]

[0783] in THF-iPrOH-MeOH (1.4:1.4:1.4 mL) Intermediate I-2 25% HCl (0.7 mL) was added to a (1.42 mmol) solution. The resulting mixture was heated to 65°C for 45 minutes, cooled, and saturated NaHCO3 (10 mL) was added. After stirring for 5 minutes, the mixture was extracted with EtOAc (100 mL × 2). The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layer was dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 40% EtOAc in hexane), Intermediate I-3 I obtained. 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.61 (s, 1H), 7.50 (dd, J = 9.6, 2.4 Hz, 1H), 7.44 (dt, J = 8.5, 1.8 Hz, 1H), 4.73 (s, 2H), 3.68 - 3.50 (m, 5H), 3.43 (m, 2H), 2.84 (t, J = 5.7 Hz, 1H), 1.55 (m, 2H), 1.39 - 1.21(m, 28H), 0.91 (t, J = 6.7 Hz, 3H).

[0784] Intermediate I-3a1: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile

[0785]

[0786] Intermediate I-3a1 was prepared according to WO2015 / 069939. For example, pages 127 to 138 of International Patent Publication WO2015 / 069939 provide a method for preparing this compound (identified as compound 14k in International Patent Publication WO2015 / 069939).

[0787] Intermediate I-3a: (3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-carbonitrile

[0788]

[0789] Intermediate I-3a1 (18.87 mmol) was dissolved in THF (100 mL). 1.0 M TBAF (28.31 mmol) in THF was added all at once at ambient temperature. The mixture was stirred for 10 minutes at ambient temperature. The reaction was determined to be complete by LCMS. The reaction mixture was quenched with water, and the organic matter was removed under reduced pressure. The crude material was partitioned into EtOAc and water. The layers were separated, and the aqueous layer was washed with EtOAc. The organic matter was combined and dried with sodium sulfate. The solid was filtered, and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography (120 g column, 0% to 10% CH3OH in CH2Cl2), intermediate I-3a Obtains. LC / MS: t 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 containing 0.1% formic acid, water containing 0.1% formic acid. Gradient: 0 min to 2.4 min: 2 to 100% ACN, 2.4 min to 2.80 min: 100% ACN, 2.8 min to 2.85 min: 100% to 2% ACN, 2.85 min to 3.0 min: 2% ACN (Flow rate: 1.8 mL / min). 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.87-7.80 (m, 3H), 6.85 (d, J = 4.5 Hz, 1H), 6.82 (d, J = 4.5 Hz, 1H), 5.74 (t, J = 5.8 Hz, 1H), 5.52 (d, J = 4.2 Hz, 1H), 5.24 (dd, J= 6.8, 4.2 Hz, 1H), 4.92 (d, J = 6.8 Hz, 1H), 3.65 (dd, J = 6.1, 1.7 Hz, 2H), 1.61 (s, 3H), 1.33 (s, 3H).

[0790] Intermediate I-4: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(heptadecyloxy)propyl) phosphate

[0791]

[0792] 1 in ACN (0.5 mL)-pyridine (0.2 mL) at room temperature H 2-chlorophenylphosphorodichloridate (0.065 mL, 0.392 mmol) was added to a solution of -1,2,4-triazole (0.844 mmol) and TEA (0.118 mL, 0.844 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and Intermediate I-3a (0.392 mmol), followed by the addition of 1-methylimidazole (0.0631 mL, 0.792 mmol). The resulting mixture was stirred at room temperature for 1 hour, and Intermediate I-3 (0.430 mmol) was added. The resulting reaction mixture was stirred for 2 hours and 30 minutes, concentrated under vacuum, and purified by silica gel column chromatography (0% to 100% MeOH in DCM), Intermediate I-4 I obtained. 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.86 (d, J= 3.5 Hz, 1H), 7.54 - 7.29 (m, 5H), 7.26 - 7.05 (m, 2H), 6.83 - 6.63 (m, 2H), 6.26 (s, 2H), 5.67 (m, 1H), 5.34 - 5.22 (m, 1H), 5.14 - 5.06 (m, 1H), 4.67 - 4.42 (m, 4H), 4.41 - 4.28 (m, 1H), 4.27 - 4.16 (m, 1H), 3.75 (m, 1H), 3.53 - 3.42 (m, 2H), 3.42 - 3.28 (m, 2H), 1.72 (s, 3H), 1.58 - 1.44 (m, 2H), 1.38 (s, 3H), 1.35 - 1.17 (m, 28H), 0.90 (m, 3H). 19 F NMR (376 MHz, acetonitrile-d3) δ -112.78, -112,79. 31 P NMR (162 MHz, acetonitrile-d3) δ -7.31, -7.36. MS m / z [M+1] = 967.

[0793] Intermediate I-5: (R)-3-((1-(octadecyloxy)-3-(tritiloxy)propane-2-yl)oxy)benzonitrile

[0794]

[0795] in DMF (10 mL) at room temperature Intermediate I-128 NaH (60% of the mineral oil) was added to a solution of (1.14 mmol). The mixture was stirred at room temperature for 1 hour, and 3-fluorobenzonitrile (115 mg, 0.950 mmol) was added. Then, the resulting mixture was heated to 60°C for 30 minutes, diluted with EtOAc (100 mL), and water (10 mL) was added to quench the reaction product. The organic phase was dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 10% EtOAc in hexane), Intermediate I-5 I obtained. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 8.9 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.43 - 7.16 (m, 16H), 4.68 (s, 2H), 3.77 - 3.66 (m, 1H), 3.56 - 3.43, (m, 2H), 3.15 (dd, J = 10.1, 3.8 Hz, 1H), 3.07 (dd, J = 10.1, 5.7 Hz, 1H), 1.42 (s, 2H), 1.34 - 1.00 (m, 30H), 0.85 (t, J = 6.6 Hz, 3H).

[0796] Intermediate I-6: (S)-3-((1-hydroxy-3-(octadecyloxy)propane-2-yl)oxy)benzonitrile

[0797]

[0798] For example, in the THF-iPrOH-MeOH (1.5:1.5:1.5 mL) prepared as described above Intermediate I-5 25% HCl (0.3 mL) was added to a solution of (0.469 mmol). The resulting mixture was heated to 65°C for 45 minutes, cooled, and saturated NaHCO3 (10 mL) was added. After stirring for 5 minutes, it was extracted with EtOAc (50 mL × 2). The aqueous layer was extracted with EtOAc (20 mL × 2). The combined organic layer was dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 40% EtOAc in hexane), Intermediate I-6 I obtained. 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.48 ― 7.42 (m, 1H), 7.37 (m, 1H), 7.34 ― 7.27 (m, 2H), 4.51 (ddd, J = 10.1, 5.7, 4.3 ㎐, 1H), 3.78 - 3.54 (m, 4H), 3.44 (m, 2H), 2.98 (t, J = 6.1 Hz, 1H), 1.51 (m, 2H), 1.38 - 1.19 (m, 30H), 0.91 (m, 3H).

[0799] Intermediate I-7: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-(3-cyanofenoxy)-3-(octadecyloxy)propyl) phosphate

[0800]

[0801] 1 in THF (2 mL) H TEA (0.139 mL, 1.00 mmol) was added to a solution of -1,2,4-triazole (1.00 mmol), and 2-chlorophenylphosphorodichloridate (0.0807 mL, 0.49 mmol) was added at room temperature and stirred for 30 minutes. To this mixture Intermediate I-3a After adding (0.38 mmol) all at once, 1-methylimidazole (0.0391 mL, 0.49 mmol) was added. After stirring the resulting mixture for 30 minutes, in THF (2 mL) Intermediate I-6 (0.38 mmol) was added dropwise. After stirring at room temperature for 15 hours, the mixture was concentrated under vacuum and purified by silica gel column chromatography (0% to 10% MeOH in DCM), Intermediate I-7 I obtained. 1 ¹H NMR (400 MHz, methanol-d4) δ 7.83 (m, 1H), 7.55–7.05 (m, 8H), 6.83–6.72 (m, 2H), 5.68 (m, 1H), 5.33–5.29 (m, 1H), 5.16 (d, J = 6.6 Hz, 0.5H), 5.11 (d, J = 6.6 Hz, 0.5H), 4.71 ― 4.64 (m, 1H), 4.60 ― 4.37 (m, 4H), 3.63 ― 3.51 (m, 2H), 3.46 ― 3.34 (m, 2H), 1.73 (s, 3H), 1.53 ― 1.42 (m, 2H), 1.38 (s, 3H), 1.34 - 1.17 (m, 30H), 0.89 (t, J = 6.7 Hz, 3H). 31 P NMR (162 MHz, methanol-d4) δ -6.46, -6.48. MS m / z [M+1] = 949.

[0802] Intermediate I-8: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-(3-cyanofenoxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0803]

[0804] Intermediate I-7 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), followed by the addition of CsF (1.55 mmol) in water (0.2 mL) and then DMAP (0.66 mmol). The resulting mixture was heated at 80°C for 3.5 hours. After diluting with PBS buffer pH 7 (10 mL), the mixture was distributed into brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layer was dried under sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 50% MeOH in DCM), Intermediate I-8 I obtained MS m / z [M+1] = 839.

[0805] Intermediate I-9: (R)-2-chloro-4-(((1-(octadecyloxy)-3-(tritiloxy)propane-2-yl)oxy)methyl)benzonitrile

[0806]

[0807] in THF (20 mL) Intermediate I-128 Sodium tert-butoxide powder (5.11 mmol) was added to a solution of (2.56 mmol). The solution was stirred at room temperature for 40 minutes. 4-(bromomethyl)-2-chlorobenzonitrile (5.11 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine (50 mL), dried with Na2SO4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0% to 10% EtOAc in hexane). Intermediate I-9 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.62 (d, J= 8.0 Hz, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.49 - 7.42 (m, 6H), 7.37 - 7.24 (m, 10H), 4.73 (s, 2H), 3.74 (m, 1H), 3.60 (d, J = 5.2 Hz, 2H), 3.44 (t, J = 6.6 Hz, 2H), 3.26 (m, 2H), 1.64 - 1.52 (m, 2H), 1.43 - 1.06 (s, 30H), 0.91 (t, J = 6.7 Hz, 3H).

[0808] Intermediate I-10: (S)-2-chloro-4-(((1-hydroxy-3-(octadecyloxy)propane-2-yl)oxy)methyl)benzonitrile

[0809]

[0810] in THF-iPrOH-MeOH (3:3:3 mL) Intermediate I-9 0.5 mL of 25% HCl was added to a solution of (0.815 mmol). The resulting mixture was heated to 65°C for 45 minutes, cooled, and 10 mL of saturated NaHCO3 was added. After stirring for 5 minutes, it was extracted with EtOAc (40 mL × 3). The combined organic layer was dried with sodium sulfate, concentrated under vacuum, and purified by silica gel chromatography (0% to 40% EtOAc in hexane). Intermediate I-10 I obtained. 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.47 (dd, J = 8.0, 1.4 Hz, 1H), 4.75 (s, 2H), 3.67 - 3.48 (m, 5H), 3.42 (m, 2H), 2.83 (t, J = 5.7 Hz, 1H), 1.54 (m, 2H), 1.40 - 1.22 (m, 30H), 0.96 - 0.86 (m, 3H).

[0811] Intermediate I-11: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl) oxy)-3-(octadecyloxy)propyl) (2-chlorophenyl) phosphate

[0812]

[0813] 1H-1,2,4-triazole (0.664 mmol) was dissolved in THF (2 mL), and TEA (0.09 mL, 0.664 mmol) was added at room temperature. 2-chlorophenyl phosphorodichloridate (0.081 mL, 0.501 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. Intermediate I-3a (0.251 mmol) was added all at once, and the mixture was stirred at room temperature for 15 minutes. To the mixture, in THF (2 mL) Intermediate I-10 (0.275 mmol) was added, and 1-methylimidazole (0.04 mL, 0.506 mmol) was added at room temperature. The resulting mixture was stirred for 1 hour, concentrated under vacuum, and purified with silica gel (0% to 10% MeOH in DCM), Intermediate I-11 I obtained. 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.86 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 6.1 Hz, 1H), 7.48 ― 7.40 (m, 1H), 7.39 ― 7.29 (m, 2H), 7.24 ― 7.12 (m, 2H), 6.80 ― 6.67 (m, 2H), 6.38 (s, 2H), 5.69 - 5.65 (m, 1H), 5.32 - 5.24 (m, 1H), 5.13 - 5.01 (m, 1H), 4.65 (s, 1H), 4.60 (s, 1H), 4.58 - 4.44 (m, 2H), 4.40 - 4.30 (m, 1H), 4.29 - 4.17 (m, 1H), 3.76 (m, 1H), 3.51 - 3.41 (m, 2H), 3.42 - 3.30 (m, 2H), 1.72 (s, 3H), 1.49 (m, 2H), 1.37 (s, 3H), 1.34 - 1.06 (m, 30H), 0.89 (t, J= 6.7 Hz, 3H). 31 P NMR (162 MHz, acetonitrile-d3) δ -7.32, -7.38. MS m / z [M+1] = 997.

[0814] Intermediate I-12: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-chloro-4-cyanobenzyl) oxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0815]

[0816] Intermediate I-11 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), followed by the addition of CsF (1.46 mmol) in water (0.2 mL), and then DMAP (0.621 mmol). The resulting mixture was heated at 80°C for 4 hours. After dilution with citric acid NaOH buffer (pH 4, 10 mL), the mixture was distributed into brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layer was dried under sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 50% MeOH in DCM), Intermediate I-12 I obtained MS m / z [M+1] = 887.

[0817] Intermediate I-14: (R)-docosan-1,2-diol

[0818]

[0819] AD-mix-β (28 g) was dissolved in t-butanol (100 mL) and water (100 mL) and cooled to 0°C. Then, 1-docosen (6.2 g, 20.1 mmol) in THF (100 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 48 hours, and Na2SO3 (30 g) was added. The mixture was extracted with EtOAc (150 mL × 3), the extract was washed with brine (100 mL), dried with sodium sulfate, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (0% to 50% EtOAc in hexane), Intermediate I-14 I obtained. 1 H NMR (400 MHz, DMSO-d6) δ 4.39 (t, J = 5.7 Hz, 1H), 4.31 (d, J = 4.9 Hz, 1H), 3.41 - 3.33 (m, 1H), 3.23 (m, 2H), 1.39 (m, 2H), 1.24 (s, 36H), 0.92 - 0.79 (m, 3H).

[0820] Intermediate I-15: (R)-1-(tritiloxy)docosan-2-ol

[0821]

[0822] Intermediate I-14 (60% purity, 4.3 mmol) was dissolved in DCM (20 mL), and TEA (1.5 mL, 10.8 mmol) was added. The resulting mixture was stirred for 5 minutes, and TrCl (4.30 mmol) in DCM (10 mL) was added dropwise at room temperature. The resulting mixture was stirred for 20 hours, and hexane (20 mL) was added. The solid was filtered, and the filtrate was concentrated under vacuum. , Purified by silica gel column chromatography (0% to 20% EtOAc in hexane), Intermediate I-15 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J = 7.7, 1.8 Hz, 6H), 7.33 (dd, J = 8.4, 6.6 Hz, 6H), 7.29 - 7.23 (m, 2H), 3.78 (m, 1H), 3.20 (dd, J = 9.4, 3.2 Hz, 1H), 3.04 (dd, J = 9.3, 7.6 Hz, 1H), 1.56 (s, 1H), 1.48 - 1.19 (m, 36H), 0.90 (t, J = 6.7 Hz, 3H).

[0823] Intermediate I-16: (R)-3-((1-(triphenyl-l4-oxydanail)docosan-2-yl)oxy)benzonitrile

[0824]

[0825] in DMF (15 mL)-toluene (10 mL) at room temperature Intermediate I-15 NaH (60% of the mineral oil, 2.85 mmol) was added to a solution of (75% purity, 1.71 mmol). The mixture was stirred at room temperature for 1 hour, and 3-fluorobenzonitrile (0.238 mL, 2.22 mmol) was added. Then, the resulting mixture was heated to 60°C for 18 hours, cooled to room temperature, quenched with an NH4Cl solution (20 mL), diluted with EtOAc (200 mL), washed with water (100 mL), dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 10% EtOAc in hexane). Intermediate I-16 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.42 (d, J = 7.4 Hz, 6H), 7.38 - 7.14 (m, 13H), 4.46 - 4.27 (m, 1H), 3.36 (dd, J = 10.2, 6.0 Hz, 1H), 3.26 (dd, J = 10.1, 4.1 Hz, 1H), 1.70 (q, J = 6.9 Hz, 2H), 1.47 - 1.04 (m, 36H), 0.91 (t, J = 6.7 Hz, 3H).

[0826] Intermediate I-17: (R)-3-((1-hydroxydocosan-2-yl)oxy)benzonitrile

[0827]

[0828] in toluene-MeOH (10:6 mL) Intermediate I-1625% HCl (1.0 mL) was added to a (1.71 mmol) solution. The resulting mixture was heated to 65°C for 90 minutes, cooled, and saturated NaHCO3 (50 mL) was added. After stirring for 5 minutes, it was extracted with EtOAc (150 mL × 2). The aqueous layer was extracted with EtOAc (100 mL). The combined organic layer was dried with sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 40% EtOAc in hexane), Intermediate I-17 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.39 (t, J = 7.9 ㎐, 1H), 7.29 - 7.25 (m, 1H), 7.24 - 7.17 (m, 2H), 4.39 (m, 1H), 3.92 - 3.72 (m, 2H), 1.75 - 1.61 (m, 2H), 1.56 (s, 1H), 1.49 - 1.21 (m, 36H), 0.98 - 0.83 (m, 3H).

[0829] Intermediate I-18: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-(3-cyanofenoxy)docosyl) phosphate

[0830]

[0831] 1H-1,2,4-triazole (0.664 mmol) was dissolved in THF (2 mL), and TEA (0.09 mL, 0.664 mmol) was added at room temperature. 2-chlorophenyl phosphorodichloridate (0.081 mL, 0.501 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 30 minutes. Intermediate I-3a (0.251 mmol) was added all at once, and the mixture was stirred at room temperature for 15 minutes. To the mixture, in THF (2 mL) Intermediate I-17 (0.275 mmol) was added, and 1-methylimidazole (0.04 mL, 0.506 mmol) was added at room temperature. The resulting mixture was stirred for 1 hour, concentrated under vacuum, and purified with silica gel (0% to 10% MeOH in DCM), Intermediate I-18 I obtained. 1 H NMR (400 MHz, acetonitrile-d3) δ 7.87 (m, 1H), 7.52 - 7.09 (m, 8H), 6.79 (m, 1H), 6.77 - 6.68 (m, 1H), 6.31 (s, 2H), 5.68 (m, 1H), 5.34 - 5.26 (m, 1H), 5.15 - 5.06 (m, 1H), 4.59 - 4.42 (m, 3H), 4.40 - 4.17 (m, 2H), 1.72 (m, 3H), 1.59 (m, 2H), 1.40 - 1.18 (m, 39H), 0.96 - 0.84 (m, 3H). 31 P NMR (162 MHz, acetonitrile-d3) δ -7.54, -7.60. MS m / z [M+1] = 948.

[0832] Intermediate I-19: ((2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ((R)-2-(3-cyanofenoxy)docosyl) hydrogen phosphate

[0833]

[0834] Intermediate I-18 (0.179 mmol) was dissolved in THF-ACN (2:1 mL), followed by the addition of CsF (1.46 mmol) in water (0.2 mL), and then DMAP (0.621 mmol). The resulting mixture was heated at 80°C for 4 hours. After dilution with citric acid NaOH buffer (pH 4, 10 mL), the mixture was distributed into brine (20 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layer was dried under sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (0% to 50% MeOH in DCM), Intermediate I-19 I obtained MS m / z [M+1] = 837.

[0835] Intermediate I-21: (2R)-1-[tert-butyl(dimethyl)silyl]oxy-3-octadecoxy-propan-2-ol

[0836]

[0837] in dichloromethane (2 mL) at 0℃t A solution of 2-butyldimethylsilyl chloride (2.32 mmol) was added over a period of 1 minute to a solution of (2S)-3-octadecoxypropane-1,2-diol (1.45 mmol) and imidazole (2.90 mmol) in dichloromethane (5 mL). After 2 hours, the ice bath was removed. After 3 hours, the reaction mixture was washed with water (5 mL). The aqueous phase was extracted with dichloromethane (10 mL). The combined organic phase was dried with sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 30% ethyl acetate / hexane). The fractions containing the product were combined, and the solvent was removed under reduced pressure, Intermediate I-21 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 3.83 (p, J = 5.4 Hz, 1H), 3.74–3.62 (m, 2H), 3.50–3.42 (m, 4H), 1.58 (q, J = 7.0 Hz, 2H), 1.27 (m, 30H), 0.91 (m, 12H), 0.09 (s, 6H).

[0838] Intermediate I-22: 3-[[(1R)-1-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-octadecoxy-ethoxy]methyl]-5-fluorobenzonitrile

[0839]

[0840] A 60% dispersion (1.31 mmol) of sodium hydride in mineral oil was suspended in tetrahydrofuran (5 mL) and cooled to 0°C. In tetrahydrofuran (2 mL) Intermediate I-21A solution of (0.654 mmol) was added over 30 seconds. After 30 minutes, a solution of 3-(bromomethyl)-5-fluorobenzonitrile (1.44 mmol) in tetrahydrofuran (2 mL) was added. The ice bath was removed. After 16 hours, the reaction mixture was quenched with water (10 mL) at 0°C. Gas generation was observed. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried with sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 20% ethyl acetate / hexane, using ELSD detection). The fractions containing the product were combined, and the solvent was removed under reduced pressure, Intermediate I-22 I obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.48 (s, 1H), 7.41 (m, 1H), 7.28 - 7.23 (m, 1H), 4.77 (s, 2H), 3.73 (d, J = 4.9 Hz, 2H), 3.66 (qd, J = 5.7, 4.1 Hz, 1H), 3.55 (qd, J = 10.3, 5.0 Hz, 2H), 3.46 (td, J = 6.7, 1.2 Hz, 2H), 1.65 - 1.52 (m, 2H), 1.28 (s, 30H), 0.91 (d, J = 7.1 Hz, 13H), 0.09 (s, 6H). 19 F NMR (376 MHz, chloroform-d) δ -110.67 ― -110.85 (m).

[0841] Intermediate I-23: 3-fluoro-5-[[(1S)-1-(hydroxymethyl)-2-octadecoxy-ethoxy]methyl]benzonitrile

[0842]

[0843] A solution of tetrabutylammonium fluoride (1.71 mL, 1.71 mmol) in tetrahydrofuran in tetrahydrofuran (5 mL) Intermediate I-22It was added to a solution of (0.569 mmol). After 45 minutes, the reaction mixture was diluted with ethyl acetate (20 mL). The organic phase was washed with water (3 × 5 mL) and brine (5 mL). The organic phase was dried with sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0% to 20% ethyl acetate / hexane, using ELSD). The fractions containing the product were combined, and the solvent was removed under reduced pressure, Intermediate I-23 I obtained. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.48 (s, 1H), 7.41–7.35 (m, 1H), 7.33–7.29 (m, 1H), 4.83–4.68 (m, 2H), 3.86–3.78 (m, 1H), 3.78–3.68 (m, 2H), 3.68–3.56 (m, 2H), 3.47 (td, J = 6.6, 2.2 Hz, 2H), 1.66–1.50 (m, 2H), 1.40–1.23 (m, 30H), 0.90 (t, J = 6.8 Hz, 3H). 19F NMR (376 MHz, chloroform-d) δ -110.36 (t, J = 8.4 Hz).

[0844] Intermediate I-24: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((3-cyano-5-fluorobenzyl)oxy)-3-(octadecyloxy)propyl) phosphate

[0845]

[0846] 2-chlorophenylphosphorodichloridate (0.124 mL, 0.755 mmol) was added dropwise to a solution of 1H-1,2,4-triazole (1.62 mmol) and TEA (0.226 mL, 1.62 mmol) in CH3CN (2.5 mL) and pyridine (2.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. In MeCN (2.5 mL) and pyridine ( / 2.5 mL) under an Ar atmosphere Intermediate I-23 A solution of (0.755 mmol) was added all at once to the above reaction mixture and stirred vigorously for 90 minutes. To this mixture Intermediate I-3a(0.755 mmol), followed by the addition of 1-methylimidazole (0.1 mL, 1.26 mmol), and the mixture was stirred overnight. The mixture was concentrated to remove pyridine and co-evaporated once with toluene (30 mL). To this mixture, 10% citric acid (43 mL), followed by 1 N NaOH (7 mL) and water (20 mL), was added to complete the transfer. The aqueous layer was extracted with EtOAc (3 × 100 mL). The organic fractions were combined, washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0 to 20% MeOH in DCM). Intermediate I-24 obtained. MS m / z [M+1] = 981.2.

[0847] Intermediate I-25: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl) oxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0848]

[0849] Intermediate I-24 (0.458 mmol) was dissolved in 2:1 THF:ACN (6:3 mL). A solution of cesium fluoride (1.83 mmol) in water (0.578 mL) was added, followed by the addition of 4-(dimethylamino)pyridine (1.6 mmol) to the solution. The reaction mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and 10% citric acid in water (20 mL) was added, followed by the addition of 2 M NaOH to adjust the pH to 3 to 4. Extraction was performed with EtOAc (50 mL × 2), and LCMS was used to confirm the absence of the desired product in the aqueous layer. The combined organic layer was washed once with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 50% MeOH in DCM). Intermediate I-25 obtained. MS m / z [M+1] = 871.3.

[0850] Intermediate I-26: (S)-5-(((1-hydroxy-3-(octadecyloxy)propane-2-yl)oxy)methyl)-2-methoxybenzonitrile

[0851]

[0852] Intermediate I-26 Using 5-(bromomethyl)-2-methoxybenzonitrile instead of 3-(bromomethyl)-5-fluorobenzonitrile, Intermediate I-23 Synthesized using a similar method. MS m / z [M+1] = 490.

[0853] Intermediate I-27: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl)hydrogen phosphate

[0854]

[0855] A stirring rod was placed in a 200 mL round-bottom flask, and 1,2,4-triazole (26.2 mmol), THF (60 mL, 15 V), and TEA (3.65 mL, 26.2 mmol) were added. The mixture was cooled to 0°C, and 2-chlorophenylphosphorodichloridate (1.96 mL, 12.1 mmol) was added dropwise over approximately 20 minutes (formation of a white precipitate). The reaction mixture was heated to room temperature and stirred for 1 hour. To this mixture, dry Intermediate I-3a(12.1 mmol) was added all at once, and the solid adhering to the flask was added to the reaction mixture using THF (30 mL) and stirred for 1 hour. The slurry was filtered, the filter cake of Et3N-HCl was rinsed with THF (about 3 to 5 Vol, 160 mL), and the filtrate was concentrated under reduced pressure (about 25 mL, 3 Vol). EtOAc (10 V, 250 mL) and water (10 V, 250 mL) were added to this mixture, transferred to a separatory funnel (using about 1 V, 100 mL of EtOAc / water), and the transfer was completed. Saturated Na2CO3 solution was added to adjust the pH of the solution to 8 to 9 (if the pH of the solution is already about 8, there is no need to add Na2CO4). The aqueous layer contained the product, and the organic layer consisted of organic impurities containing trace amounts of the desired product. The aqueous layer was collected in a 500 mL round-bottom flask, a stirring rod was inserted, and 5% aqueous HCl solution was added dropwise over 30 to 40 minutes until the pH reached approximately 3 (continuing addition until no further precipitate formed), at which point the slurry began to solidify. After the solid formed and then disappeared, the mixture was allowed to stand for 1 hour, at which point an oily, yellowish droplet formed (the pure product). The solution was transferred to a separatory flask, extracted with EtOAc (200 mL × 3), and extracted once with DCM / IPA (4:1, 100 mL). The combined organic layer was dried with Na2SO4, the solvent was concentrated, and the mixture was dried, Intermediate I-27 I obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.77 (d, J = 91.2 Hz, 2H), 8.40 (s, 1H), 8.07 (s, 1H), 7.50 (dd, J = 19.3, 8.1 Hz, 2H), 7.29 - 7.20 (m, 1H), 7.15 (d, J = 4.5 Hz, 1H), 7.10 (t, J= 7.7 Hz, 1H), 6.98 (d, J = 4.5 Hz, 1H), 5.66 (d, J = 3.6 Hz, 1H), 5.32 (dd, J = 6.6, 3.8 Hz, 1H), 5.12 (d, J = 6.6 Hz, 1H), 4.31 - 4.13 (m, 2H), 1.69 (s, 3H), 1.39 (s, 3H). MS m / z [M+1] = 522.0.

[0856] Intermediate I-28: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-4-methoxybenzyl)oxy)-3-(octadecyloxy)propyl) phosphate.

[0857]

[0858] Intermediate I-26 (0.041 mmol), Intermediate I-27 (0.061 mmol) was placed in a 20 mL vial and dried under vacuum (1 hour); DCM (2 mL) was added, followed by NMI (13.4 μL, 0.163 mmol), TEA (11.5 μL, 0.081 mmol), and then Bop-Cl (10.4 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM, loaded onto a 24 g column, and eluted with 100% Hex (4 min), 0% to 100% EtOAc (6 min), and 100% EtOAc (6 min). The product was eluted with 100% EtOAc, and the fractions containing the pure product were combined and concentrated. Intermediate I-28 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.93 (d, J = 6.5 Hz, 1H), 7.58 - 7.32 (m, 4H), 7.23 - 7.02 (m, 2H), 6.90 (dd, J = 8.6, 5.0 Hz, 1H), 6.72 (d, J = 4.5 Hz, 1H), 6.60 (dd, J= 6.8, 4.5 Hz, 1H), 5.77 - 5.61 (m, 2H), 5.28 (td, J = 6.5, 3.1 Hz, 1H), 5.13 (dd, J = 15.1, 6.6 Hz, 1H), 4.68 - 4.41 (m, 5H), 4.40 - 4.22 (m, 1H), 3.91 (s, 3H), 3.79 (dp, J = 22.7, 5.1 Hz, 1H), 3.51 (dd, J = 16.0, 5.3 Hz, 2H), 3.41 (q, J = 6.4 Hz, 2H), 1.79 (d, J = 2.4 Hz, 3H), 1.60 - 1.46 (m, 2H), 1.39 (s, 3H), 1.27 (d, J = 2.5 Hz, 30H), 0.90 (t, J = 6.7 Hz, 3H). MS m / z [M+1] = 993.3.

[0859] Intermediate I-29: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-cyano-4-methoxybenzyl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0860]

[0861] Intermediate I-28 (0.02 mmol) was dissolved in 2:1 THF:ACN (1:0.5 mL). A solution of cesium fluoride (0.101 mmol) in water (0.026 mL) was added, followed by the addition of 4-(dimethylamino)pyridine (0.08 mmol) to the solution. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, and 10% citric acid in water (20 mL) was added, followed by the addition of 2 M NaOH to adjust the pH to 3 to 4. Extraction was performed with EtOAc (50 mL × 2), and LCMS was used to confirm the absence of the desired product in the aqueous layer. The combined organic layer was washed once with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 50% MeOH in DCM). Intermediate I-29 I obtained.1 ¹H NMR (400 MHz, methanol- d 4) δ 7.85 (s, 1H), 7.62 - 7.53 (m, 2H), 7.11 - 7.00 (m, 1H), 6.87 (d, J = 4.5 Hz, 1H), 6.81 (d, J = 4.5 Hz, 1H), 5.65 (d, J = 3.6 Hz, 1H), 5.26 (dd, J = 6.6, 3.7 Hz, 1H), 5.15 (d, J = 6.6 Hz, 1H), 4.66 - 4.49 (m, 2H), 4.20 - 4.08 (m, 2H), 3.95 (t, J = 5.4 Hz, 2H), 3.92 (s, 3H), 3.72 (dt, J = 9.1, 4.7 Hz, 1H), 3.56 ― 3.36 (m, 4H), 2.91 ― 2.72 (m, 6H, 1.5eq Citrate), 1.71 (s, 3H), 1.54 (m, 2H), 1.40 (s, 3H), 1.29 (d, J = 7.3 Hz, 30H), 0.92 (t, J = 6.7 Hz, 3H). MS m / z [M+1] = 883.2.

[0862] Intermediate I-30: (S)-6-((1-hydroxy-3-(octadecyloxy)propane-2-yl)oxy)picolinonitrile

[0863]

[0864] Intermediate I-30 Using 6-fluoropicolinonitrile instead of 3-fluorobenzonitrile, Intermediate I-16 Synthesized using a similar method. MS m / z [M+1] = 447.2.

[0865] Intermediate I-31: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((6-cyanopyridine-2-yl)oxy)-3-(octadecyloxy)propyl) phosphate

[0866]

[0867] Intermediate I-30 (0.119 mmol), Intermediate I-27(0.178 mmol) was placed in a 20 mL vial and dried under vacuum (1 hour), then DCM (3 mL), NMI (38 μL, 0.476 mmol), TEA (33 μL, 0.238 mmol), followed by Bop-Cl (0.143 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, an excess of NMI (38 μL, 4 eq), TEA (35 μL, 2 eq, until the solution became clear), followed by Bop-Cl (36 mg, 4 eq) was added, and the mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM, loaded onto a 24 g column, and eluted with 100% Hex (3 min), 0% to 100% EtOAc (6 min), and 100% EtOAc (6 min). The product is eluted with 100% EtOAc, fractions containing the pure product are combined and concentrated, Intermediate I-31 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.98 - 7.86 (m, 1H), 7.61 (dt, J = 21.6, 8.0 Hz, 1H), 7.44 - 7.22 (m, 3H), 7.20 - 7.00 (m, 2H), 6.98 - 6.88 (m, 1H), 6.72 (dd, J = 4.5, 2.5 Hz, 1H), 6.64 - 6.57 (m, 1H), 5.78 (s, 2H), 5.68 (dt, J = 8.0, 3.2 Hz, 1H), 5.48 (dt, J = 28.2, 4.8 Hz, 1H), 5.27 (ddd, J = 12.0, 6.8, 3.1 ㎐, 1H), 5.14 (ddd, J = 19.1, 11.5, 6.6 Hz, 1H), 4.72 - 4.36 (m, 4H), 3.79 - 3.61 (m, 2H), 3.55 - 3.33 (m, 2H), 1.78 (d, J = 5.4 Hz, 3H), 1.54 (dt,J = 11.0, 7.2 Hz, 2H), 1.41 - 1.36 (m, 3H), 1.26 (d, J = 6.0 Hz, 30H), 0.90 (t, J = 6.7 Hz, 3H). MS m / z [M+1] = 950.1.

[0868] Intermediate I-32: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((6-cyanopyridine-2-yl)oxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0869]

[0870] Intermediate I-31 (0.062 mmol) was dissolved in 2:1 THF:ACN (2:1 mL). A solution of cesium fluoride (0.311 mmol) in water (0.078 mL) was added, followed by the addition of 4-(dimethylamino)pyridine (0.249 mmol) to the solution. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, and 10% citric acid in water (20 mL) was added, followed by the addition of 2 M NaOH to adjust the pH to 3 to 4. Extraction was performed using MeTHF / EtOAc (3:2, 50 mL × 2), and LCMS was used to confirm the absence of the desired product in the aqueous layer. The combined organic layer was washed once with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 50% MeOH in DCM). Intermediate I-32 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.85 (d, J = 6.6 Hz, 1H), 7.73 (q, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 14.6, 8.6 Hz, 1H), 6.83 (dt, J = 12.9, 5.0 Hz, 2H), 5.69 - 5.58 (m, 1H), 5.44 (t, J = 5.1 Hz, 1H), 5.27 (td,J = 8.1, 7.5, 3.8 ㎐, 1H), 5.16 (t, J = 5.4 Hz, 1H), 4.66 — 4.32 (m, 1H), 4.22 — 4.03 (m, 3H), 3.70 — 3.57 (m, 2H), 3.51 — 3.34 (m, 2H), 1.69 (s, 3H), 1.52 — 1.42 (m, 2H), 1.38 (d, J = 2.9 Hz, 3H), 1.26 (d, J = 17.7 Hz, 30H), 0.90 (t, J = 6.6 Hz, 3H). MS m / z [M+1] = 840.1.

[0871] Intermediate I-33: (S)-5-(((1-hydroxy-3-(octadecyloxy)propane-2-yl)oxy)methyl) picolinonitrile

[0872]

[0873] Intermediate I-33 Using 5-(bromomethyl)picolinonitrile instead of 3-(bromomethyl)-5-fluorobenzonitrile, Intermediate I-23 Synthesized using a method similar to that. MS m / z [M+1] = 461.4.

[0874] Intermediate I-34: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((6-cyanopyridine-3-yl)methoxy)-3-(octadecyloxy)propyl) phosphate

[0875]

[0876] Intermediate I-33 (0.119 mmol), Intermediate I-27(0.178 mmol) was placed in a 20 mL vial and dried under vacuum (1 hour), then DCM (3 mL), NMI (38 μL, 0.476 mmol), TEA (33 μL, 0.238 mmol), followed by Bop-Cl (0.143 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, an excess of NMI (38 μL, 4 eq), TEA (35 μL, 2 eq, until the solution became clear), followed by Bop-Cl (36 mg, 4 eq) was added, and the mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure. The crude product was dissolved in DCM, loaded onto a 24 g column, and eluted with 100% Hex (3 min), 0% to 100% EtOAc (6 min), and 100% EtOAc (6 min). The product is eluted with 100% EtOAc, fractions containing the pure product are combined and concentrated, Intermediate I-34 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 8.60 (dd, J = 19.4, 2.0 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.83 (ddd, J = 14.0, 8.0, 2.1 ㎐, 1H), 7.58 (t, J = 8.4 Hz, 1H), 7.47 - 7.31 (m, 2H), 7.22 - 7.00 (m, 2H), 6.71 (dd, J = 4.5, 3.2 Hz, 1H), 6.60 (dd, J = 11.2, 4.5 Hz, 1H), 5.80 (s, 2H), 5.66 (t, J = 2.3 Hz, 1H), 5.34 - 5.24 (m, 1H), 5.12 (dd, J = 20.0, 6.6 Hz, 1H), 4.86 - 4.65 (m, 2H), 4.62 - 4.18 (m, 4H), 3.94 - 3.77 (m, 1H), 3.53 (dd, J= 16.2, 5.2 Hz, 2H), 3.41 (qd, J = 6.8, 2.0 Hz, 2H), 1.79 (d, J = 3.5 Hz, 3H), 1.61 - 1.48 (m, 2H), 1.39 (s, 3H), 1.27 (d, J = 2.1 Hz, 32H), 0.90 (t, J = 6.7 Hz, 3H). MS m / z [M+1] = 964.8.

[0877] Intermediate I-35: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((6-cyanopyridine-3-yl) methoxy)-3-(octadecyloxy)propyl) hydrogen phosphate

[0878]

[0879] Intermediate I-34 (0.068 mmol) was dissolved in 2:1 THF:ACN (2:1 mL). A solution of cesium fluoride (0.342 mmol) in water (0.092 mL) was added, followed by the addition of 4-(dimethylamino)pyridine (0.342 mmol) to the solution. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, and 10% citric acid in water (8.5 mL) was added, followed by the addition of 2 M NaOH to adjust the pH to 3 to 4. Extraction was performed using MeTHF / EtOAc (3:2, 50 mL × 2), and LCMS was used to confirm the absence of the desired product in the aqueous layer. The combined organic layer was washed once with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 50% MeOH in DCM). Intermediate I-35 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.85 (d, J = 6.6 Hz, 1H), 7.73 (q, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 14.6, 8.6 Hz, 1H), 6.83 (dt, J= 12.9, 5.0 Hz, 2H), 5.67 - 5.55 (m, 1H), 5.44 (t, J = 5.1 Hz, 1H), 5.27 (td, J = 8.1, 7.5, 3.8 ㎐, 1H), 5.16 (t, J = 5.4 Hz, 1H), 4.67 — 4.32 (m, 2H), 4.24 — 3.99 (m, 3H), 3.76 — 3.53 (m, 2H), 3.50 — 3.35 (m, 3H), 1.69 (s, 3H), 1.52 — 1.42 (m, 2H), 1.38 (d, J = 2.9 Hz, 3H), 1.26 (d, J = 17.7 Hz, 30H), 0.90 (t, J = 6.6 Hz, 3H). MS m / z [M+1] = 854.3.

[0880] Intermediate I-36: (R)-1-(tritiloxy)nonadecan-2-ol

[0881]

[0882] A solution of (R)-2-((tritiloxy)methyl)oxirane (6.32 mmol, 1 equiv.) and copper(I) iodide (1.81 mmol, 0.286 equiv.) in THF (20 mL) was cooled in an ice bath. Hexadecyl magnesium bromide (24 mL, 0.4 M, 1.52 equiv.) was slowly added over 35 minutes. The solution was stirred for 4 hours while slowly raising it from the ice bath to room temperature. The reaction mixture was quenched with saturated ammonium chloride (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The organic fraction was dried with Na2SO4, filtered, concentrated under vacuum, and then purified twice by silica gel chromatography (0% to 15% EtOAc in hexane), Intermediate I-36 I obtained. 1 H NMR (400 MHz, chloroform- d) δ 7.50 - 7.20 (m, 15H), 3.80 - 3.71 (m, 1H), 3.21 - 3.13 (m, 1H), 3.06 - 2.98 (m, 1H), 2.29 (d, J = 3.4 Hz, 1H), 1.46 - 1.16 (m, 32H), 0.92 - 0.84 (m, 3H).

[0883] Intermediate I-37: (R)-3- fluoro -5-(((1-( Tritiloxy ) Nonadekan -2-days) Oxy ) methyl Benzonitrile

[0884]

[0885] in THF (10 mL) Intermediate I-36 Sodium tert-butoxide (2.08 mL, 2.0 M in THF, 2 equiv.) was added to a solution of (2.08 mmol, 1 equiv.). After stirring the solution at room temperature for 20 minutes, 3-(bromomethyl)-5-fluorobenzonitrile (4.05 mmol, 1.94 equiv.) was added. The solution was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine (50 mL), dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 10% EtOAc in hexane). Intermediate I-37 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.48 - 7.20 (m, 18H), 4.71 (d, J = 12.8 Hz, 1H), 4.55 (d, J= 12.8 Hz, 1H), 3.56 - 3.47 (m, 1H), 3.23 - 3.17 (m, 2H), 1.57 - 1.47 (m, 2H), 1.34 - 1.18 (m, 30H), 0.92 - 0.83 (m, 3H). 19 F NMR (376 MHz, chloroform- d ) δ -110.57 ― -110.69 (m).

[0886] Intermediate I-38: (R)-3-fluoro-5-(((1-hydroxynonadecane-2-yl)oxy)methyl)benzonitrile

[0887]

[0888] in 1:1:1 THF:iPrOH:MeOH (total 21 mL) Intermediate I-37 Concentrated HCl (0.53 mL, 6.37 mmol, 3.85 equiv.) was added to a solution of (1.66 mmol, 1 equiv.). The reaction mixture was heated to 65°C and stirred for 1 hour and 30 minutes. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 100% EtOAc in hexane), Intermediate I-38 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.46 - 7.43 (m, 1H), 7.36 - 7.31 (m, 1H), 7.30 - 7.24 (m, 1H), 4.64 - 4.62 (m, 2H), 3.80 - 3.70 (m, 1H), 3.66 - 3.48 (m, 2H), 1.79 - 1.71 (m, 1H), 1.68 - 1.45 (m, 2H), 1.40 - 1.16 (m, 30H), 0.91 - 0.84 (m, 3H). 19 F NMR (376 MHz, chloroform- d ) δ -110.27 ― -110.40 (m).

[0889] Intermediate I-39: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((R)-2-((3-cyano-5-fluorobenzyl)oxy)nonadecyl) phosphate

[0890]

[0891] 1H-1,2,4-triazole (0.744 mmol, 2.15 equiv.) was injected into an oven-dried round-bottom flask. The triazole was dissolved in ACN (5.0 mL) and pyridine (5.0 mL). After adding triethylamine (0.104 mL, 0.744 mmol, 2.15 equiv.) to the solution, 2-chlorophenylphosphorodichloridate (0.06 mL, 0.346 mmol, 1 equiv.) was added. After stirring the reaction mixture at room temperature for 24 minutes, Intermediate I-3a After adding (0.346 mmol, 1 equiv.) all at once, 1-methylimidazole (0.06 mL, 0.698 mmol, 2.02 equiv.) was added. The solution was stirred for 1 hour. Intermediate I-38 (0.380 mmol, 1.1 equiv.) was added, and the reaction mixture was stirred for an additional 2 hours and 30 minutes. The reaction mixture was quenched with a buffer of 4:1 citric acid (20% aqueous solution): 1M NaOH (19 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic fractions were combined, washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 20% MeOH in DCM). Intermediate I-39 I obtained MS m / z [M+1] = 937.27.

[0892] Intermediate I-40: ((3aS,4R,6S,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((3-cyano-5-fluorobenzyl) oxy)nonadecyl) hydrogen phosphate

[0893]

[0894] Intermediate I-390.244 mmol, 1 equiv. of cesium fluoride was dissolved in 2:1 THF:ACN (total 4.5 mL). After adding cesium fluoride (2.12 mmol, 8.68 equiv.) dissolved in water (0.30 mL) to the solution, 4-(dimethylamino)pyridine (0.900 mmol, 3.69 equiv.) was added. The reaction mixture was heated to 80°C and stirred for 5 hours and 30 minutes. The reaction mixture was quenched with a buffer containing citric acid (2.86 mmol, 11.7 equiv.) and NaOH (0.29 mL, 2 M, 2.34 equiv.) in 20 mL of water. The aqueous layer was extracted with EtOAc (2 × 50 mL). The organic fractions are combined, washed with brine, dried with Na2SO4, filtered, and concentrated under vacuum, then purified by silica gel chromatography (0% to 50% MeOH in DCM), Intermediate I-40 I obtained. 1 ¹H NMR (400 MHz, methanol- d 4) δ 7.82 (s, 1H), 7.51 - 7.47 (m, 1H), 7.43 - 7.34 (m, 2H), 6.86 - 6.77 (m, 2H), 5.63 (d, J = 3.6 Hz, 1H), 5.29 - 5.23 (m, 1H), 5.13 (d, J = 6.6 Hz, 1H), 4.73 (d, J = 13.1 Hz, 1H), 4.54 ― 4.46 (m, 1H), 4.16 ― 4.07 (m, 2H), 3.94 ― 3.82 (m, 2H), 3.60 ― 3.49 (m, 1H), 1.69 (s, 3H), 1.47 ― 1.20 (m, 35H), 0.93 - 0.86 (m, 3H). 19 F NMR (376 MHz, methanol- d 4) δ -112.67 ― -113.35 (m). 31 P NMR (162 MHz, methanol- d 4) δ -0.12 ― -0.64 (m). MS m / z[M+1] = 827.24.

[0895] Intermediate I-41: (R)-2-methoxy-4-(((1-(tritiloxy)henicosan-2-yl)oxy)methyl)benzonitrile

[0896]

[0897] in THF (6.0 mL) cooled in an ice bath Intermediate I-112 Sodium tert-butoxide (2.0 mL, 2.0 M in THF, 2.12 equiv.) was added to a solution of (1.88 mmol, 1.0 equiv.). 4-(bromomethyl)-2-methoxybenzonitrile (2.57 mmol, 1.36 equiv.) was added all at once. The solution was stirred overnight at room temperature. The reaction mixture was heated to 60°C and stirred for 5 hours and 30 minutes, then stirred overnight at room temperature. The solution was cooled in an ice bath, and sodium tert-butoxide (1.00 mL, 2.0 M in THF, 1.06 equiv.) was added, followed by additional 4-(bromomethyl)-2-methoxybenzonitrile (0.792 mmol, 0.420 equiv.). After stirring for 7 hours and 30 minutes, additional 4-(bromomethyl)-2-methoxybenzonitrile (1.08 mmol, 0.575 equiv.) was added, and the solution was stirred again at room temperature overnight. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic fractions were combined, washed with brine, dried with Na2SO4, filtered, and concentrated under vacuum, then purified twice by silica gel chromatography (0% to 75% EtOAc in hexane, followed by 0% to 15% EtOAc in hexane), Intermediate I-41 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.49 (d, 1H), 7.47 - 7.41 (m, 6H), 7.35 - 7.20 (m, 9H), 7.02 - 6.99 (m, 1H), 6.96 - 6.92 (m, 1H), 4.72 (d,J = 13.0 Hz, 1H), 4.59 (d, J = 13.0 Hz, 1H), 3.84 (s, 3H), 3.57 ― 3.48 (m, 1H), 3.24 ― 3.14 (m, 2H), 1.58 ― 1.48 (m, 2H),1.37 ― 1.15 (m, 34H), 0.91 ― 0.84 (m, 3H).

[0898] Intermediate I-42: (R)-4-(((1-hydroxyhenicosan-2-yl)oxy)methyl)-2-methoxybenzonitrile

[0899]

[0900] in 1:1:1 THF:iPrOH:MeOH (total 18.0 mL) Intermediate I-41 Concentrated HCl (0.33 mL, 3.91 mmol, 3.85 equiv.) was added to a solution of (1.02 mmol, 1 equiv.). The reaction mixture was heated to 65°C and stirred for 4 hours and 30 minutes. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 20% EtOAc in hexane, followed by 0% to 100% EtOAc in hexane), Intermediate I-42 I obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.55 - 7.50 (m, 1H), 7.02 - 6.99 (m, 1H), 6.99 - 6.94 (m, 1H), 4.69 - 4.59 (m, 2H), 3.96 - 3.93 (m, 3H), 3.78 - 3.70 (m, 1H), 3.64 - 3.47 (m, 2H), 1.85 - 1.74 (m, 1H), 1.69 - 1.17 (m, 36H), 0.92 - 0.84 (m, 3H).

[0901] Intermediate I-43: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl)((R)-2-((4-cyano-3-methoxybenzyl)oxy)henicosyl) phosphate

[0902]

[0903] in DCM (2.0 mL) Intermediate I-42 (0.192 mmol, 1 equiv.), Intermediate I-27 BOP-Cl (0.617 mmol, 3.22 equiv.) was added to a solution of (0.192 mmol, 1 equiv.), triethylamine (0.04 mL, 0.287 mmol, 1.5 equiv.), and 1-methylimidazole (0.04 mL, 0.502 mmol, 2.62 equiv.). The solution was stirred at room temperature for 4 hours. An additional 5 mg of ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl(2-chlorophenyl) hydrogen phosphate (0.00958 mmol, 0.05 equiv.) was added, and the solution was stirred at room temperature for 6 days. The reaction mixture was diluted to 2:1 Et2O:EtOAc (60 mL) and quenched with 4:1 water:saturated NaHCO3 (50 mL). The layers were separated, and the aqueous layer was extracted with 2:1 Et2O:EtOAc (60 mL) and once more with EtOAc (50 mL). The organic extracts are combined, dried with Na2SO4, filtered, concentrated under vacuum, and then purified with silica gel (0% to 10% MeOH in DCM). Intermediate I-43 I obtained. MS m / z [M+1] = 977.4.

[0904] Intermediate I-44: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl ((R)-2-((4-cyano-3-methoxybenzyl) oxy)henicosyl) hydrogen phosphate

[0905]

[0906] Intermediate I-43Cesium fluoride (0.102 mmol, 1.0 equiv.) was dissolved in 2:1 THF:ACN (total 4.5 mL). After adding cesium fluoride (1.45 mmol, 14.2 equiv.) dissolved in water (0.70 mL) to the solution, 4-(dimethylamino)pyridine (0.409 mmol, 4 equiv.) was added. The reaction mixture was heated to 80°C and stirred for 5 hours and 30 minutes. The reaction mixture was quenched with a buffer containing citric acid (4.65 mL, 0.22 M, 10 equiv.) and NaOH (0.10 mL, 2 M, 2 equiv.). The aqueous layer was extracted with EtOAc (2x). The organic fractions are combined, washed with brine, dried with Na2SO4, filtered, and concentrated under vacuum, then purified by silica gel chromatography (0% to 50% MeOH in DCM), Intermediate I-44 I obtained MS m / z [M+1] = 867.4.

[0907] Intermediate I-45: (S)-Icosan-1,2-diol

[0908]

[0909] AD-mix-α (1.32 g per 1 mmol of olefin) was added to a solution of tBuOH (50 mL) and water (50 mL). The mixture was vigorously stirred for 5 minutes, then cooled in an ice bath over 10 minutes. Eicocene (8.77 mol, 1 equiv.) was added all at once, and the reaction mixture was stirred overnight at room temperature. Sodium sulfite (15.0 g, 0.119 mol, 13.6 equiv.) was added, and the solution was stirred at room temperature for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to remove tBuOH. The concentrated filtrate was diluted with water (25 mL) and extracted with EtOAc (3 × 75 mL). The organic extract is washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, purified with silica gel (0% to 100% EtOAc in hexane), and then further eluted using 0% to 40% MeOH in DCM. Intermediate I-45 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 3.78 - 3.62 (m, 2H), 3.50 - 3.40 (m, 1H), 2.04 - 1.19 (m, 36H), 0.92 - 0.85 (m, 3H).

[0910] Intermediate I-46: (S)-1-(tritiloxy)icosan-2-ol

[0911]

[0912] in DCM (10 mL) Intermediate I-45Triethylamine (0.17 mL, 1.24 mmol, 1.15 equiv.) was added to a solution of (1.08 mmol, 1 equiv.) and 4-(dimethylamino)pyridine (0.426 mmol, 0.394 equiv.). Subsequently, trityl chloride (1.10 mmol, 1.02 equiv.) was added. The reaction mixture was stirred overnight at room temperature. An additional 25 mg of trityl chloride (0.090 mmol, 0.083 equiv.) was added, and the solution was stirred for an additional 6 hours at room temperature. The reaction mixture was diluted with DCM (50 mL) and poured into ice water (50 mL). The layers were separated, and the aqueous layer was extracted with an additional 50 mL of DCM. The organic fractions are combined, washed with brine (50 mL), dried with Na2SO4, filtered, concentrated under vacuum, and then purified with silica gel (0% to 90% DCM in hexane). Intermediate I-46 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.46 - 7.20 (m, 15H), 3.80 - 3.71 (m, 1H), 3.18 (dd, J = 9.3, 3.3 ㎐, 1H), 3.02 (dd, J = 9.4, 7.6 Hz, 1H), 2.29 (s, 1H), 1.47 - 1.15 (m, 34H), 0.91 - 0.84 (m, 3H).

[0913] Intermediate I-47: (S)-3-fluoro-5-(((1-(tritiloxy)icosan-2-yl)oxy)methyl)benzonitrile

[0914]

[0915] in THF (3.0 mL) Intermediate I-46Sodium tert-butoxide (0.29 mL, 2.0 M in THF, 2 equiv.) was added to a solution of (0.294 mmol, 1 equiv.). After stirring the solution at room temperature for 5 minutes, 3-(bromomethyl)-5-fluorobenzonitrile (0.784 mmol, 2.67 equiv.) was added. The solution was stirred overnight at room temperature. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3 × 25 mL). The organic fractions were combined, washed with brine, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 10% EtOAc in hexane). Intermediate I-47 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.52 - 7.21 (m, 18H), 4.71 (d, J = 12.8 Hz, 1H), 4.55 (d, J = 12.8 Hz, 1H), 3.55 - 3.48 (m, 1H), 3.23 - 3.18 (m, 2H), 1.64 - 1.44 (m, 2H), 1.34 - 1.20 (m, 32H), 0.91 - 0.85 (m, 3H). 19 F NMR (376 MHz, chloroform-d) δ -110.57 ― -110.72 (m).

[0916] Intermediate I-48: (S)-3-fluoro-5-(((1-hydroxyicosan-2-yl)oxy)methyl)benzonitrile

[0917]

[0918] in 1:1:1 THF:iPrOH:MeOH (total 6 mL) Intermediate I-47Concentrated HCl (0.10 mL, 1.20 mmol, 4.19 equiv.) was added to a solution of (0.286 mmol, 1 equiv.). The reaction mixture was heated to 65°C and stirred for 1 hour and 30 minutes. The solution was quenched with saturated sodium bicarbonate (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, dried with Na2SO4, filtered, concentrated under vacuum, and then purified by silica gel chromatography (0% to 100% EtOAc in hexane), Intermediate I-48 I obtained. 1 H NMR (400 MHz, chloroform- d ) δ 7.45 (s, 1H), 7.37 - 7.31 (m, 1H), 7.29 - 7.24 (m, 1H), 4.65 - 4.61 (m, 2H), 3.78 - 3.70 (m, 1H), 3.65 - 3.56 (m, 1H), 3.56 - 3.48 (m, 1H), 1.88 - 1.45 (m, 3H), 1.41 - 1.19 (m, 32H), 0.88 (t, J = 6.7 Hz, 3H). 10 F NMR (376 MHz, chloroform-d) δ -110.26 ― -110.38 (m).

[0919] Intermediate I-49: ((3aS,4R,6aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl (2-chlorophenyl) ((S)-2-((3-cyano-5-fluorobenzyl)oxy)icosyl) phosphate

[0920]

[0921] in DCM (5.0 mL) Intermediate I-48 (0.148 mmol, 1 equiv.), Intermediate I-27BOPCl (0.537 mmol, 4 equiv.) was added to a solution of (0.134 mmol, 1 equiv.), triethylamine (0.07 mL, 0.537 mmol, 4 equiv.), and 1-methylimidazole (0.02 mL, 0.268 mmol, 2 equiv.). The solution was stirred overnight at room temperature. An additional 140 mg of BOP-Cl (0.550 mmol, 4.1 equiv.) and 0.05 mL of 1-methylimidazole (0.627 mmol, 4.68 equiv.) were added, and the solutio...

Claims

Claim 1 Compound of formula V or a pharmaceutically acceptable salt thereof: In the above equation, each R 1A is independently a 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or N and O; R 6 is H or -C(O)C1-C6 alkyl and R 7 is H or -C(O)C1-C6 alkyl; m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21; and n is 1 or 2. Claim 2 A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof: Claim 3 Compound of Formula III or a pharmaceutically acceptable salt thereof: In the above equation, each R 1A is independently a 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or N and O; R 6 is H or -C(O)C1-C6 alkyl and R 7 is H or -C(O)C1-C6 alkyl; m is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21; and n is 1 or 2. Claim 4 A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof: . Claim 5 A compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof: . Claim 6 In paragraph 1, the following compounds or pharmaceutically acceptable salts thereof: . Claim 7 In paragraph 1, the following compounds or pharmaceutically acceptable salts thereof: . Claim 8 A pharmaceutical preparation for treating or preventing a viral infection selected from the group consisting of infections of the Pneumoviridae and Picornaviridae, comprising a pharmaceutically effective amount of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Claim 9 In paragraph 8, the above-mentioned viral infection is a pharmaceutical preparation that is a pneumovirus infection. Claim 10 In claim 9, the above pneumovirus and virus infection is a pharmaceutical preparation in which the virus is a respiratory syncytial virus infection or a human metapneumovirus infection. Claim 11 In paragraph 9, the above-mentioned pneumovirus and virus infection is a pharmaceutical preparation that is a human metapneumovirus infection. Claim 12 In paragraph 8, the above-mentioned viral infection is a pharmaceutical preparation that is a picornavirus infection. Claim 13 In Clause 12, the above picornavirus infection is a pharmaceutical preparation that is a human rhinovirus infection. 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