Nucleotide prodrug compounds

Abstract

Provided herein are nucleotide prodrug compounds, their preparation, and their uses, such as for treating viral infectious diseases or disorders.

Description

Technical Field

[0001] The present invention relates to the fields of chemistry and medicine. More specifically, the present invention relates to nucleotide prodrug compounds, methods for preparing the same, and uses thereof. In some embodiments, such compounds can be used to selectively deliver certain pharmaceutical preparations to target organs. Background Art

[0002] The following background description is provided to assist in understanding the present invention but is not intended to constitute or describe prior art.

[0003] Synthetic nucleotide analogs are widely used as antiviral and anticancer agents. Prodrug technology has been used to improve the molecular properties of nucleotides to make them more bioavailable to target organs and / or cells, including improving oral bioavailability. Therefore, in addition to enhanced oral bioavailability, new compounds with improved prodrug activation characteristics could significantly enhance the therapeutic benefits of nucleotide analog-based therapies. Summary of the Invention

[0004] New nucleotide prodrug compounds, their preparation and uses are described. Some embodiments are new nucleotide prodrug compounds that are delivered orally to target organs where the compound provides therapeutic benefit. Other embodiments include new nucleotide prodrug compounds that treat diseases, conditions or disorders including hepatitis, malaria, viral infections, parasitic infections and coronavirus infections. On the other hand, the nucleotide prodrug compounds are used to treat diseases that benefit from increased drug distribution to target organs and similar tissues and cells. On the other hand, the nucleotide prodrug compounds are used to increase the pharmacological or clinical activity of certain classes of drug compounds, such as similar compounds derived from nucleotides. In some embodiments, the nucleotide prodrug compounds can be used to more efficiently deliver the nucleotide compounds to target organs and cells orally and / or by inhalation. Some other embodiments relate to a method for preparing a nucleotide prodrug compound.

[0005] Some embodiments provided herein comprise compounds of Formula I:

[0006]

[0007] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0008] where R 1 、R 2 、R 3 、R 4 and n has any value described herein.

[0009] Some embodiments relate to a pharmaceutical composition comprising one or more of the compounds described above, and one or more pharmaceutically acceptable excipients.

[0010] Some embodiments relate to a pharmaceutical composition comprising a compound as described above, and one or more pharmaceutically acceptable excipients.

[0011] Some embodiments relate to a method of treating a disease, disorder, or condition comprising administering an effective amount of one of the compounds described above.

[0012] In some embodiments, the disease, disorder or condition is a viral disease, disorder or condition.

[0013] Some embodiments relate to a method of treating a viral infection, comprising administering to a subject in need thereof an effective amount of one of the compounds described above.

[0014] Some embodiments further comprise administering to the individual in need thereof an effective amount of at least one additional therapeutic agent.

[0015] In some embodiments, the individual is a mammal.

[0016] In some embodiments, the individual is a human.

[0017] In some embodiments, the cell is in vivo.

[0018] In some embodiments, the cells are ex vivo.

[0019] In some embodiments, the cell is a hepatocyte.

[0020] In some embodiments, the cell is a mammalian cell.

[0021] In some embodiments, the cell is a human cell.

[0022] Some embodiments of the compounds, compositions, and methods provided herein comprise a pharmaceutical composition comprising a compound provided herein and one or more pharmaceutically acceptable excipients.

[0023] Some embodiments of the compounds, compositions, and methods provided herein comprise a method of treating a viral disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound provided herein.

[0024] Some embodiments of the compounds, compositions, and methods provided herein comprise a method of treating a disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound provided herein.

[0025] Some embodiments also comprise administering to an individual in need thereof an effective amount of one or more additional therapeutic agents.

[0026] In some embodiments, the individual is a mammal.

[0027] In some embodiments, the individual is a human.

[0028] Some embodiments also encompass the use of a compound provided herein in combination with other therapeutic agents.

[0029] Some embodiments of the compounds, compositions, and methods provided herein include a composition described herein for use in the preparation of a pharmaceutical formulation for treating a disease or condition caused by a viral infection.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Shown are graphs of the blood concentrations of the corresponding nucleosides in rats at selected time points after intravenous administration of Remdesivir, oral administration of Remdesivir, or oral administration of Compound 105.

[0032] Figure 2 Shown are graphs of the blood concentrations of the corresponding nucleosides in rats at selected time points after intravenous administration of remdesivir, oral administration of remdesivir, or oral administration of compound 105.

[0033] Figure 3 Graphs showing liver concentrations of the corresponding triphosphates in rats at selected time points after intravenous administration of remdesivir, oral administration of remdesivir, or oral administration of compound 105.

[0034] Figure 4 A graph showing the ratio of (concentration of the corresponding nucleoside in the liver) / (concentration of the corresponding nucleoside in the blood) in rats at selected time points after intravenous administration of remdesivir, oral administration of remdesivir, or oral administration of compound 105.

[0035] Figure 5 Graphs showing blood concentrations of the corresponding nucleosides in rats at selected time points after administration of inhaled remdesivir or intratracheal compound 105.

[0036] Figure 6 Graphs showing lung concentrations of the corresponding nucleosides in rats at selected time points after administration of inhaled remdesivir or intratracheal compound 105.

[0037] Figure 7 Graphs showing lung concentrations of the corresponding triphosphates in rats at selected time points after administration of inhaled remdesivir or intratracheal compound 105. Detailed Description of the Invention

[0039] Embodiments of the present invention relate to compositions and methods related to novel nucleotide prodrug compounds, methods for their preparation, and uses thereof. In some embodiments, these novel nucleotide prodrug compounds facilitate the delivery of nucleotide-derived pharmaceutical agents containing nucleobase derivatives / analogs and prodrugs, such as ribonucleotides and deoxyribonucleotides, into cells.

[0040] These nucleotide prodrug compounds and their stereoisomers and pharmaceutically acceptable salts are represented by Formula I:

[0041]

[0042] or a stereoisomer or a pharmaceutically acceptable salt thereof,

[0043] where R 1 、R 2 、R 3 、R 4 and n has any value described herein.

[0044] In some embodiments, R 1 Selected from: H, optionally substituted C1-C 15 Alkyl, optionally substituted C3-C 15 Cycloalkyl and optionally substituted C2-C 15 Alkenyl.

[0045] In some embodiments, R 1 is an optionally substituted C1-C 15 alkyl.

[0046] In some embodiments, R 1 It is an unsubstituted C1-C6 alkyl group.

[0047] In some embodiments, R 1 It's ethyl.

[0048] In some embodiments, R 1 It's n-propyl.

[0049] In some embodiments, R 1 It is isopropyl.

[0050] In some embodiments, R 1 It's methyl.

[0051] In some embodiments, R 2 is selected from the group consisting of halogen, optionally substituted alkyl and optionally substituted alkoxy.

[0052] In some embodiments, R 3is selected from: H, optionally substituted acyl and C-carboxyl.

[0053] In some embodiments, R 3 It’s H.

[0054] In some embodiments, R 4 is selected from the group consisting of: H, optionally substituted acyl, C-amido, and C-carboxyl.

[0055] In some embodiments, n is 0, 1, 2, or 3.

[0056] In some embodiments, n is 0.

[0057] In some embodiments, n is 1.

[0058] In some embodiments, R 4 In some embodiments, R 4 It is an acyl group.

[0059] In some embodiments, the compound is selected from:

[0060]

[0061] In some embodiments, the nucleotide prodrug compounds of Formula I are substrates for enzymes such as the cytochrome p450 isozyme CYP3A (monooxygenase family), dehydrogenases, esterases, and amidases.

[0062] In some embodiments, the compound is activated within the cell when the prodrug moiety is cleaved, releasing the compound in active form.

[0063] In some embodiments, disclosed compounds are used to improve pharmacokinetic properties, such as extending the half-life of nucleotides or enhancing the absorption of nucleotides. In addition, disclosed methods can be used to achieve sustained delivery of biologically relevant nucleotides. Due to the enhanced pharmacokinetic properties of the nucleotide prodrug compounds of Formula I, these compounds are used to treat viral infections or diseases. In some embodiments, a method for preparing these compounds is described.

[0064] Compounds of Formula I have asymmetric centers where the stereochemistry may not be specified, and general references to compounds of Formula I encompass diastereomeric mixtures of these compounds as well as individual stereoisomers.

[0065] In some embodiments, an effective amount of a disclosed compound is used to treat a disease, disorder, or condition in a subject in need thereof.

[0066] In some embodiments, the compounds described herein are used to treat viral infections.

[0067] In some embodiments, the compounds described herein are used in combination with one or more additional therapeutic agents.

[0068] In some embodiments, the compounds described herein are used to prepare a medicament for treating a viral infection.

[0069] In some embodiments, the compounds described herein are used in a method of treating a viral infection comprising administering an effective amount of the compound to a subject in need thereof.

[0070] Some embodiments of the compounds, compositions, and methods provided herein comprise a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier.

[0071] Some embodiments further comprise administering to an individual in need thereof an effective amount of another therapeutic agent or agents in combination with a compound provided herein.

[0072] In some embodiments, the individual is a mammal.

[0073] In some embodiments, the individual is a human.

[0074] Some embodiments of the compounds, compositions, and methods provided herein comprise a method of testing a compound in a cell comprising contacting the cell with a disclosed compound.

[0075] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers including racemates. The separation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise stated, all of these isomers and mixtures thereof are included within the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise stated, all of these forms are included within the scope of the compounds disclosed herein, including any polymorphic form. In addition, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or commonly used organic solvents. Unless otherwise stated, such solvates are included within the scope of the compounds disclosed herein.

[0076] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be reasonably represented by other chemical structures even though they are kinetically represented; the skilled artisan recognizes that such structures represent only a very small fraction of such compound samples. Even though resonance forms or tautomers are not represented herein, such compounds are considered to be within the scope of the described structures.

[0077] Isotopes may be present in the described compounds. Each chemical element represented in a compound structure 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 in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, unless the context clearly dictates otherwise, compounds referred to herein encompass all possible isotopic forms.

[0078] definition

[0079] Unless otherwise expressly stated, the following terms are defined to have the following meanings in accordance with the present disclosure and as used herein. It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not limitations of the claimed subject matter. In this application, unless otherwise stated, the use of the singular includes the plural. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" as well as other forms such as "includes" and "included" is not limiting.

[0080] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the exact amount. Thus, "about 10%" means "about 10%" as well as "10%."

[0081] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance occurs or does not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, an optionally substituted group means that the group is unsubstituted or substituted.

[0082] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a composition comprising "a therapeutic agent" includes compositions having one or more therapeutic agents.

[0083] As used herein, “C a to C b ” or “C a-b ” (where “a” and “b” are integers) refers to the number of carbon atoms in the specified group. That is, the group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4"Alkyl" refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0084] As used herein, "alkyl" refers to a fully saturated (i.e., not containing double or triple bonds) straight or branched hydrocarbon chain. An alkyl group may have 1 to 20 carbon atoms (whenever a numerical range appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although this definition also encompasses the presence of the term "alkyl" without a specified numerical range). An alkyl group may also be a medium-sized alkyl group having 1 to 9 carbon atoms. An alkyl group may also be a lower alkyl group having 1 to 4 carbon atoms. An alkyl group may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0085] As used herein, a substituent group is derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged by another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it means that the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 carbocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 C1-C6 alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclic (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclic-C1-C6 alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted by substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e.,ether), aryloxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyloxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclyloxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryloxy (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkoxy (optionally substituted by halogen , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6 alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkoxy (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkoxy (optionally substituted with halogen, 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 (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7 carbocyclylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 3-10 membered heterocyclylthio (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroarylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7 carbocyclyl-C1-C6 alkylthio (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkylthio(optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3-10 membered heterocyclyl-C1-C6 alkylthio(optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl(C1-C6)alkylthio(optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), amino, amino(C1-C6)alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxyl, O-carboxyl, acyl, cyano, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted," the group may be substituted with the substituents described above.

[0086] As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0087] "Heteroacyl" refers to -C(=O)R, where R is C 1-6 Heteroalkyl.

[0088] "Alkoxymethylene" refers to -CH2OR, where R is C1-6 Alkyl or heteroalkyl, both optionally substituted.

[0089] An "O-carboxyl" group refers to a "-OC(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0090] A "C-carboxyl" group refers to a "-C(=O)OR" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0091] A "cyano" group refers to a "-CN" group.

[0092] A "cyanato" group refers to a "-OCN" group.

[0093] An "isocyanato" group refers to a "-NCO" group.

[0094] A "thiocyanato" group refers to a "-SCN" group.

[0095] An "isothiocyanato" group refers to a "-NCS" group.

[0096] A "sulfinyl" group refers to a "-S(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0097] "Sulfonyl" refers to a "-SO2R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0098] "S-sulfonamido" refers to "-SO2NR A R B" group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0099] "N-sulfonamido" refers to "-N(R A )SO2R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0100] "O-carbamoyl" refers to "-OC(=O)NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0101] "N-carbamoyl" refers to "-N(R A )C(=O)OR B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0102] "O-thiocarbamoyl" refers to "-OC(=S)NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0103] "N-thiocarbamoyl" refers to "-N(R A )C(=S)OR B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl are as defined herein.

[0104] "C-amido" refers to "-C(=O)NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, as defined herein, each of which is optionally substituted by one or more substituents selected from the group consisting of: -OH, C 1-6 Alkyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkyl and optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkoxy.

[0105] "N-amido" refers to "-N(R A )C(=O)R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, as defined herein, each of which is optionally substituted by one or more substituents selected from the group consisting of: -OH, C 1-6 Alkyl, C3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkyl and optionally C 1-6 Alkoxy or -OH substituted C 1-6 Alkoxy.

[0106] "Amino" refers to "-NR A R B " group, wherein R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl are as defined herein. Non-limiting examples include free amino (ie, -NH2).

[0107] "Aminoalkyl" refers to an amino group linked through an alkylene group.

[0108] "Alkoxyalkyl" refers to an alkoxy group attached through an alkylene group, such as "C 2-8 Alkoxyalkyl" etc.

[0109] The term "acyloxy" refers to a -OC(O)R group where R is an alkyl group.

[0110] The term "alkoxy" or "alkyloxy" refers to OR, where R is alkyl or heteroalkyl, each optionally substituted.

[0111] The term "carboxyl" refers to C(O)OH.

[0112] The term "oxo" refers to a =0 group.

[0113] The term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine) and I (iodine).

[0114] The term "haloalkyl" refers to an alkyl group containing at least one halogen, and in another aspect 1 to 3 halogen atoms. Suitable halogen atoms include F, Cl and Br.

[0115] The term "haloacyl" refers to a -C(O)-haloalkyl group.

[0116] The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, and includes straight chain, branched chain and cyclic groups. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl.

[0117] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, and includes straight chain, branched chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl.

[0118] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When an aryl is a system, each ring in the system is an aromatic ring. An aryl group may have from 6 to 18 carbon atoms, although this definition also encompasses the presence of the term "aryl" without specifying a numerical range. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group may be designated as "C 6-10 Aryl", "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0119] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms (i.e., elements other than carbon) in the ring backbone, including but not limited to nitrogen, oxygen, and sulfur. When a heteroaryl is a ring system, each ring in the system is an aromatic ring. A heteroaryl group may have 5-18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the presence of the term "heteroaryl" without specifying a numerical range. In some embodiments, a heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. A heteroaryl group may be designated as a "5-7 membered heteroaryl," "5-10 membered heteroaryl," or similar designations. A heteroaryl group may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 2-12-13-14-16-17-18-17 ... 3-8 Heterocyclic groups, and substituted and benzo and pyrido fused derivatives thereof, such as fused derivatives linked via a ring-forming carbon atom. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, nitro, alkylamide, acyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, 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, quinazoline, In some embodiments, the substituents are halogen, hydroxy, cyano, OC 1-6 -alkyl, C 1-6 -alkyl, hydroxy-C 1-6 -alkyl and amino-C 1-6 -alkyl.

[0120] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group may have 3 to 10 carbon atoms (when appearing herein, a numerical range such as "3 to 10" refers to each integer within a given range). A cycloalkyl group may be designated as "C3-C8 cycloalkyl" or similar designations. By way of example only, "C3-C8 cycloalkyl" means that there are three to eight carbon atoms in the carbocyclyl ring or ring system.

[0121] 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 in the ring backbone. The heterocyclyl group may have any degree of saturation, provided that at least one ring in the ring system is not an aromatic ring. Heteroatoms may be present in non-aromatic rings or aromatic rings in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), but this definition also covers the existence of the term "heterocyclyl" without specifying a numerical range. The heterocyclyl group may also be a medium-sized heterocyclyl group having 3 to 10 ring members. The heterocyclyl group may also be a heterocyclyl group having 3 to 6 ring members. Heterocycloalkyl groups may be designated as "3-15 membered heterocycloalkyl", "4-10 membered heterocycloalkyl", "3-15 membered C 2-14 Heterocycloalkyl", "5-9 membered C 4-8 Heterocycloalkyl", "5-10 membered C 4-9 Heterocycloalkyl", "5-membered C 3-4 Heterocycloalkyl", "6-membered C 4-5 Heterocycloalkyl", "7-membered C 5-6Heterocycloalkyl", "bicyclic or tricyclic 9-15 membered C 8-14 Heterocycloalkyl", "monocyclic or bicyclic 3-10 membered C 2-9 Heterocycloalkyl", "bicyclic 8-10 membered C 4-9 Heterocycloalkyl", "bicyclic 8-10 membered C 5-9 Heterocycloalkyl", "monocyclic 4-7 membered C 3-6 Heterocycloalkyl", "monocyclic 5-6 membered C 3-5 The heterocyclic group may also be a C2-C9 heterocyclic group having 3 to 10 ring members and having one to three of O (oxygen), N (nitrogen) or S (sulfur). The heterocyclic group may be designated as a "3-10 membered C2-C9 heterocyclic group" or similar names. In preferred six-membered monocyclic heterocyclic groups, the heteroatoms are selected from one to three of O (oxygen), N (nitrogen) or S (sulfur), and in preferred five-membered monocyclic heterocyclic groups, the heteroatoms are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). Examples of heterocyclic rings include, but are not limited to, nitrogen heterocyclic groups, acridinyl groups, carbazolyl groups, pyrrolidonyl, pyrrolidone, pyrrolidone, 4-piperidone, pyrazolinyl, pyrazolidinone, 1,3-dioxinyl, 1,3-dioxane, 1,4-dioxolanyl ... heterocyclohexenyl, 1,4-dioxane, 1,3-oxathiinyl, 1,4-oxathiinyl, 1,4-oxathiinyl, 2H-1,2-oxazinyl, trioxazinyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl, and tetrahydroquinolinyl.

[0122] Similarly, when two "adjacent" R groups are referred to as forming a ring "together with the atoms to which they are attached," it is meant that the entire unit formed by the atoms, intervening bonds, and the two R groups is the ring. For example, when the following substructures are present:

[0123]

[0124] R 1 and R 2is defined as being selected from hydrogen and alkyl, or R 1 and R 2 When R is taken together with the atoms to which it is attached to form an aryl or carbocyclic group, it means 1 and R 2 May be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0125]

[0126] wherein A is an aryl ring or a carbocyclyl containing the depicted double bond.

[0127] Where a substituent is described as a divalent group (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, a substituent described as -AE- or The substituents of include substituents that are oriented such that A is attached at the left-most attachment point of the molecule as well as cases where A is attached at the right-most attachment point of the molecule.

[0128] The phrase "therapeutically effective amount" means an amount of a compound or combination of compounds that partially or completely improves, alleviates, or eliminates one or more symptoms of a particular disease or condition, or prevents, ameliorates, or delays the onset of one or more symptoms of a particular disease or condition. Such an amount can be administered as a single dose, or can be administered according to an effective regimen. Repeated administration may be required to achieve the desired result (e.g., treatment of a disease and / or condition).

[0129] The term "pharmaceutically acceptable salt" includes salts of compounds of Formula I derived from combinations of compounds of the present invention with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, adipic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic 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, hydrochloric hemiglycolic acid, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, methylbromic acid, methylsulfuric acid, 2-naphthalenesulfonic acid, oleic acid, 4,4'-methylenebis-[3-hydroxy-2-naphthoic acid], polygalacturonic acid, stearic acid, sulfosalicylic acid, tannic acid, isophthalic acid, and the like. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts are particularly preferred. In some embodiments, treatment of a compound disclosed herein with an inorganic base causes the compound to lose a labile hydrogen to yield a salt form comprising an inorganic cation, such as Li + 、Na + , K + Mg 2+ and Ca 2+ Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0130] When the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more halogens, which may be the same or different. For example, "haloalkyl" includes each of the substituents CF3, CHF2, and CH2F.

[0131] The term "patient" refers to the animal being treated, including mammals such as dogs, cats, cows, horses, sheep, and humans. In some embodiments, the patient is a male or female mammal. In some embodiments, the patient is male or female.

[0132] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a biologically active compound due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, and / or a metabolic chemical reaction, or a combination thereof. Standard prodrugs are formed using groups attached to functional groups associated with the drug (e.g., HO-, HS-, HOOC-, HOOPR2-), which are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters, wherein the group is an alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and esters of hydroxyl, thiol, and amine, wherein the attached group is an acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups shown are examples, but not exhaustive, and those skilled in the art can prepare other known types of prodrugs. Prodrugs must undergo some form of chemical transformation to produce a compound that is biologically active or serves as a precursor to a biologically active compound. In some cases, prodrugs have biological activity, which is generally lower than that of the drug itself, and improve drug efficacy or safety by improving oral bioavailability, pharmacodynamic half-life, etc. Prodrug forms of the compounds can be utilized, for example, to improve bioavailability; improve subject acceptability, such as by masking or reducing unpleasant characteristics, such as bitter taste or gastrointestinal irritation; alter solubility, such as for intravenous use; provide extended or sustained release or delivery; improve formulation convenience; or provide site-specific delivery of the compound.

[0133] The term "stereoisomer" refers to the relative or absolute spatial relationship of the R groups attached to the central carbon or phosphorus atom of the stereoisomer, and refers to a single isomer or any combination of single isomers, such as a racemic mixture and a diastereomeric mixture. When a compound has two stereogenic centers, there are four potential stereoisomers.

[0134] The term "enhanced oral bioavailability" refers to an increase in absorption of a reference drug dose by at least about 50%. In another aspect, the compound has an increase in oral bioavailability (compared to the reference drug) by at least about 100% or a doubling of absorption. Measurement of oral bioavailability generally refers to the measurement of a prodrug, drug, or drug metabolite in blood, plasma, tissue, or urine after oral administration compared to measurements after parenteral administration.

[0135] The term "therapeutic index" refers to the ratio of the dose of a drug or prodrug that produces a therapeutically beneficial response relative to the dose that produces an adverse response, such as death, elevation of markers suggestive of toxicity, and / or pharmacological side effects.

[0136] The term "sustained delivery" refers to the prolonged period of therapeutically effective drug levels due to the presence of a prodrug.

[0137] The term "treating" or "treatment" of a disease includes inhibiting the disease (slowing or stopping or partially arresting its development), preventing the disease, alleviating the symptoms or side effects of the disease (including palliative treatment) and / or palliating the disease (causing regression of the disease).

[0138] The term "biologic" refers to a compound that has biological activity or molecular properties that can be used for therapeutic or diagnostic purposes, such as compounds that carry radioactive isotopes or heavy atoms.

[0139] The term "molecular pathway" refers to a series of molecular events in a tissue, such as a receptor regulatory sequence, an enzyme regulatory sequence, or a biosynthetic sequence, that is involved in a physiological or pathophysiological function in a living animal.

[0140] Administration and pharmaceutical compositions

[0141] The disclosed compounds can be used alone or in combination with other treatments. When used in combination with other drugs, these compounds can be administered as a daily dose or as an appropriate fraction of a daily dose (e.g., twice daily). The compounds can be administered after a course of treatment with another drug, during a course of treatment with another drug, as part of a treatment regimen, or before treatment with another drug in a treatment regimen.

[0142] Examples of pharmaceutically acceptable salts include acetate, adipate, benzenesulfonate, bromide, camphorsulfonate, chloride, citrate, edisylate, estolate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, methanesulfonate, methylbromide, methylsulfate, naphthylsulfonate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terephthalate, toluenesulfonate, and triethyl iodide.

[0143] The compositions containing the active ingredients can be 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 via oral, rectal, transmucosal, enteral, enteral, topical, transdermal, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular, and / or parenteral administration.

[0144] When the compound is administered orally, it can be prepared, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavorings, colorants, and preservatives, to provide a palatable preparation. Tablets containing a mixture of the active ingredient with nontoxic, pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients may include, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate, or glyceryl monostearate or glyceryl distearate with a wax may be employed.

[0145] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin; or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily medium, such as peanut oil, liquid paraffin or olive oil.

[0146] Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain, for example, antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be present in single-dose or multi-dose sealed containers, such as ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Injections and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0147] In some embodiments, the unit dosage formulation contains a daily dose or unit, daily divided dose, or an appropriate fraction thereof. However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the age, weight, general health, sex, and diet of the individual being treated; time and route of administration; rate of excretion; other medications previously taken; and the severity of the specific disease being treated, as is well understood by those skilled in the art.

[0148] The actual dosage of the compounds described herein depends on the specific compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of those skilled in the art. In some embodiments, the daily dosage may be from about 0.1 mg to about 100 mg or more per kilogram of body weight, from about 0.25 mg or as low as about 50 mg per kilogram of body weight, from about 0.5 mg or as low as about 25 mg per kilogram of body weight, or from about 1.0 mg to about 10 mg per kilogram of body weight. Thus, for administration to a 70 kg human, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day to about 2000 mg or more per day, or from about 70 mg per day to about 1000 mg per day.

[0149] Treatment

[0150] Some embodiments of the present invention include methods of treating a disease, disorder, or condition selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver disease, malaria, viral infections, parasitic infections, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia, hormonal disorders, HIV, and various types of cancer using a compound described herein or a composition comprising a compound described herein. Some methods include administering a compound, composition, or pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the subject can be an animal, such as a mammal or a human. In some embodiments, the subject is a human.

[0151] Some embodiments provide a method of treating an infection caused by an infectious agent with an effective amount of one or more compounds as disclosed herein, wherein the infectious agent is a virus. In some embodiments, the virus is a single-stranded RNA virus. In other embodiments, the virus is a double-stranded RNA virus. In other embodiments, the virus is a positive-sense ssRNA virus. In some embodiments, the virus is a negative-sense ssRNA virus. In some embodiments, the virus is a double-stranded DNA virus. In other embodiments, the virus is a single-stranded DNA virus.

[0152] In some embodiments, the virus may be a coronavirus. In some embodiments, the virus may be a poxvirus. In some embodiments, the virus may be a smallpox virus. In some embodiments, the virus may be a Marburg virus. In some embodiments, the virus may be an Ebola virus. In some embodiments, the virus may be a flavivirus. In some embodiments, the virus may be an influenza virus. In some embodiments, the virus may be a parainfluenza virus. In some embodiments, the virus may be a respiratory syncytial virus. In some embodiments, the virus may be a measles virus. In some embodiments, the virus may be a human immunodeficiency virus. In some embodiments, the virus may be a human papillomavirus. In some embodiments, the virus may be a varicella-zoster virus. In some embodiments, the virus may be a herpes simplex virus. In some embodiments, the virus may be a cytomegalovirus. In some embodiments, the virus may be an Epstein-Barr virus. In some embodiments, the virus may be a JC virus. In some embodiments, the virus may be a rhabdovirus. In some embodiments, the virus may be a rotavirus. In some embodiments, the virus may be a rhinovirus. In some embodiments, the virus may be an adenovirus. In some embodiments, the virus may be a papillomavirus. In some embodiments, the virus may be a parvovirus. In some embodiments, the virus may be a picornavirus. In some embodiments, the virus may be a poliovirus. In some embodiments, the virus may be a hantavirus. In some embodiments, the virus may be a filovirus. In some embodiments, the virus may be a coxsackievirus. In some embodiments, the virus may be an equine encephalitis virus. In some embodiments, the virus may be a Rift Valley fever virus. In some embodiments, the virus may be an alphavirus. In some embodiments, the virus may be hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, or hepatitis E virus.

[0153] 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.

[0154] Further embodiments include administering a combination of compounds to an individual in need thereof. The combination may include a compound, composition, or pharmaceutical composition described herein with an additional drug.

[0155] Some embodiments include co-administering the compounds, compositions, and / or pharmaceutical compositions described herein with one or more additional drugs or additional therapeutic agents. "Co-administered" means that two or more drugs appear in the patient's bloodstream at the same time, regardless of the time or manner in which the drugs are actually administered. In one embodiment, the drugs are administered simultaneously. In one such embodiment, combined administration is achieved by combining the drugs in a single dosage form. In another embodiment, the drugs are administered sequentially, in one embodiment, by the same route, such as orally. In another embodiment, the drugs are administered by different routes, such as one orally and the other intravenously.

[0156] The following examples are included to further illustrate the present invention. These examples should not, of course, be construed as specifically limiting the present invention. Variations from these examples within the scope of the claims are within the purview of those skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that, having mastered this disclosure, one skilled in the art will be able to make and use the present invention without the need for exhaustive examples.

[0157] Synthesis of compounds

[0158] The following procedures for preparing the novel compounds illustrate general procedures for preparing nucleotide prodrug compounds.

[0159] Scheme 1 describes a general synthetic method for compounds of formula I. Nucleoside (1) is reacted with phosphine diamine (2) in the presence of 4,5-dicyanoimidazole to give a cyclic product of structure 3; and the crude reaction mixture is then treated with an oxidizing agent, such as tert-butyl peroxide, to give the final product 4 of formula I.

[0160] Plan I

[0161]

[0162] R has the R 1 Definition. Example

[0163] Some compounds of formula I were prepared as described below.

[0164] Example 1

[0165] Ethyl 2-((((4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-7-hydroxy-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 101)

[0166]

[0167] Compound 101 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-ethoxy)carbonylbenzyloxy)phosphine diamine and (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile according to the method described in Scheme I. 22 H 22 N5O8P [M-1] + Calculated value: 514.11. Exp. value: 514.1.

[0168] Example 2

[0169] Propyl 2-((((4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-7-hydroxy-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 102)

[0170]

[0171] Compound 102 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-propoxy)carbonylbenzyloxy)phosphine diamine and (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile according to the method described in Scheme 1. 23 H 24 N5O8P [M-1] + Calculated value: 528.13. Exp. value: 258.1.

[0172] Example 3

[0173] Isopropyl 2-((((4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-7-hydroxy-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 103)

[0174]

[0175] Compound 103 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-isopropoxy)carbonylbenzyloxy)phosphine diamine and (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile according to the method described in Scheme I. 23 H 24 N5O8P [M-1] + Calculated value: 528.13. Exp. value: 258.1.

[0176] Example 4

[0177] Isopropyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 104)

[0178]

[0179] Compound 104 was prepared by standard acylation of compound 103 with acetic anhydride in the presence of triethylamine. 25 H 26 N5O9P [M-1] + Calculated value: 570.14. Exp. value: 570.1.

[0180] Example 5

[0181] Ethyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxidotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 105)

[0182]

[0183] Compound 105 was prepared by standard acylation of compound 101 with acetic anhydride in the presence of triethylamine. 24 H 24 N5O9P [M-1] + Calculated value: 556.12. Exp. value: 556.1.

[0184] Example 6

[0185] Ethyl 2-((((4aR,6R,7R,7aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxido-7-(propionyloxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphaben-2-yl)oxy)methyl)benzoate (Compound 106)

[0186]

[0187] Compound 106 was prepared by standard acylation of compound 101 with propionic anhydride in the presence of triethylamine. 25 H 26 N5O9P [M-1] + Calculated value: 570.14. Exp. value: 570.1.

[0188] Example 7

[0189] Methyl 2-((((4aR,6R,7R,7aS)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-7-hydroxy-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 107)

[0190]

[0191] Compound 107 was prepared from N,N,N',N'-tetraisopropyl-1-(2-(2-methoxy)carbonylbenzyloxy)phosphine diamine and (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile according to the method described in Scheme I. 21 H 20 N5O8P [M-1] + Calculated value: 500.09. Experimental value: 500.0.

[0192] Example 8

[0193] Methyl 2-((((4aR,6R,7R,7aR)-7-acetoxy-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphabenzen-2-yl)oxy)methyl)benzoate (Compound 108)

[0194]

[0195] Compound 108 was prepared by standard acylation of compound 107 with acetic anhydride in the presence of triethylamine. 23 H 22 N5O9P [M-1] + Calculated value: 542.11. Exp. value: 542.1.

[0196] Biological Examples

[0197] The example methods described herein include the following. It should be understood that the following are examples and the method is not limited to these examples.

[0198] Example 9: Tissue distribution after oral administration of reference compounds and disclosed compounds

[0199] Rats were given an intravenous injection of remdesivir (2 mg / kg), oral remdesivir (5 mg / kg), and oral test compound (5 mg / kg). Fasted rats were orally dosed by oral gavage. Plasma concentrations of circulating metabolites, nucleosides, were determined by HPLC-UV, and liver concentrations of active triphosphates were measured by LC-MS using standard chromatography.

[0200] Figure 1 Results are shown for the first study in which blood concentrations of the metabolite nucleoside were measured for up to 8 hours following administration of Compound 105 and a reference compound. Figure 2 Results from the second study, in which blood concentrations were measured after 1 and 5 hours, showed that oral administration of compound 105 resulted in exposures that were two-fold higher than those of oral remdesivir, and that intravenous administration of remdesivir resulted in even greater exposures, especially over a longer period of time. Figure 3 Additional results from a second study are shown, in which liver concentrations of nucleoside triphosphates were measured after 1 and 5 hours. Although the liver-to-blood ratio produced by Compound 105 was the same as that produced by Remdesivir, Compound 105 exhibited significantly higher liver exposure than either intravenous or oral Remdesivir. Figure 4 is a graph showing the ratio of (concentration of the corresponding nucleoside in the liver) / (concentration of the corresponding nucleoside in the blood) obtained from the second study after 1 hour and 5 hours.

[0201] Table 1 contains blood and liver levels of various test compounds after 1 and 5 hours compared to oral remdesivir. The results show that the test compounds provide significantly higher liver exposure than remdesivir.

[0202] Table 1 Blood nucleoside (Nuc) and liver nucleoside triphosphate (NTP) levels 1 hour and 5 hours after oral administration of compound.

[0203]

[0204] *≥2x means the concentration is at least two-fold higher than the concentration produced by the reference compound.

[0205] Example 10: Tissue distribution following inhalation administration of reference compounds and disclosed compounds.

[0206] Rats were administered 2 mg / kg of remdesivir or the designated test compounds by inhalation. Lung concentrations of the metabolites nucleosides and their triphosphates were measured by LC-MS using standard chromatographic methods.

[0207] Figure 5 Blood levels of the metabolite nucleoside are shown 1 hour and 5 hours after administration of Compound 105 and a reference compound. Compound 105 provided higher exposure than remdesivir. Figure 6 Showing lung levels of the metabolite nucleoside. Compound 105 provided more than 4-fold higher exposure than remdesivir. Figure 7 The levels of nucleoside triphosphates in the lungs are shown. Remdesivir was below quantitative levels, while compound 105 provided significant lung exposure to the triphosphates.

[0208] All numbers used in this specification indicating quantities of ingredients, reaction conditions, etc. should be understood as being modified in all cases by the term "about". Therefore, unless otherwise indicated, the numerical parameters set forth herein are approximate values ​​that may vary depending on the desired properties sought to be obtained. At a minimum, and without attempting to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority to this application, each numerical parameter should be interpreted in accordance with the number of significant digits and conventional rounding techniques.

[0209] As used herein, language of degree, such as the terms "approximately," "about," "substantially," and "substantially" as used herein, refers to a value, amount, or characteristic that is close to a stated value, amount, or characteristic and still performs a desired function or achieves a desired result. For example, the terms "approximately," "about," "substantially," and "substantially" may refer to an amount that is less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount. As another example, in certain embodiments, the terms "substantially parallel" and "substantially parallel" refer to a value, amount, or characteristic that deviates from exact parallelism by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or other. Similarly, in certain embodiments, the terms "substantially perpendicular" and "substantially perpendicular" refer to a value, amount, or characteristic that deviates from exact perpendicular by less than or equal to 15%, 10%, 5%, 3%, 1%, 0.1%, or other.

[0210] The above description discloses several methods and materials. The present invention is susceptible to modifications of methods and materials, as well as changes in manufacturing methods and equipment. Such modifications will become apparent to those skilled in the art upon consideration of the present invention or practice of the invention disclosed herein. Therefore, the present invention is not intended to be limited to the specific embodiments disclosed herein, but rather encompasses all modifications and alternatives within the true scope and spirit of the invention.

[0211] All references cited herein, including but not limited to published and unpublished applications, patents, and references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. If publications, patents, or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material.

[0212] While certain implementations and examples have been described, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention.

Claims

1. Compounds of formula I: in: R 1 Selected from: H, C1-C 15 alkyl; R 2 Selected from: halogen; R 3 Selected from: H; R 4 Selected from: H, -C(=O)R, wherein R is hydrogen, C 1-6 alkyl; and n is 0, 1, 2, or 3; or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein n is 1.

3. The compound of claim 1, wherein n is 0.

4. The compound according to any one of claims 1 to 3, wherein R 1 It is C1-C 15 alkyl.

5. The compound of claim 4, wherein R 1 It is an unsubstituted C1-C6 alkyl group.

6. The compound of claim 4, wherein R 1 It's ethyl.

7. The compound of claim 4, wherein R 1 It's n-propyl.

8. The compound of claim 4, wherein R 1 It is isopropyl.

9. The compound of claim 4, wherein R 1 It's methyl.

10. The compound of any one of claims 1 to 3, wherein R 4 is -C(=O)R, wherein R is hydrogen, C 1-6 alkyl.

11. The compound of claim 1 , wherein the compound is selected from:

12. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a viral infection, wherein the virus is selected from respiratory syncytial virus, Marburg virus, Ebola virus and coronavirus.

13. The use according to claim 12, wherein The coronavirus is selected from MERS-CoV and SARS-CoV.

14. The use according to claim 12, wherein The coronavirus is SARS-CoV-2.

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