Antiviral prodrug compound

Abstract

Provided herein are nucleotide prodrug compounds, their preparation and their uses, for example, in the treatment of diseases or conditions of viral infection.

Description

Technical Field

[0001] Field The present disclosure relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to antiviral prodrug compounds, their preparation, and their use. In some embodiments, such compounds are useful for selectively delivering a particular agent to a target organ.

Background Art

[0002] Background The following background description is provided to assist in the understanding of the present invention and is not an admission that they are prior art or represent prior art.

[0003] Coronaviruses cause diseases in mammals and birds. Some coronaviruses can cause severe infections that can even lead to death in humans. Due to the unpredictability of coronavirus outbreaks, drugs against coronaviruses are not well developed. The current SARS-CoV-2 pandemic has led medical doctors to reuse existing antiviral agents as a short-term solution. Human coronaviruses are RNA viruses that contain positive-sense single-stranded RNA in their viral core, and their replication is by their RNA-dependent RNA polymerases that share highly similar sequences with other known viruses. A well-known class of antiviral agents is called nucleoside(tide) polymerase inhibitors. The mechanism of action of this class is to bind themselves to a specific site on the polymerase and incorporate them into the viral replication chain reaction for termination. A number of polymerase inhibitors and well-established antiviral drug targets are known. A library of these agents could theoretically contain drugs that can block known or future unknown coronaviruses. Various such agents are under clinical development for COVID-19 treatment.

[0004] Prodrug technology has been used to improve the properties of nucleoside molecules such that their nucleosides exhibit higher bioavailability, including improvement of oral bioavailability and cell permeability to target cells. Thus, a new type of prodrug that exhibits improved delivery efficiency over existing prodrug technologies can significantly improve the therapeutic benefit of nucleoside analog-based therapies.

Summary of the Invention

[0005] Summary Novel nucleotide prodrug compounds, their preparation and their use are described. Some embodiments are novel nucleotide prodrug compounds that are orally delivered to a target organ, where the compounds provide a therapeutic benefit. Further embodiments include novel nucleotide prodrug compounds for treating diseases, disorders or conditions including hepatitis, malaria, viral infections, parasitic infections, and coronavirus infections. Another aspect includes the use of nucleotide prodrug compounds for treating diseases where enhanced drug distribution to a target organ and similar tissues and cells is beneficial. In another aspect, the nucleotide prodrug compounds are used to increase the pharmacological or clinical activity of a particular class of pharmaceutical compounds, such as nucleotide-derived analog compounds. In some embodiments, the nucleotide prodrug compounds are useful for more efficient oral delivery of nucleotide compounds to target organs and cells. Some further embodiments relate to methods of manufacturing nucleotide prodrug compounds.

[0006] Some embodiments provided herein include compounds of Formulas I, II, and III: TIFF0007699205000001.tif127128, or stereoisomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , BASE and n have any of the values provided herein.

[0007] Some embodiments relate to pharmaceutical compositions comprising one or more of the above compounds and a pharmaceutically acceptable excipient.

[0008] Some embodiments relate to pharmaceutical compositions comprising one of the above compounds and a pharmaceutically acceptable excipient.

[0009] Some embodiments relate to methods of treating a disease, disorder or condition comprising administering an effective amount of one of the above compounds.

[0010] In some embodiments, the disease, disorder or condition is a viral infection disease, disorder or condition.

[0011] Some embodiments relate to methods of treating viral infection comprising administering an effective amount of one of the above compounds to a subject in need thereof.

[0012] Some embodiments further comprise administering to a subject in need thereof an effective amount of at least one additional therapeutic agent.

[0013] In some embodiments, the subject is a mammal.

[0014] In some embodiments, the subject is a human.

[0015] In some embodiments, the cells are in vivo.

[0016] In some embodiments, the cells are ex vivo.

[0017] In some embodiments, the cells are human cells.

[0018] Some embodiments of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising one of the compounds provided herein and a pharmaceutically acceptable excipient.

[0019] Some aspects of the compounds, compositions, and methods provided herein include a method of treating a viral infection disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of one of the compounds provided herein.

[0020] Some aspects of the compounds, compositions, and methods provided herein include a method of treating a disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of one of the compounds provided herein.

[0021] Some aspects also include administering to the subject in need thereof an effective amount of one or more additional therapeutic agents.

[0022] In some aspects, the subject is a mammal.

[0023] In some aspects, the subject is a human.

[0024] Some aspects also include the use of one of the compounds provided herein in combination with an additional therapeutic agent.

[0025] Some aspects of the compounds, compositions, and methods provided herein include one of the compounds provided herein for use in the preparation of a medicament for the treatment of a viral infection disease or condition. [The present invention 1001] Compounds of formula I, II, and III, or stereoisomers or pharmaceutically acceptable salts thereof: TIFF0007699205000002.tif127128 Wherein, R 1 is H, optionally substituted C 1 ~C 15 alkyl, optionally substituted C 3 ~C 15 cycloalkyl, and optionally substituted C 2 ~C 15 alkenyl, selected from the group consisting of, R 2is selected from the group consisting of halogen, optionally substituted alkyl, and optionally substituted alkyloxy, R 3 is selected from the group consisting of H, optionally substituted acyl, C-carboxy, and C-amide, BASE is TIFF0007699205000003.tif26128 selected from the group consisting of, R 4 is selected from the group consisting of H, optionally substituted acyl, and C-carboxy, R 5 is selected from the group consisting of H, optionally substituted acyl, C-carboxy, and C-amide groups, n is 0, 1, 2, or 3. [The present invention 1002] The compound of the present invention 1001, wherein n is 1. [The present invention 1003] The compound of the present invention 1001, wherein n is 0. [The present invention 1004] R 3 The compound of any one of the present inventions 1001 to 1003, wherein is H. [The present invention 1005] R 1 The compound of any one of the present inventions 1001 to 1004, wherein is optionally substituted C 1 ~C 15 alkyl. [The present invention 1006] R 1 The compound of the present invention 1005, wherein is unsubstituted C 1 ~C 6 alkyl. [The present invention 1007] R 1 The compound of the present invention 1006, wherein is ethyl. [The present invention 1008] R 1 The compound of the present invention 1006, wherein is n-propyl. [The present invention 1009] R 1 The compound of the present invention 1006, wherein is i-propyl. [The present invention 1010] TIFF0007699205000004.tif105136 The compound of the present invention 1001, selected from the group consisting of. [The present invention 1011] The compound of any one of the present inventions 1001 to 1010, for use in the treatment of viral infections. [The present invention 1012] A pharmaceutical composition comprising the compound of any one of the present inventions 1001 to 1010 in combination with one or more additional therapeutic agents. [The present invention 1013] Use of the compound of any one of the present inventions 1001 to 1010 in the preparation of a medicament for treating viral infections. [The present invention 1014] A method for treating viral infections, comprising the step of administering to a subject in need thereof an effective amount of the compound of any one of the present inventions 1001 to 1010. [The present invention 1015] The method of the present invention 1014, wherein the subject is a mammal. [The present invention 1016] The method of the present invention 1015, wherein the mammal is a human.

BEST MODE FOR CARRYING OUT THE INVENTION

[0026] DETAILED DESCRIPTION The present aspect relates to novel nucleotide prodrug compounds, compositions and methods related to their preparation and their use. In some aspects, the novel nucleotide prodrug compounds facilitate the delivery of nucleotide-derived substances, such as ribonucleotides and deoxyribonucleotides, including nucleobase derivatives / analogs and prodrugs, into cells.

[0027] These nucleotide prodrug compounds and their stereoisomers and pharmaceutically acceptable salts are represented by Formulas I, II, and III: TIFF0007699205000005.tif127128 or its stereoisomer or pharmaceutically acceptable salt, wherein R 1 , R 2 , R 3 , BASE and n have any of the values provided herein.

[0028] In some aspects, R 1 is H, optionally substituted C1-C 15 alkyl, optionally substituted C3-C 15 cycloalkyl, and optionally substituted C2-C 15It is selected from the group of alkenyls.

[0029] In some embodiments, R 1 is optionally substituted C1-C 15 alkyl.

[0030] In some embodiments, R 1 is unsubstituted C1-C6 alkyl.

[0031] In some embodiments, R 1 is ethyl.

[0032] In some embodiments, R 1 is n-propyl.

[0033] In some embodiments, R 1 is i-propyl.

[0034] In some embodiments, R 2 is selected from the group of halogen, optionally substituted alkyl, and optionally substituted alkyloxy.

[0035] In some embodiments, R 3 is selected from the group of H, optionally substituted acyl, C-carboxy, and C-amide.

[0036] In some embodiments, R 3 is H.

[0037] In some embodiments, BASE is selected from TIFF0007699205000006.tif26128.

[0038] In some embodiments, R 4 is selected from the group of H, optionally substituted acyl, and C-carboxy.

[0039] In some embodiments, R 5is selected from the group consisting of H, optionally substituted acyl, C-carboxy, and C-amide.

[0040] In some embodiments, R 4 and R 5 are H.

[0041] In some embodiments, n is 0, 1, 2, or 3.

[0042] In some embodiments, n is 0.

[0043] In some embodiments, n is 1.

[0044] In some embodiments, the compound is selected from the group consisting of TIFF0007699205000007.tif105142.

[0045] In some embodiments, the nucleotide prodrug compound of formula I is a substrate for enzymes such as esterase, cytochrome p450 isozyme CYP3A (a family of monooxygenases), dehydrogenase, and amidase. In some embodiments, the nucleotide prodrug compound of formula I is a substrate for esterase, cytochrome p450 isozyme CYP3A, or dehydrogenase.

[0046] In some embodiments, the compound is activated intracellularly by cleavage of the prodrug moiety that releases the active form of the compound.

[0047] In some embodiments, the disclosed compounds are used for improving pharmacokinetic properties, such as prolonging the half-life of nucleosides or enhancing absorption or cellular permeability. Further, the disclosed methods can be used to achieve sustained delivery of biologically relevant nucleosides. Since the pharmacokinetic properties of the nucleoside prodrug compounds of Formulas I, II, and III are enhanced, the compounds are used for treating viral infection diseases or conditions. In some embodiments, methods for manufacturing these compounds are described.

[0048] In some embodiments, the disclosed compounds are used to avoid the initial kinase activation of nucleosides, which can improve the effects of nucleosides.

[0049] The compounds of Formulas I, II, and III have asymmetric centers whose stereochemistry may not be specified, and when generally referring to the compounds of Formulas I, II, and III, mixtures of diastereomers of these compounds are included as well as the individual stereoisomers.

[0050] In some embodiments, an effective amount of the disclosed compounds is used to treat a disease, disorder, or condition in a subject in need thereof.

[0051] In some embodiments, the compounds described herein are used to treat viral infection.

[0052] In some embodiments, the compounds described herein are used in combination with one or more additional therapeutic agents.

[0053] In some embodiments, the compounds described herein are used in the preparation of a medicament for treating viral infection.

[0054] In some embodiments, the compounds described herein are used in a method for treating viral infection that includes the step of administering to a subject in need thereof an effective amount of the compound.

[0055] Some aspects of the compounds, compositions, and methods provided herein include pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0056] Some aspects also include administering to a subject in need thereof an effective amount of a second or multiple therapeutic agents in combination with a compound provided herein.

[0057] In some aspects, the subject is a mammal.

[0058] In some aspects, the subject is a human.

[0059] Some aspects of the compounds, compositions, and methods provided herein include methods of testing a compound intracellularly, comprising contacting a cell with the disclosed compound.

[0060] If the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers including racemates. Separation of individual isomers or selective synthesis of individual isomers is accomplished by application of various methods well known to those skilled in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Further, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms including any polymorphic forms are included within the scope of the compounds disclosed herein. Additionally, some of the compounds disclosed herein can form solvates (i.e., hydrates) with water or solvates with common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0061] One of ordinary skill in the art will understand that some of the structures described herein may be resonance forms or tautomers of compounds in which other chemical structures may predominate, even dynamically, and one of ordinary skill in the art will understand that such structures may only account for a very small percentage of a sample of such a compound. Such compounds are considered to be within the scope of the structures described, even if such resonance forms or tautomers are not shown herein.

[0062] Isotopes may be present in the compounds described. Each chemical element shown in the structure of a compound may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present within the compound. At any position in the compound where a hydrogen atom may be present, that hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein include all possible isotopic forms unless the context clearly indicates otherwise.

[0063] Definitions As used herein and in accordance with the present disclosure, the following terms are defined to have the following meanings unless otherwise expressly stated. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and / or" unless otherwise indicated. Further, the use of the term "including" and other forms, such as "includes" and "included", is not limiting.

[0064] As used herein, ranges and amounts may be expressed as “about” a particular value or range. “About” includes the exact amount. Thus, “about 10%” means “about 10%” and also means “10%”.

[0065] As used herein, “any” or “optionally” means that the event or situation described thereafter may or may not occur, and that the description includes examples where the event or situation occurs and examples where it does not occur. For example, an optionally substituted group means that the group is unsubstituted or substituted.

[0066] As used herein, the singular forms “a”, “an” and “the” include plural references unless the context clearly indicates otherwise. Thus, for example, a reference to a composition containing “a therapeutic agent” includes a composition containing one or more therapeutic agents.

[0067] As used herein, “a” and “b” being integers in “C a ~C b ” or “C a~b ” represents the number of carbon atoms in the indicated group. That is, the group may contain “a” to “b” carbon atoms including the upper and lower limits. Thus, for example, a “C1 - C4 alkyl” or “C 1~4 alkyl” group represents all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-.

[0068] As used herein, "alkyl" represents a straight or branched chain hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have from 1 to 20 carbon atoms (throughout this specification, a numerical range such as "1 to 20" represents each integer within that range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, and this definition also encompasses the use of the term "alkyl" when no numerical range is indicated). An alkyl group can also be a medium-sized alkyl having 1 to 9 carbon atoms. An alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. An alkyl group can be represented by "C1-C4 alkyl" or similar notations. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0069] As used herein, a substituted group is derived from an unsubstituted parent group and has one or more hydrogen atoms replaced by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclic-C1-C6 alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 10-membered heterocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6 alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclic oxy (optionally substituted with halo,(3 - 10 - membered heterocyclyloxy which may be substituted with C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy), (5 - 10 - membered heteroaryloxy which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy), C3 - C7 carbocyclic - C1 - C6 alkoxy which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, 3 - 10 - membered heterocyclyl - C1 - C6 alkoxy which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, aryl(C1 - C6)alkoxy which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, 5 - 10 - membered heteroaryl(C1 - C6)alkoxy which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, sulfhydryl (mercapto), halo(C1 - C6)alkyl (e.g., - CF3), halo(C1 - C6)alkoxy (e.g., - OCF3), C1 - C6 alkylthio, arylthio which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, C3 - C7 carbocyclicthio which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, 3 - 10 - membered heterocyclyl - thio which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, 5 - 10 - membered heteroaryl - thio which may be substituted with halo, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkyl, and C1 - C6 haloalkoxy, C3 - C7 carbocyclic - C1 - C6 alkylthio which may be substituted with halo, C1 - C6 alkyl,(3-10 membered heterocyclyl-C1-C6 alkylthio, which may be substituted with C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio (which may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo(=O), meaning that it is substituted with one or more substituents independently selected therefrom. When a group is denoted as "optionally substituted", it always means that the group can be substituted with the above substituents.,

[0070] As used herein, "acyl" represents -C(=O)R, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclyl, C 6~10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.,

[0071] "Heteroacyl" represents -C(=O)R, where R is C 1~6 heteroalkyl.,

[0072] "Alkyloxymethylene" represents -CH2OR, where R is C 1~6 alkyl or heteroalkyl, all of which may be optionally substituted.,

[0073] The "O-carboxy" group represents a "-OC(=O)R" group, where R is, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, selected therefrom.

[0074] The "C-carboxy" group represents a "-C(=O)OR" group, where R is, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, selected therefrom. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0075] The "cyano" group represents a "-CN" group.

[0076] The "cyanato" group represents a "-OCN" group.

[0077] The "isocyanato" group represents a "-NCO" group.

[0078] The "thiocyanato" group represents a "-SCN" group.

[0079] The "isothiocyanato" group represents a "-NCS" group.

[0080] The "sulfinyl" group represents a "-S(=O)R" group, where R is, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, selected therefrom.

[0081] The "sulfonyl" group represents a "-SO2R" group, where R is, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected.

[0082] The "S-sulfonamide" group represents a "-SO2NR A R B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected.

[0083] The "N-sulfonamide" group represents a "-N(R A )SO2R B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each independently selected.

[0084] The "O-carbamyl" group represents a "-OC(=O)NR A R B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C3~7 Carbocyclic, C 6~10 Selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic.

[0085] The "N-carbamyl" group represents the "-N(R A )C(=O)OR B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected.

[0086] The "O-thiocarbamyl" group represents the "-OC(=S)NR A R B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected.

[0087] The "N-thiocarbamyl" group represents the "-N(R A )C(=S)OR B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic selected.

[0088] The "C-amide" group represents the "-C(=O)NR A R B " group, where R A and R B are each independently, as defined herein, -OH, C 1~6 alkyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic, C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkyl, and C 1~6 alkoxy optionally substituted with alkoxy or -OH, and C 1~6 alkoxy hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic, each optionally substituted with one or more substituents selected from the group consisting of

[0089] The "N-amide" group represents the "-N(R A )C(=O)R B " group, where R A and R B are each independently, as defined herein, -OH, C 1~6 alkyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclic, C 1~6 alkyl optionally substituted with alkoxy or -OH, and C 1~6 alkyl, and C 1~6 alkoxy optionally substituted with alkoxy or -OH, and C 1~6 alkoxy hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C3~7 Carbocyclic, C 6~10 Selected from aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic.

[0090] The "amino" group represents a "-NR A R B " group, where R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclic. Non-limiting examples include free amino (i.e., -NH2).

[0091] The "aminoalkyl" group represents an amino group connected through an alkylene group.

[0092] The "alkoxyalkyl" group represents an alkoxy group connected through an alkylene group, such as "C 2~8 alkoxyalkyl", etc.

[0093] The term "acyloxy" represents -OC(O)R, where R is alkyl.

[0094] The term "alkoxy" or "alkyloxy" represents OR, where R is alkyl or heteroalkyl, all of which may be optionally substituted.

[0095] The term "carboxyl" represents C(O)OH.

[0096] The term "oxo" represents the =O group.

[0097] The term "halogen" or "halo" represents F (fluoro), Cl (chloro), Br (bromo), and I (iodo).

[0098] The term "haloalkyl" refers to an alkyl group containing at least one halogen and, in a further aspect, 1 to 3 halo atoms. Suitable halo atoms include F, Cl, and Br.

[0099] The term "haloacyl" refers to a -C(O)-haloalkyl group.

[0100] The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. The alkenyl group may be substituted. Suitable alkenyl groups include allyl.

[0101] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. The alkynyl group may be substituted. Suitable alkynyl groups include ethynyl.

[0102] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon within its ring skeleton. When aryl is a ring system, every ring within the system is aromatic. An aryl group can have 6 to 18 carbon atoms, although this definition also encompasses the use of the term "aryl" where no numerical range is indicated. In some embodiments, an aryl group has 6 to 10 carbon atoms. An aryl group can be denoted by "C 6~10 aryl", "C6 or C 10 aryl", or similar notations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0103] As used herein, "heteroaryl" represents an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing one or more heteroatoms, i.e., elements other than carbon including, but not limited to, nitrogen, oxygen, and sulfur, within its ring skeleton. When heteroaryl is a ring system, every ring within the system is aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting its ring skeleton, including carbon atoms and heteroatoms), although this definition also encompasses the use of the term "heteroaryl" where a numerical range is not indicated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group can be denoted by "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or similar notations. The heteroaryl group may be substituted. Examples of heteroaryl groups include aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom, or up to 4 nitrogen atoms, or a combination of one oxygen or sulfur atom and up to 2 nitrogen atoms, as well as their substituted derivatives and benzo and pyrido fused derivatives, for example, connected through one of the ring-forming carbon atoms, but are not limited thereto. In some embodiments, the heteroaryl group is halo, hydroxy, amino, cyano, nitro, alkylamide, acyl, C 1~6 alkoxy, C 1~6 alkyl, C 1~6It may be substituted with one or more substituents independently selected from hydroxyalkyl, C1-6 aminoalkyl, C1-6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolidine, cinnoline, phthalazine, quinazoline, and quinoxaline, including unsubstituted and mono- or di-substituted derivatives thereof, but not limited thereto. In some embodiments, the substituents are halo, hydroxy, cyano, O-C 1~6 alkyl, C 1~6 alkyl, hydroxy-C 1~6 alkyl, and amino-C 1~6 alkyl.

[0104] As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can have 3 to 10 carbon atoms (when used herein, a numerical range such as "3 to 10" always represents each integer within that range). A cycloalkyl group is denoted by "C3-C8 cycloalkyl" or a similar notation. By way of example only, "C3-C8 cycloalkyl" indicates that there are 3 to 8 carbon atoms in the carbocyclic ring or ring system.

[0105] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring structure that is fully saturated or partially saturated and contains at least one heteroatom selected from nitrogen, oxygen, and sulfur within its ring skeleton. Heterocyclyl can have any degree of saturation, provided that at least one ring within the ring system is not aromatic. The heteroatom can be present in either a non-aromatic ring or an aromatic ring within the ring system. A heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms constituting its ring skeleton, including carbon atoms and heteroatoms), although this definition also encompasses the use of the term "heterocyclyl" where no numerical range is indicated. A heterocyclyl group can also be a medium-sized heterocyclyl having 3 to 10 ring members. A heterocyclyl group can also be a heterocyclyl having 3 to 6 ring members. A heterocycloalkyl group is "3- to 15-membered heterocycloalkyl", "4- to 10-membered heterocycloalkyl", "3- to 15-membered C 2~14 heterocycloalkyl", "5- to 9-membered C 4~8 heterocycloalkyl", "5- to 10-membered C 4~9 heterocycloalkyl", "5-membered C 3~4 heterocycloalkyl", "6-membered C 4~5 heterocycloalkyl", "7-membered C 5~6 heterocycloalkyl", "bicyclic or tricyclic 9- to 15-membered C 8~14 heterocycloalkyl", "monocyclic or bicyclic 3- to 10-membered C 2~9 heterocycloalkyl", "bicyclic 8- to 10-membered C 4~9 heterocycloalkyl", "bicyclic 8- to 10-membered C 5~9 heterocycloalkyl", "monocyclic 4- to 7-membered C 3~6 heterocycloalkyl", "monocyclic 5- to 6-membered C 3~5"heterocycloalkyl", or may be represented by similar notations. The heterocyclyl group may also be a C2-C9 heterocyclyl having 3 to 10 ring members containing 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur). The heterocyclyl group may be represented by "3- to 10-membered C2-C9 heterocyclyl" or similar notations. In a preferred 6-membered monocyclic heterocyclyl, the heteroatom is selected from 1 to a maximum of 3 O (oxygen), N (nitrogen), or S (sulfur), and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom is selected from one or two heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur). Examples of the heterocyclyl ring include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0106] The term "therapeutically effective amount" means an amount of a compound or combination of compounds that partially or completely ameliorates, alleviates, or eliminates one or more symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more symptoms of a particular disease or condition. Such amount can be administered in a single dose or can be administered according to a regimen that is effective. Repeated dosing may be required to achieve the desired result (e.g., treatment of a disease and / or condition).

[0107] The term "pharmaceutically acceptable salt" includes salts of the compounds of Formula I obtained from combinations of the compounds of the present aspect with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can form salts include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, (+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonic acid, 1,2-ethanedisulfonic acid, dodecylsulfonic acid, salicylic acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthalenecarboxylic acid], polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, terphtahalic acid, etc. Inorganic bases that can form salts include bases containing, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., and particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. In some embodiments, treatment of the compounds disclosed herein with inorganic bases results in the loss of labile hydrogens from the compounds to give inorganic cations such as Li + 、Na + 、K + 、Mg 2+ and Ca 2+Provide salt forms including etc. Organic bases capable of forming salts include, for example, primary, secondary and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, etc., especially isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, etc.

[0108] When the number of the indicated substituents is not specified (e.g., "heteroalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. For example, "haloalkyl" includes each of the substituents CF3, CHF2 and CH2F.

[0109] The term "patient" refers to an animal to be treated including mammals such as dogs, cats, cows, horses, sheep, and humans. In some embodiments, the patient is a mammal of either male or female. In some embodiments, the patient is a human male or female.

[0110] As used herein, the term "prodrug" refers to any compound that, when administered to a living system, results in a biologically active compound as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and / or metabolic chemical reactions, or any combination thereof. Standard prodrugs are formed using groups that are attached to drug-associated functional groups that are cleaved in vivo, such as HO-, HS-, HOOC-, HOOPR2-. Standard prodrugs include carboxylic acid esters in which the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol and amine in which the added group is an acyl group, alkoxycarbonyl, aminocarbonyl, phosphate or sulfate, but are not limited thereto. The groups shown are examples and are not exclusive, and one of ordinary skill in the art will be able to prepare various other known prodrugs. A prodrug must undergo some form of chemical change to produce a compound that is a precursor of a biologically active or biologically active compound. In some instances, prodrugs are biologically active to a lesser extent than the drug itself and function to improve the efficacy or safety of the drug through improved oral bioavailability, pharmacokinetic half-life, etc. Compounds in prodrug form can be used, for example, to improve the acceptability of a subject by masking or reducing unpleasant characteristics such as bitterness or gastrointestinal irritation to improve bioavailability, to change solubility for intravenous use, to provide long-term or sustained release or delivery, to improve formulation ease, or to provide site-specific delivery of the compound.

[0111] The term "stereoisomer" refers to the relative or absolute spatial relationship of R groups attached to a stereocenter that is either a carbon or phosphorus atom, and represents individual isomers or any combination of individual isomers, such as racemic mixtures and diastereomeric mixtures. If a compound has two stereocenters, four potential stereoisomers exist.

[0112] The term "enhanced oral bioavailability" represents an increase of at least about 50% in the absorption of the dose of the reference drug. In a further aspect, the increase in the oral bioavailability of the compound (compared to the reference drug) is an absorption of at least about 100% or twice. The measurement of oral bioavailability typically represents the measurement of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration compared to after parenteral administration.

[0113] The term "therapeutic index" represents the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response to the dose that produces an unwanted response, such as death, an increase in a marker that is an indicator of toxicity, and / or a pharmacological side effect.

[0114] The term "sustained delivery" represents an increase in the period during which an extended therapeutically effective drug level is seen by the provision of a prodrug.

[0115] The term "treating" or "treatment" of a disease includes suppressing the disease (slowing or stopping or partially stopping its progression), preventing the disease, providing relief from the symptoms or side effects of the disease (including palliative treatment), and / or reducing the disease (regressing the disease).

[0116] The term "biological substance" represents a compound having biological activity or having molecular properties that can be used for therapeutic or diagnostic purposes, such as a compound having a radioisotope or a heavy atom.

[0117] Administration of pharmaceutical compositions The disclosed compounds can be used alone or in combination with other treatments. When these compounds are used in combination with other agents, they can be administered as a daily dose or as appropriate divided amounts of the daily dose (e.g., b.i.d.). The compounds may be administered after a course of treatment with another agent, during a course of treatment with another agent, as part of a treatment regimen, or before treatment with another agent in one treatment program.

[0118] Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methyl bromide, methyl sulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, tosylate, and triethiodide.

[0119] Compositions containing the active ingredient can be made in any form suitable for the intended method of administration. In some embodiments, the compounds of the methods and / or compositions described herein can be provided through oral administration, rectal administration, transmucosal administration, enteral administration, parenteral administration, topical administration, transdermal administration, intrathecal administration, intracerebroventricular administration, intraperitoneal administration, intranasal administration, intraocular administration, and / or parenteral administration.

[0120] When the compound is administered through oral administration, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions can include one or more ingredients including sweetening agents, flavoring agents, coloring agents and preservatives to provide a palatable preparation. Tablets containing the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated, or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, a delaying substance such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0121] Preparations for oral use can also be provided as hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient can be mixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil.

[0122] Formulations suitable for parenteral administration include, for example, aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition that requires only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the above kinds.

[0123] In some embodiments, the unit-dose formulation contains the daily dose or unit of the drug, a daily sub-dose, or an appropriate fractional amount thereof. However, as is well understood by those skilled in the art, the specific dosage level for any individual patient may depend on a variety of factors including the activity of the specific compound being used; the age, body weight, general health, sex, and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated.

[0124] The actual dosage of the compounds described herein depends on the specific compound and the condition being treated, and the selection of an appropriate dosage is well within the knowledge of those skilled in the art. In some embodiments, the daily dose can be from about 0.1 mg / kg body weight to about 100 mg / kg body weight or more, from about 0.25 mg / kg or less to about 50 mg / kg, from about 0.5 mg / kg or less to about 25 mg / kg, from about 1.0 mg / kg body weight to about 10 mg / kg body weight. Thus, for administration to a 70 kg human, the dosage range can be from about 7 mg per day to about 7000 mg per day, from about 35 mg or less per day to about 2000 mg or more per day, from about 70 mg per day to about 1000 mg per day.

[0125] Treatment methods Some aspects of the present invention include methods of treating a disease, disorder or condition selected from the group consisting of hepatitis, malaria, viral infection, coronavirus infection, parasitic infection, and compositions comprising a compound described herein. Some methods include administering to a subject in need thereof a compound, composition, or pharmaceutical composition described herein. In some aspects, the subject can be an animal, such as a mammal, a human. In some aspects, the subject is a human.

[0126] Some aspects provide methods of treating an infection caused by an infectious agent that is a virus, using an effective amount of one or more compounds disclosed herein. In some aspects, the virus is a single-stranded RNA virus. In other aspects, the virus is a double-stranded RNA virus. In yet other aspects, the virus is a positive-sense ssRNA virus. In some aspects, the virus is a negative-sense ssRNA virus. In some aspects, the virus is a double-stranded DNA virus. In other aspects, the virus is a single-stranded DNA virus.

[0127] In some embodiments, the virus can be a coronavirus. In some embodiments, the virus can be a pox virus. In some embodiments, the virus can be a smallpox virus. In some embodiments, the virus can be a Marburg virus. In some embodiments, the virus can be an Ebola virus. In some embodiments, the virus can be a flavivirus. In some embodiments, the virus can be an influenza virus. In some embodiments, the virus can be a parainfluenza virus. In some embodiments, the virus can be a respiratory syncytial virus. In some embodiments, the virus can be a rubella virus. In some embodiments, the virus can be a human immunodeficiency virus. In some embodiments, the virus can be a human papillomavirus. In some embodiments, the virus can be a varicella-zoster virus. In some embodiments, the virus can be a herpes simplex virus. In some embodiments, the virus can be a cytomegalovirus. In some embodiments, the virus can be an Epstein-Barr virus. In some embodiments, the virus can be a JC virus. In some embodiments, the virus can be a rhabdovirus. In some embodiments, the virus can be a rotavirus. In some embodiments, the virus can be a rhinovirus. In some embodiments, the virus can be an adenovirus. In some embodiments, the virus can be a papillomavirus. In some embodiments, the virus can be a parvovirus. In some embodiments, the virus can be a picornavirus. In some embodiments, the virus can be a poliovirus. In some embodiments, the virus can be a hantavirus. In some embodiments, the virus can be a filovirus. In some embodiments, the virus can be a coxsackievirus. In some embodiments, the virus can be an equine encephalitis virus. In some embodiments, the virus can be a Rift Valley fever virus.In some embodiments, the virus can be an alphavirus. In some embodiments, the virus can be hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, or hepatitis E virus.

[0128] In some embodiments, the virus can be a coronavirus. In some embodiments, the coronavirus can be MERS-CoV. In other embodiments, the coronavirus can be SARS-CoV. In some embodiments, the coronavirus can be SARS-CoV-2.

[0129] Further embodiments include administering a combination of compounds to a subject in need thereof. The combination can include the compounds, compositions, pharmaceutical compositions described herein, together with additional medicaments.

[0130] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with additional medicaments or additional therapeutic agents. "Co-administer" means that two or more agents can be found simultaneously in the bloodstream of a patient, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, combination administration is achieved by combining these agents in one dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, e.g., orally. In another embodiment, the agents are administered via different routes, e.g., one is administered orally and the other is administered i.v.

[0131] To further illustrate the present invention, the following examples are included. Of course, these examples should not be regarded as specifically limiting the present invention. Variations of these examples within the scope of the appended claims are within the understanding of those skilled in the art and are considered to be included within the scope of the invention described and claimed herein. The reader will understand that the present disclosure and those skilled in the art of this technology can prepare and use the present invention even without comprehensive examples.

[0132] Synthesis of compounds The following preparation procedures of the novel compounds show the general procedures used to prepare nucleotide prodrug compounds.

[0133] Scheme I shows the general synthesis of the compounds of formulas I, II, and III. The hydroxyl groups at the 3’ and 5’ positions of the nucleoside (1) are reacted with phosphanediamine (2) in the presence of 4,5-dicyanoimidazole to form a cyclic product of structure 3, and then this crude reaction mixture is treated with an oxidizing agent, such as tert-butyl hydroperoxide (TBHP), to obtain the final product 4 of formulas I, II, and III.

[0134] Scheme I TIFF0007699205000008.tif41157R has the definition as R above 1 and is so defined.

Examples

[0135] Some representative compounds were prepared as outlined below.

[0136] Example 1 Ethyl 2 - ((((4aR,6R,7R,7aR)-7 - acetoxy - 6 - (4 - (hydroxyamino)-2 - oxopyrimidin - 1(2H)-yl)-2 - oxide tetrahydro - 4H - furo[3,2 - d][1,3,2]dioxaphosphinin - 2 - yl)oxy)methyl)benzoate (Compound 101) Compound 101 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(amino)pyrimidin-2(1H)-one according to the method described in Scheme I.

[0137] Ethyl 2-((((4aR,6R,7R,7aR)-7-hydroxy-6-(4-(amino)-2-oxopyrimidin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 101a) To a mixture of 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(amino)pyrimidin-2(1H)-one (5.0 g, 20 mmol) and N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine (1.0 equiv) in THF / acetonitrile was added DCI (2.5 equiv), and the mixture was then heated at 55 °C for 2 h. The crude mixture was then treated with TBHP (2.5 equiv) at 0 °C for 30 min. Compound 101a was obtained in about 10% yield by standard workup and subsequent column purification.

[0138] Ethyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(4-(amino)-2-oxopyrimidin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 101b) Compound 101a was treated with acetic anhydride (1.0 equiv) in acetonitrile in the presence of DMAP and triethylamine at room temperature for 2 h. The acylated Compound 101b was obtained in about 80% yield by standard workup and subsequent purification.

[0139] Ethyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 101) Compound 101b was treated with hydroxylamine HCl salt (2.0 equiv) in acetonitrile at 37 °C overnight. The hydroxylated product, Compound 101, was obtained in an isolated yield of approximately 15% by standard workup and subsequent purification. C 21 H 24 N3O 11 Calculated [M+1] for + : 526.12. Found: 526.2.

[0140] Example 2 Ethyl 2-((((4aR,6R,7R,7aS)-7-hydroxy-6-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 102) TIFF0007699205000010.tif32128 Compound 102 can be prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-(hydroxyamino)pyrimidin-2(1H)-one according to the method described in Scheme I.

[0141] Example 3 Ethyl 2-((((4aR,6S,7S,7aS)-6-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-7-hydroxy-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 103) TIFF0007699205000011.tif31128 Compound 103 can be prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and (2S,3R,4S,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol according to the method described in Scheme I.

[0142] Example 4 Ethyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(3-carbamoyl-5-fluoro-2-oxopyrazin-1(2H)-yl)-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 104) TIFF0007699205000012.tif35128 Compound 104 can be prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and 4-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-fluoro-3-oxo-3,4-dihydropyrazine-2-carboxamide according to the method described in Scheme I.

[0143] Example 5 Ethyl 2-((((4aR,6R,7R,7aR)-6-(2-amino-6-(methylamino)-9H-purin-9-yl)-7-fluoro-7-methyl-2-oxide tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 105) TIFF0007699205000013.tif30128 Compound 105 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol according to the method described in Scheme I. C 22 H 26 [M+1] calculated for FN6O7P + : 537.17. Found: 537.2.

[0144] Example 6 Ethyl 2-((((4aR,6S,7aS)-6-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-methylene-2-oxidehexahydrocyclopenta[d][1,3,2]dioxaphosphinin-2-yl)oxy)methyl)benzoate (Compound 106) TIFF0007699205000014.tif27128 Compound 106 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethyloxy)carbonylbenzyloxy)phosphanediamine and 2-amino-9-((1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl)-1,9-dihydro-6H-purin-6-one according to the method described in Scheme I. C 22 H 24 [M+1] calculated for N5O7P + : 502.15. Found: 502.1.

[0145] Biological examples Examples of the use of the method include the following. It will be understood that the following are examples and that the method is not limited to these examples only.

[0146] Example 7 Tissue distribution after oral administration of reference compounds and disclosed compounds Compare the liver specificity of the disclosed compounds to the corresponding active compounds in the liver and other organs that may be targets of toxicity.

[0147] Methods Administer the reference compound and the nucleotide prodrug compound to fasted rats by oral gavage at 5 - 50 mg / kg. Determine the plasma concentrations of metabolites and parent compounds in the circulation and the hepatic portal vein by HPLC - UV, and measure the concentrations in their liver, small intestine, and other organs by LC - MS using standard chromatography methods. Measure the ratio of the novel compound to the corresponding reference compound in the nucleoside phosphate levels in the liver and lung and the nucleoside levels in the hepatic portal vein (HPV) and systemic blood 1 hour after oral administration of the selected compound at a dose of 5 mg / kg nucleoside equivalent in rats.

[0148] All numerical values representing amounts of ingredients, reaction conditions, etc. used herein should be understood to be modified in all instances by the term "about". Accordingly, unless indicated otherwise, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. In the broadest sense and not as an attempt to limit the application of the doctrine of equivalents to any claim of any application claiming priority from this application, each numerical parameter should be construed in light of the number of significant figures and ordinary rounding conventions.

[0149] Terms such as those shown in this specification, for example, the terms "about", "approximately", "substantially", and "substantially" as used in this specification, still represent values, amounts, or characteristics that are close to the values, amounts, or characteristics mentioned and that perform the desired function or achieve the desired result. For example, the terms "about", "approximately", "substantially", and "substantially" may represent amounts within less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the amount mentioned. As another example, in certain embodiments, the terms "substantially parallel" and "substantially parallel" represent values, amounts, or characteristics that deviate from exact parallelism by 15%, 10%, 5%, 3%, 1%, 0.1%, etc. or less. Similarly, in certain embodiments, the terms "substantially perpendicular" and "substantially perpendicular" represent values, amounts, or characteristics that deviate from exact perpendicularity by 15%, 10%, 5%, 3%, 1%, 0.1%, etc. or less.

[0150] The above description discloses various methods and materials. In the present invention, modifications to methods and materials as well as changes to manufacturing methods and equipment are possible. Such modifications will be apparent to those skilled in the art from a consideration of the present disclosure or from the practice of the invention disclosed herein. Therefore, it is not intended that the present invention be limited to the specific embodiments disclosed herein, which encompasses all modifications and changes made within the true scope and spirit of the present invention.

[0151] All references cited herein, including but not limited to published or unpublished applications, patents, and references, are hereby incorporated by reference in their entirety and thereby form a part of this specification. In the event that the publications and patents or patent applications incorporated by reference conflict with the disclosure herein, this specification is intended to supersede any such conflicting materials and / or be preferred over any such conflicting materials.

[0152] Although several embodiments and examples are described, it should be understood that numerous and diverse modifications can be made without departing from the spirit of the present invention.

Claims

1. A compound of formula I, II, or III, or a stereoisomer or pharmaceutically acceptable salt thereof: Wherein, R 1 is selected from the group consisting of H, optionally substituted C 1 to C 15 alkyl, optionally substituted C 3 to C 15 cycloalkyl, and optionally substituted C 2 to C 15 alkenyl, R 2 is selected from the group consisting of halogen, optionally substituted alkyl, and optionally substituted alkyloxy, R 3 is selected from the group consisting of H, optionally substituted acyl, C-carboxy, and C-amide, BASE is, selected from the group consisting of, R 4 is selected from the group consisting of H, optionally substituted acyl, and C-carboxy, R 5 is selected from the group consisting of H, optionally substituted acyl, C-carboxy, and C-amide, n is 0, 1, 2, or 3.

2. The compound according to claim 1, wherein n is 1.

3. The compound according to claim 1, wherein n is 0.

4. R 3 The compound according to any one of claims 1 to 3, wherein R is H.

5. R 1 is optionally substituted C 1 -C 15 alkyl, a compound according to any one of claims 1 to 4.

6. R 1 is unsubstituted C 1 -C 6 -alkyl, the compound according to claim 5.

7. R 1 The compound according to claim 6, wherein R is ethyl.

8. R 1 The compound according to claim 6, wherein R is n-propyl.

9. R 1 The compound according to claim 6, wherein R is i-propyl. The compound according to claim 1, selected from the group consisting of [

10. ].

11. A pharmaceutical composition for treating viral infection, comprising the compound according to any one of claims 1 to 10.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, in combination with one or more additional therapeutic agents.

13. Use of the compound according to any one of claims 1 to 10 in the preparation of a medicament for treating viral infection.

14. A pharmaceutical composition for use in a method of treating viral infection, comprising the compound according to any one of claims 1 to 10, wherein the method comprises administering an effective amount of the compound to a subject in need thereof.

15. The pharmaceutical composition according to claim 14, wherein the subject is a mammal.

16. The pharmaceutical composition according to claim 15, wherein the mammal is a human.

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