Patent Application
20110190514
Pyrone analogs such as flavonoids have been shown to have beneficial health effects. It has been discovered that pyrone analogs can reduce side effects caused by administration of a therapeutic agent. In another aspect, pyrone analogs can act as blood-tissue barrier (BTB) transport protein modulators, providing beneficial effects such as lowering the side effects of co-administered therapeutic agents.
Certain pyrone analogs have been described in, e.g. U.S. Patent Application Publication Nos. 2006011130 and 20060111308. This application builds upon that work.
In one aspect of the invention compounds are provided which include pyrone analogs of Formula I:
where X is O, S, or NR′ and where R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R3 and R4 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
or R3 and R4 are taken together to form a C5-C10heterocyclyl, C5-C10cycloalkyl, aryl, or heteroaryl;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
where the compound of Formula I is not the compound of Formula A when Rf is hydrogen; and where the compound of Formula I is not one of the following compounds:
In some embodiments, the compound of Formula I is not the compound of Formula A when Rf is —PO3K2.
In some embodiments of the invention, the pyrone analog of Formula I is of Formula II:
where X1, X2, X3, and X4 are independently CR5, O, S, or N; and each instance of R5 is independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula II is of Formula III:
where R6, R7, R8, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the compounds of Formula II are of Formula IV:
where R10 and R11 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the compounds of Formula II are of Formula V:
where R12 and R13 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula II is of Formula VI:
R14 and R15 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In various embodiments of Formulae I, II, III, IV, V, or VI, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In various embodiments of the invention, the pyrone analog of Formula III is of Formula VII:
In other embodiments, the compound of Formula III is a compound of Formula VIII:
In some embodiments, the compound of Formula III is of Formula IX:
where R6, R7, R8, and R9 are independently hydrogen, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, the compound of Formula III is of Formula X:
In some embodiments, the compound of Formula III is of Formula XI:
In some embodiments, the compound of Formula III is of Formula XII:
In some embodiments, the compound of Formula III is of Formula XIII:
In some embodiments, the compound of Formula III is of Formula XIV:
In some embodiments, the compound of Formula III is of Formula XV:
In some embodiments, the compound of Formula III is of Formula XVI:
where R20 is independently hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments, the compound of Formula III is of Formula XVII:
where R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments, the compound of Formula III is of Formula XVIII:
where each instance of R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and t is an integer of 0, 1, 2, 3, or 4.
In some embodiments, the compound of Formula III is of Formula XIX:
where each instance of R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
m is an integer of 0, 1, or 2.
In some embodiments, the compound of Formula III is of Formula XX:
where each instance of R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
p is an integer of 0, 1, 2 or 3.
In some embodiments, the compound of Formula III is of Formula XXI:
where R21 is hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments, the compound of Formula III is of Formula XXII:
wherein X5 is a C1 to C4 group, optionally interrupted by O, S, NR23, or NR23R23 as valency permits, forming a ring which is aromatic or nonaromatic;
wherein R21 is hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
each instance of R23 is independently hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, acyloxy, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, heteroaryl, C5-C10heterocyclyl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments, the compound of Formula III is of Formula XXIII:
wherein R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z; and
Het is a 3 to 10 membered optionally substituted monocyclic or bicyclic heteroaromatic or heteroalicyclic ring system containing 1, 2, 3, 4, or 5 heteroatoms selected from the group of O, S, and N, with the proviso that no two adjacent ring atoms are O or S, wherein the ring system is unsaturated, partially unsaturated or saturated, wherein any number of the ring atoms have substituents as valency permits which are hydrogen, hydroxyl, carboxyaldehyde, alkylcarboxaldehyde, imino, C1-C10 alkyl, C1-C10 alkynyl, C1-C10 alkenyl, carboxyl, carbohydrate, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C5-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, heteroaryl, C5-C10heterocyclyl, C5-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, the compound of Formula IV is of Formula XXIV or Formula XXV:
In some embodiments, the compound of Formula IV is of Formula XXVI or Formula XXVII:
In some embodiments, the compound of Formula IV is of Formula XXVIII:
In some embodiments, the compound of Formula V is of Formula XXIX or Formula XXX:
In some embodiments, the compound of Formula V is of Formula XXXI:
In some embodiments, the compound of Formula VI is of Formula XXXII or Formula XXXIII:
In some embodiments, the compound of Formula VI is of Formula XXXIV:
In some embodiments of the invention, R2 is —H, —OH, —OCH2CH3, or —OCH3.
In other embodiments of the invention, R5 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3 or —Cl.
In yet other embodiments of the invention, R6 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3, or —Cl.
In other embodiments of the invention, R7 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3, or —Cl.
In some embodiments of the invention, R8 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3, —O-glucoronide, or —Cl.
In other embodiments of the invention, R9 is —H, —OH, —OCH2CH3, or —OCH3.
In some embodiments of the invention, R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In other embodiments of the invention, R17 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments of the invention, R18 is —H, —CH3, —CH2CH3, —OCH2CH3, —OCH3, —Cl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In other embodiments of the invention, R19 is H, CH3, —CH2CH3, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z.
In some embodiments of the invention, WY is H2, Na2, or K2.
In other embodiments of the invention, Z is Ca or Mg.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In another aspect of the invention, a pharmaceutical composition is provided comprising a compound of Formula I and a pharmaceutically acceptable carrier.
Reference will now be made in detail to particularly preferred embodiments of the invention. Examples of the preferred embodiments are illustrated in the following Examples section.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.
This invention provides compositions and methods utilizing pyrone analogs and their metabolites. Pyrone analogs, for example, flavonoids can enhance the effectiveness of therapeutic agents, for example, immunosuppressants or analgesics when administered in combination with such agents (see U.S. patent application Ser. Nos. 11/281,771, 11/281,984, and 11/553,924, and “Soluble Pyrone Analogs Methods and Compositions” Attorney Docket No. 31423-716.102, “Phosphorylated Pyrone Analogs and Methods” Attorney Docket No. 31423-720.102, “Methods and Compositions for Therapeutic Treatment” Attorney Docket No. 31423-732.101, “Methods and Compositions for Therapeutic Treatment” Attorney Docket No. 31423-733.101, and “Methods and Compositions for Therapeutic Treatment” Attorney Docket No. 31423-734.101, all of which are herein incorporated by reference in their entirety). Pyrone analogs of the invention may be used to modulate an effect caused by the therapeutic agent; e.g., to treat an animal suffering from a condition (e.g. side effect) caused by administration of a therapeutic agent. In some therapeutic interventions, administration of a therapeutic agent to an animal, which treats a first condition or disorder, causes a side effect, e.g., a second condition or disorder having one or more symptoms distinct from those of the first condition or disorder. This invention also provides novel analogs of these compounds which can have increased effectiveness, e.g., increased modulatory activity, solubility, and/or bioavailability, particularly oral bioavailability. In some embodiments, the compounds act in combination with a therapeutic agent to reduce side effects and/or enhance the effectiveness of the therapeutic agent. The pyrone analogs of the invention may comprise a monocylic or bicyclic nucleus, which may have nitrogen or oxygen substitution within the ring, thus encompassing heteroaromatic compounds in the definition of the aromatic compounds of the invention. These compounds may further comprise an aromatic or heteroaromatic moiety attached to one of the ring carbon atoms. The novel pyrone analogs of the invention may additionally comprise substituents including carbohydrate derivatization on one or more of the hydroxyl moieties. In some embodiments of the invention, the compounds of the present invention can have increased time course of drug effect, in some cases having a longer half life of drug effect, thus prolonging the effects of reducing side effects and/or enhancing the effectiveness of therapeutic agents. In another embodiment of the invention, a carbohydrate derivatized pyrone analog of the invention is metabolized to a glucuronide derivative, which is more active, more bioavailable and/or confers a longer half life of drug effect. In a further embodiment of the invention, the glucuronide derivatized pyrone analog itself is used in the compositions and methods of the invention.
In one aspect, the invention provides compositions and methods utilizing pyrone analogs as agents which reduce or eliminate a side effect of one or more substances. In some embodiments, the invention provides compositions and methods utilizing a combination of a therapeutic agent and a pyrone analog of the invention and/or its metabolite that acts as an agent to reduce or eliminate one or more side effect of the therapeutic agent. Typically, the effect-decreasing agent is a modulator of a blood tissue barrier (BTB) or a placental barrier transport protein. The methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more effects of a substance, e.g., therapeutic agent, be reduced or eliminated. In embodiments further utilizing a therapeutic agent, the methods and compositions are useful in the treatment of an animal in need of treatment, where it is desired that one or more side effects of the therapeutic agent be reduced or eliminated while one or more of the therapeutic effects (e.g., peripheral effects) of the agent are retained or enhanced.
In some embodiments of the invention, the therapeutic agent is an immunosuppressant, such as a calcineurin inhibitor, e.g., cyclosporine, tacrolimus, or a tacrolimus analog. In some embodiments of the invention, the therapeutic agent is an analgesic agent, such as an opiate or a non-opiate analgesic. In some embodiments of the invention, the therapeutic agent is a non-analgesic agent. The polyphenol and/or its metabolite acting as an agent causing a decrease in the side effects of the therapeutic agent, e.g., a modulator of a BTB transport protein may be an activator or an inhibitor of the protein. The modulatory effect may be dose-dependent, e.g., some modulators act as activators in one dosage range and inhibitors in another. In some embodiments, a modulator of a BTB transport protein is used in a dosage wherein it acts primarily as an activator.
Typically, the use of a pyrone analog of the invention and/or its metabolite, results in a decrease in one or more side effects of the therapeutic agent. The therapeutic effect(s) of the agent may be decreased, remain the same, or increase; however, in preferred embodiments, if the therapeutic effect is decreased, it is not decreased to the same degree as the side effects. It will be appreciated that a given therapeutic agent may have more than one therapeutic effect and or one or more side effects, and it is possible that the therapeutic ratio (in this case, the ratio of change in desired effect to change in undesired effect) may vary depending on which effect is measured. However, in some embodiments, at least one therapeutic effect of the therapeutic agent is decreased to a lesser degree than at least one side effect of the therapeutic agent.
In addition, in some embodiments, one or more therapeutic effects of the agent is enhanced by use in combination with a pyrone analog of the invention and/or its metabolite acting, optionally while one or more side effects of the therapeutic agent is reduced or substantially eliminated. For example, in some embodiments, the analgesic effect of an analgesic agent is enhanced while one or more CNS effects of the agent is reduced or substantially eliminated.
Without being bound by theory, and as an example only of a possible mechanism, it is thought that the methods and compositions of the invention operate by reducing or eliminating the concentration of the therapeutic agent from one or more compartments of the body, while retaining or even increasing the effective concentration of the agent in the other compartments.
A pyrone analog of the invention may be converted in vivo to metabolites that have differing activities in the modulation of one or more BTB transport modulators, and these metabolites are also encompassed by the compositions and methods of the invention.
As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a plurality of such compounds, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may “consist of” or “consist essentially of” the described features.
Compounds useful in the invention include compounds having a general formula corresponding to Formula Q, where the numbering of atom centers is as shown, and is used throughout the specification. The numbering is retained even for analogs with variant structures, i.e., heteroatom substitution.
“Acyl” refers to a —(C═O)— radical which is attached to two other moieties through the carbon atom. Those groups may be chosen from alkyl alkenyl, alkynyl, aryl, heterocylic, heteroaliphatic, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an acyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Acyloxy” refers to a R(C═O)O— radical wherein R is alkyl aryl, heteroaryl or heterocyclyl. Unless stated otherwise specifically in the specification, an acyloxy group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2) —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Alkylaryl” refers to an (alkyl)aryl radical, where alkyl and aryl are as defined herein.
“Aralkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as defined herein.
“Alkoxy” refers to a (alkyl)O radical, where alkyl is as described herein and contains 1 to 10 carbons (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C1-C4 alkoxy group. A alkoxy moiety is optionally substituted by one or more of the substituents described as suitable substituents for an alkyl radical.
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, i-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e. C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e. C2-C10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Amine” refers to a —N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
An “amide” refers to a chemical moiety with formula —C(O)NHR or —NHC(O)R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
“Aromatic” or “aryl” refers to an aromatic radical with six to ten ring atoms (e.g., C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl, fluorenyl, and naphthyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —CN—ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Carboxaldehyde” refers to a —(C═O)H radical.
“Carboxyl” refers to a —(C═O)OH radical.
“Carbohydrate” as used herein, includes, but not limited to, monosaccharides, disaccharides, oligosaccharides, or polysaccharides. Monosaccharide for example includes, but not limited to, aldotrioses such as glyceraldehyde, ketotrioses such as dihydroxyacetone, aldotetroses such as erythrose and threose, ketotetroses such as erythrulose, aldopentoses such as arabinose, lyxose, ribose and xylose, ketopentoses such as ribulose and xylulose, aldohexoses such as allose, altrose, galactose, glucose, gulose, idose, mannose and talose, ketohexoses such as fructose, psicose, sorbose and tagatose, heptoses such as mannoheptulose, sedoheptulose, octoses such as octolose, 2-keto-3-deoxy-manno-octonate, nonoses such as sialoseallose. Disaccharides for example includes, but not limited to, glucorhamnose, trehalose, sucrose, lactose, maltose, galactosucrose, N-acetyllactosamine, cellobiose, gentiobiose, isomaltose, melibiose, primeverose, hesperodinose, and rutinose. Oligosaccharides for example includes, but not limited to, raffinose, nystose, panose, cellotriose, maltotriose, maltotetraose, xylobiose, galactotetraose, isopanose, cyclodextrin (α-CD) or cyclomaltohexaose, β-cyclodextrin (β-CD) or cyclomaltoheptaose and γ-cyclodextrin (γ-CD) or cyclomaltooctaose. Polysaccharide for example includes, but not limited to, xylan, mannan, galactan, glucan, arabinan, pustulan, gellan, guaran, xanthan, and hyaluronan. Some examples include, but not limited to, starch, glycogen, cellulose, inulin, chitin, amylose and amylopectin.
A compound of Formula I having a carbohydrate moeity can be referred to as the pyrone aromatic glycoside or the pyrone aromatic saccharide. As used herein, “carbohydrate” further encompasses the glucuronic as well as the glycosidic derivative of compounds of Formula I. Where the pyrone analog has no carbohydrate moeity, it can be referred to as the aglycone. Further, where a phenolic hydroxy is derivatized with any of the carbohydrates described above, the carbohydrate moiety is referred to as a glycosyl residue. Unless stated otherwise specifically in the specification, a carbohydrate group is optionally substituted by one or more substituents which are independently: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Cyano” refers to a —CN moiety.
“Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. C2-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which are independently: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Ester” refers to a chemical radical of formula —COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which are independently: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
“Heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aryl group (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteraryl moiety is optionally substituted by one or more substituents which are independently: hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10heterocyclic, C3-C10cycloalkyl, CN, —ORa—SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring (e.g., C3-C18 heterocyclyl) radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heteroaryl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocyclyl. In some embodiments, it is a C4-C10 heterocyclyl. In some embodiments, it is a C3-C10heterocyclyl. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl moiety is optionally substituted by one or more substituents which are independently: hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10heterocyclic, C3-C10cycloalkyl, —CN, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Heteroalicyclic” refers to a cycloalkyl radical that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless stated otherwise specifically in the specification, a heteroalicyclic group is optionally substituted by one or more substituents which independently are: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Imino” refers to the ═N—H radical.
“Isocyanato” refers to a —NCO radical.
“Isothiocyanato” refers to a —NCS radical.
“Mercaptyl” refers to a (alkyl)S or (H)S radical.
“Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
“Nitro” refers to the NO2 radical.
“Oxa” refers to the —O— radical.
“Oxo” refers to the ═O radical.
“Sulfinyl” refers to a —S(═O)—R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon)
“Sulfonyl” refers to a —S(═O)2—R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
“Sulfonamidyl” refers to a —S(═O)2—NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
“Sulfoxyl” refers to a —S(═O)2OH radical.
“Sulfonate” refers to a —S(═O)2—OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
“Thiocyanato” refers to a —CNS radical.
“Thioxo” refers to the ═S radical.
“Substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloakyl substituent may have a halide substituted at one or more ring carbons, and the like. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.
The compounds presented herein may possess one or more chiral centers and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns.
The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
Pyrone analogs of Formula I and their pharmaceutically/veterinarily acceptable salt or esters are provided in this invention,
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R3 and R4 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, Carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
or R3 and R4 are taken together to form a C5-C10heterocyclyl, C5-C10cycloalkyl, aryl, or heteroaryl;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula I is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula I is not one of the following compounds:
In some embodiments, the compound of Formula I is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10Cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R3 is hydrogen. In some embodiments, R3 is hydroxyl. In some embodiments, R3 is optionally substituted C1-C10 alkyl. In some embodiments, R3 is unsubstituted C1-C10 alkyl. In some embodiments, R3 is substituted C1-C10 alkyl. In some embodiments, R3 is unsubstituted C1-C10 alkyl. In some other embodiments, R3 is substituted C1-C10 alkyl. In some embodiments, R3 is unsubstituted C2-C10 alkynyl. In some embodiments, R3 is substituted C2-C10 alkynyl. In some embodiments, R3 is unsubstituted C2-C10 alkenyl. In some embodiments, R3 is substituted C2-C10 alkenyl. In some embodiments, R3 is carboxyl. In some embodiments, R3 is unsubstituted carbohydrate. In some embodiments, R3 is substituted carbohydrate. In some embodiments, R3 is unsubstituted ester. In some embodiments, R3 is substituted ester. In some embodiments, R3 is unsubstituted acyloxy. In some embodiments, R3 is substituted acyloxy. In some embodiments, R3 is nitro. In some embodiments, R3 is halogen. In some embodiments, R3 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R3 is substituted C1-C10 aliphatic acyl. In some embodiments, R3 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R3 is substituted C6-C10 aromatic acyl. In some embodiments, R3 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R3 is substituted C6-C10 aralkyl acyl. In some embodiments, R3 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R3 is substituted C6-C10 alkylaryl acyl. In some embodiments, R3 is unsubstituted alkoxy. In some embodiments, R3 is substituted alkoxy. In some embodiments, R3 is unsubstituted amine. In some embodiments, R3 is substituted amine. In some embodiments, R3 is unsubstituted aryl. In some embodiments, R3 is substituted aryl. In some embodiments, R3 is unsubstituted C4-C10heterocyclyl. In some embodiments, R3 is substituted C4-C10heterocyclyl. In some embodiments, R3 is unsubstituted heteroaryl. In some embodiments, R3 is substituted heteroaryl. In some embodiments, R3 is unsubstituted C3-C10cycloalkyl. In some embodiments, R3 is substituted C3-C10cycloalkyl. In some embodiments, R3 is —OPO3WY. In some embodiments, R3 is —OCH2PO4WY. In some embodiments, R3 is —OCH2PO4Z. In some embodiments, R3 is —OPO3Z.
In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxyl. In some embodiments, R4 is optionally substituted C1-C10 alkyl. In some embodiments, R4 is unsubstituted C1-C10 alkyl. In some embodiments, R4 is substituted C1-C10 alkyl. In some embodiments, R4 is unsubstituted C1-C10 alkyl. In some other embodiments, R4 is substituted C1-C10 alkyl. In some embodiments, R4 is unsubstituted C2-C10 alkynyl. In some embodiments, R4 is substituted C2-C10 alkynyl. In some embodiments, R4 is unsubstituted C2-C10 alkenyl. In some embodiments, R4 is substituted C2-C10 alkenyl. In some embodiments, R4 is carboxyl. In some embodiments, R4 is unsubstituted carbohydrate. In some embodiments, R4 is substituted carbohydrate. In some embodiments, R4 is unsubstituted ester. In some embodiments, R4 is substituted ester. In some embodiments, R4 is unsubstituted acyloxy. In some embodiments, R4 is substituted acyloxy. In some embodiments, R4 is nitro. In some embodiments, R4 is halogen. In some embodiments, R4 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R4 is substituted C1-C10 aliphatic acyl. In some embodiments, R4 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R4 is substituted C6-C10 aromatic acyl. In some embodiments, R4 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R4 is substituted C6-C10 aralkyl acyl. In some embodiments, R4 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R4 is substituted C6-C10 alkylaryl acyl. In some embodiments, R4 is unsubstituted alkoxy. In some embodiments, R4 is substituted alkoxy. In some embodiments, R4 is unsubstituted amine. In some embodiments, R4 is substituted amine. In some embodiments, R4 is unsubstituted aryl. In some embodiments, R4 is substituted aryl. In some embodiments, R4 is unsubstituted C4-C10heterocyclyl. In some embodiments, R4 is substituted C4-C10heterocyclyl. In some embodiments, R4 is unsubstituted heteroaryl. In some embodiments, R4 is substituted heteroaryl. In some embodiments, R4 is unsubstituted C3-C10cycloalkyl. In some embodiments, R4 is substituted C3-C10cycloalkyl. In some embodiments, R4 is —OPO3WY. In some embodiments, R4 is —OCH2PO4WY. In some embodiments, R4 is —OCH2PO4Z. In some embodiments, R4 is —OPO3Z.
In some embodiments, R3 and R4 are taken together to form an unsubstituted C5-C10heterocyclyl. In other embodiments, R3 and R4 are taken together to form a substituted C5-C10heterocyclyl. In some embodiments, R3 and R4 are taken together to form an unsubstituted C5-C10cycloalkyl. In some embodiments, R3 and R4 are taken together to form a substituted C5-C10cycloalkyl. In some embodiments, R3 and R4 are taken together to form an unsubstituted aryl. In some embodiments, R3 and R4 are taken together to form a substituted aryl. In some embodiments, R3 and R4 are taken together to form an unsubstituted heteroaryl. In some embodiments, R3 and R4 are taken together to form a substituted heteroaryl.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
The 2,3 bond may be saturated or unsaturated in the compounds of Formula I.
In some embodiments of the invention, the pyrone analog is of Formula II and its pharmaceutically/veterinarily acceptable salts thereof:
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
X1, X2, X3, and X4 are independently CR5, O, S, or N;
each instance of R5 is independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, Carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
W and Y are independently hydrogen, methyl, ethyl, alkyl carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula II is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula II is not one of the following compounds:
In some embodiments, the compound of Formula II is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10Cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, X1 is CR5.
In other embodiments, X1 is O.
In yet other embodiments, X1 is S.
In further embodiments, X1 is N.
In some embodiments, X2 is CR5.
In other embodiments, X2 is O.
In yet other embodiments, X2 is S.
In further embodiments, X2 is N.
In some embodiments, X3 is CR5.
In other embodiments, X3 is O.
In yet other embodiments, X3 is S.
In further embodiments, X3 is N.
In other embodiments, X4 is CR5.
In some embodiments, X4 is O.
In yet other embodiments, X4 is S.
In some embodiments, X4 is N.
In some embodiments, X1, X2, X3, and X4 are CR5.
In some embodiments, X1 is N, and X2, X3, and X4 are CR5.
In some embodiments, X2 is N, and X1, X3, and X4 are CR5;
In some embodiments, X3 is N, and X1, X2, and X4 are CR5;
In some embodiments, X4 is N, and X1, X2, and X3 are CR5;
In some embodiments, X1 and X3 are CR5 and X2 and X4 are N.
In some embodiments, X2 and X4 are CR5 and X1 and X3 are N.
In some embodiments, X2 and X3 are CR5 and X1 and X4 are N.
In some embodiments, at least one of X1, X2, X3 or X4 is N.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In various embodiments, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate 1. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R17 is hydrogen. In some embodiments, R17 is hydroxy. In some embodiments, R17 is carboxaldehyde. In some embodiments, R17 is unsubstituted amine. In some embodiments, R17 is substituted amine. In some embodiments, R17 is unsubstituted C1-C10 alkyl. In some embodiments, R17 is unsubstituted C2-C10 alkynyl. In some embodiments, R17 is substituted C2-C10 alkynyl. In some embodiments, R17 is unsubstituted C2-C10 alkenyl. In some embodiments, R17 is substituted C2-C10 alkenyl. In some embodiments, R17 is carboxyl. In some embodiments, R17 is unsubstituted carbohydrate. In some embodiments, R17 is substituted carbohydrate. In some embodiments, R17 is unsubstituted ester. In some embodiments, R17 is substituted ester. In some embodiments, R17 is unsubstituted acyloxy. In some embodiments, R17 is substituted acyloxy. In some embodiments, R17 is nitro. In some embodiments, R17 is halogen. In some embodiments, R17 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R17 is substituted C1-C10 aliphatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R17 is substituted C6-C10 aromatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R17 is substituted C6-C10 aralkyl acyl. In some embodiments, R17 is unsubstituted C6-C10 alkylaryl acyl. n some embodiments, R17 is substituted C6-C10 alkylaryl acyl. In some embodiments, R17 is unsubstituted alkoxy. In some embodiments, R17 is substituted alkoxy. In some embodiments, R17 is unsubstituted aryl. In some embodiments, R17 is substituted aryl. In some embodiments, R17 is unsubstituted C3-C10heterocyclyl. In some embodiments, R17 is substituted C3-C10heterocyclyl. In some embodiments, R17 is unsubstituted heteroaryl. In some embodiments, R17 is substituted heteroaryl. In some embodiments, R17 is unsubstituted C3-C10cycloalkyl. In some embodiments, R17 is substituted C3-C10cycloalkyl. In some embodiments, R17 is —OPO3WY. In some embodiments, R17 is —OCH2PO4WY. In some embodiments, R17 is —OCH2PO4Z. In some embodiments, R17 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is carboxaldehyde. In some embodiments, R5 is unsubstituted amine. In some embodiments, R5 is substituted amine. In some embodiments, R5 is unsubstituted C1-C10 alkyl. In some embodiments, R5 is substituted C1-C10 alkyl. In some embodiments, R5 is unsubstituted C2-C10 alkynyl. In some embodiments, R5 is substituted C2-C10 alkynyl. In some embodiments, R5 is unsubstituted C2-C10 alkenyl. In some embodiments, R5 is substituted C2-C10 alkenyl. In some embodiments, R5 is carboxyl. In some embodiments, R5 is unsubstituted carbohydrate. In some embodiments, R5 is substituted carbohydrate. In some embodiments, R5 is unsubstituted ester. In some embodiments, R5 is substituted ester. In some embodiments, R5 is unsubstituted acyloxy. In some embodiments, R5 is substituted acyloxy. In some embodiments, R5 is nitro. In some embodiments, R5 is halogen. In some embodiments, R5 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R5 is substituted C1-C10 aliphatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R5 is substituted C6-C10 aromatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R5 is substituted C6-C10 aralkyl acyl. In some embodiments, R5 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R5 is substituted C6-C10 alkylaryl acyl. In some embodiments, R5 is unsubstituted alkoxy. In some embodiments, R5 is substituted alkoxy. In some embodiments, R5 is unsubstituted aryl. In some embodiments, R5 is substituted aryl. In some embodiments, R5 is unsubstituted C3-C10heterocyclyl. In some embodiments, R5 is substituted C3-C10 heterocyclyl. In some embodiments, R5 is unsubstituted heteroaryl, In some embodiments, R5 is unsubstituted C3-C10cycloalkyl. In some embodiments, R5 is substituted C3-C10cycloalkyl. In some embodiments, R5 is —OPO3WY. In some embodiments, R5 is —OCH2PO4—Y. In some embodiments, R5 is —OCH2PO4Z. In some embodiments, R5 is —OPO3Z.
In various embodiments of the invention, the pyrone analog is of Formulae III, IV, V, or VI as illustrated in Scheme I.
In some embodiments of the invention where X1, X2, X3, and X4 of Formula II are CR5, the compound is of Formula III or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, R8, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation;
wherein the compound of Formula III is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula III is not one of the following compounds:
In some embodiments, the compound of Formula III is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In various embodiments, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl. In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R8 is hydrogen. In some embodiments, R8 is hydroxyl. In some embodiments, R8 is carboxaldehyde. In some embodiments, R8 is unsubstituted amine. In some embodiments, R8 is substituted amine. In some embodiments, R8 is unsubstituted C1-C10 alkyl. In some embodiments, R8 is substituted C1-C10 alkyl. In some embodiments, R8 is unsubstituted C2-C10 alkynyl. In some embodiments, R8 is substituted C2-C10 alkynyl. In some embodiments, R8 is unsubstituted C2-C10 alkenyl. In some embodiments, R8 is substituted C2-C10 alkenyl. In some embodiments, R8 is carboxyl. In some embodiments, R8 is unsubstituted carbohydrate. In some embodiments, R8 is substituted carbohydrate. In some embodiments, R8 is unsubstituted ester. In some embodiments, R8 is substituted ester. In some embodiments, R8 is unsubstituted acyloxy. In some embodiments, R8 is substituted acyloxy. In some embodiments, R8 is nitro. In some embodiments, R8 is halogen. In some embodiments, R8 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R8 is substituted C1-C10 aliphatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R8 is substituted C6-C10 aromatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R8 is substituted C6-C10 aralkyl acyl. In some embodiments, R8 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R8 is substituted C6-C10 alkylaryl acyl. In some embodiments, R8 is unsubstituted alkoxy. In some embodiments, R8 is substituted alkoxy. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is substituted aryl. In some embodiments, R8 is unsubstituted C3-C10heterocyclyl. In some embodiments, R8 is substituted C3-C10 heterocyclyl. In some embodiments, R8 is unsubstituted heteroaryl, In some embodiments, R8 is unsubstituted C3-C10cycloalkyl. In some embodiments, R8 is substituted C3-C10cycloalkyl. In some embodiments, R8 is —OPO3WY. In some embodiments, R8 is —OCH2PO4WY. In some embodiments, R8 is —OCH2PO4Z. In some embodiments, R8 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R9 is substituted C6-C10 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate 1. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R17 is hydrogen. In some embodiments, R17 is hydroxy. In some embodiments, R17 is carboxaldehyde. In some embodiments, R17 is unsubstituted amine. In some embodiments, R17 is substituted amine. In some embodiments, R17 is unsubstituted C1-C10 alkyl. In some embodiments, R17 is unsubstituted C2-C10 alkynyl. In some embodiments, R17 is substituted C2-C10 alkynyl. In some embodiments, R17 is unsubstituted C2-C10 alkenyl. In some embodiments, R17 is substituted C2-C10 alkenyl. In some embodiments, R17 is carboxyl. In some embodiments, R17 is unsubstituted carbohydrate. In some embodiments, R17 is substituted carbohydrate. In some embodiments, R17 is unsubstituted ester. In some embodiments, R17 is substituted ester. In some embodiments, R17 is unsubstituted acyloxy. In some embodiments, R17 is substituted acyloxy. In some embodiments, R17 is nitro. In some embodiments, R17 is halogen. In some embodiments, R17 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R17 is substituted C1-C10 aliphatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R17 is substituted C6-C10 aromatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R17 is substituted C6-C10 aralkyl acyl. In some embodiments, R17 is unsubstituted C6-C10 alkylaryl acyl. n some embodiments, R17 is substituted C6-C10 alkylaryl acyl. In some embodiments, R17 is unsubstituted alkoxy. In some embodiments, R17 is substituted alkoxy. In some embodiments, R17 is unsubstituted aryl. In some embodiments, R17 is substituted aryl. In some embodiments, R17 is unsubstituted C3-C10heterocyclyl. In some embodiments, R17 is substituted C3-C10heterocyclyl. In some embodiments, R17 is unsubstituted heteroaryl. In some embodiments, R17 is substituted heteroaryl. In some embodiments, R17 is unsubstituted C3-C10cycloalkyl. In some embodiments, R17 is substituted C3-C10cycloalkyl. In some embodiments, R17 is —OPO3WY. In some embodiments, R17 is —OCH2PO4WY. In some embodiments, R17 is —OCH2PO4Z. In some embodiments, R17 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In various embodiments of the invention, the pyrone analog is of Formula VII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, R8, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
s is an integer of 0, 1, 2, or 3;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula VII is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula VII is not the compound wherein:
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-nitro;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-methoxy;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is methyl, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is methoxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0; or
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy.
In some embodiments, the compound of Formula VII is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl, In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl. In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R8 is hydrogen. In some embodiments, R8 is hydroxyl. In some embodiments, R8 is carboxaldehyde. In some embodiments, R8 is unsubstituted amine. In some embodiments, R8 is substituted amine. In some embodiments, R8 is unsubstituted C1-C10 alkyl. In some embodiments, R8 is substituted C1-C10 alkyl. In some embodiments, R8 is unsubstituted C2-C10 alkynyl. In some embodiments, R8 is substituted C2-C10 alkynyl. In some embodiments, R8 is unsubstituted C2-C10 alkenyl. In some embodiments, R8 is substituted C2-C10 alkenyl. In some embodiments, R8 is carboxyl. In some embodiments, R8 is unsubstituted carbohydrate. In some embodiments, R8 is substituted carbohydrate. In some embodiments, R8 is unsubstituted ester. In some embodiments, R8 is substituted ester. In some embodiments, R8 is unsubstituted acyloxy. In some embodiments, R8 is substituted acyloxy. In some embodiments, R8 is nitro. In some embodiments, R8 is halogen. In some embodiments, R8 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R8 is substituted C1-C10 aliphatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R8 is substituted C6-C10 aromatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R8 is substituted C6-C10 aralkyl acyl. In some embodiments, R8 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R8 is substituted C6-C10 alkylaryl acyl. In some embodiments, R8 is unsubstituted alkoxy. In some embodiments, R8 is substituted alkoxy. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is substituted aryl. In some embodiments, R8 is unsubstituted C3-C10heterocyclyl. In some embodiments, R8 is substituted C3-C10 heterocyclyl. In some embodiments, R8 is unsubstituted heteroaryl, In some embodiments, R8 is unsubstituted C3-C10cycloalkyl. In some embodiments, R8 is substituted C3-C10cycloalkyl. In some embodiments, R8 is —OPO3WY. In some embodiments, R8 is —OCH2PO4WY. In some embodiments, R8 is —OCH2PO4Z. In some embodiments, R8 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R9 is substituted C6-C10 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R17 is hydrogen. In some embodiments, R17 is hydroxy. In some embodiments, R17 is carboxaldehyde. In some embodiments, R17 is unsubstituted amine. In some embodiments, R17 is substituted amine. In some embodiments, R17 is unsubstituted C1-C10 alkyl. In some embodiments, R17 is unsubstituted C2-C10 alkynyl. In some embodiments, R17 is substituted C2-C10 alkynyl. In some embodiments, R17 is unsubstituted C2-C10 alkenyl. In some embodiments, R17 is substituted C2-C10 alkenyl. In some embodiments, R17 is carboxyl. In some embodiments, R17 is unsubstituted carbohydrate. In some embodiments, R17 is substituted carbohydrate. In some embodiments, R17 is unsubstituted ester. In some embodiments, R17 is substituted ester. In some embodiments, R17 is unsubstituted acyloxy. In some embodiments, R17 is substituted acyloxy. In some embodiments, R17 is nitro. In some embodiments, R17 is halogen. In some embodiments, R17 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R17 is substituted C1-C10 aliphatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R17 is substituted C6-C10 aromatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R17 is substituted C6-C10 aralkyl acyl. In some embodiments, R17 is unsubstituted C6-C10 alkylaryl acyl. n some embodiments, R17 is substituted C6-C10 alkylaryl acyl. In some embodiments, R17 is unsubstituted alkoxy. In some embodiments, R17 is substituted alkoxy. In some embodiments, R17 is unsubstituted aryl. In some embodiments, R17 is substituted aryl. In some embodiments, R17 is unsubstituted C3-C10heterocyclyl. In some embodiments, R17 is substituted C3-C10heterocyclyl. In some embodiments, R17 is unsubstituted heteroaryl. In some embodiments, R17 is substituted heteroaryl. In some embodiments, R17 is unsubstituted C3-C10cycloalkyl. In some embodiments, R17 is substituted C3-C10cycloalkyl. In some embodiments, R17 is —OPO3WY. In some embodiments, R17 is —OCH2PO4WY. In some embodiments, R17 is —OCH2PO4Z. In some embodiments, R17 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In other embodiments of the invention, the pyrone analog of the invention is a compound of Formula VIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, R8, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula VIII is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula VII is not the compound wherein:
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-nitro;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and
R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and
R18 is 5′-methoxy;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is methyl, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is methoxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0; or
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy.
In some embodiments, the compound of Formula VIII is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY.
In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z. In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl, In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R8 is hydrogen. In some embodiments, R8 is hydroxyl. In some embodiments, R8 is carboxaldehyde. In some embodiments, R8 is unsubstituted amine. In some embodiments, R8 is substituted amine. In some embodiments, R8 is unsubstituted C1-C10 alkyl. In some embodiments, R8 is substituted C1-C10 alkyl. In some embodiments, R8 is unsubstituted C2-C10 alkynyl. In some embodiments, R8 is substituted C2-C10 alkynyl. In some embodiments, R8 is unsubstituted C2-C10 alkenyl. In some embodiments, R8 is substituted C2-C10 alkenyl. In some embodiments, R8 is carboxyl. In some embodiments, R8 is unsubstituted carbohydrate. In some embodiments, R8 is substituted carbohydrate. In some embodiments, R8 is unsubstituted ester. In some embodiments, R8 is substituted ester. In some embodiments, R8 is unsubstituted acyloxy. In some embodiments, R8 is substituted acyloxy. In some embodiments, R8 is nitro. In some embodiments, R8 is halogen. In some embodiments, R8 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R8 is substituted C1-C10 aliphatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R8 is substituted C6-C10 aromatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R8 is substituted C6-C10 aralkyl acyl. In some embodiments, R8 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R8 is substituted C6-C10 alkylaryl acyl. In some embodiments, R8 is unsubstituted alkoxy. In some embodiments, R8 is substituted alkoxy. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is substituted aryl. In some embodiments, R8 is unsubstituted C3-C10heterocyclyl. In some embodiments, R8 is substituted C3-C10 heterocyclyl. In some embodiments, R8 is unsubstituted heteroaryl, In some embodiments, R8 is unsubstituted C3-C10cycloalkyl. In some embodiments, R8 is substituted C3-C10cycloalkyl. In some embodiments, R8 is —OPO3WY. In some embodiments, R8 is —OCH2PO4WY. In some embodiments, R8 is —OCH2PO4Z. In some embodiments, R8 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aromatic acyl. In some embodiments, R9 is substituted C6-C1 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog is of Formula IX or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, R8, and R9 are independently hydrogen, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula IX is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula IX is not the compound wherein:
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-nitro;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6, R7, R8, and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and
R18 is 5′-hydroxy;
R2 is hydrogen, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is hydroxy, s is 1, and
R18 is 5′-methoxy;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is methyl, R17 is hydroxy, and s is 0;
R2 is hydroxy, R6 and R8 are hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R17 is methoxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R8, and R9 are hydrogen, R7 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy;
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, and s is 0; or
R2 is hydroxy, R6, R7, and R9 are hydrogen, R8 is hydroxy, R16 is hydrogen, R17 is hydroxy, s is 1, and R18 is 5′-hydroxy.
In some embodiments, the compound of Formula VIII is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl. In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R8 is hydrogen. In some embodiments, R8 is carboxaldehyde. In some embodiments, R8 is unsubstituted amine. In some embodiments, R8 is substituted amine. In some embodiments, R5 is unsubstituted C1-C10 alkyl. In some embodiments, R8 is substituted C1-C10 alkyl. In some embodiments, R8 is unsubstituted C2-C10 alkynyl. In some embodiments, R8 is substituted C2-C10 alkynyl. In some embodiments, R8 is unsubstituted C2-C10 alkenyl. In some embodiments, R8 is substituted C2-C10 alkenyl. In some embodiments, R8 is carboxyl. In some embodiments, R8 is unsubstituted carbohydrate. In some embodiments, R8 is substituted carbohydrate. In some embodiments, R8 is unsubstituted ester. In some embodiments, R8 is substituted ester. In some embodiments, R8 is unsubstituted acyloxy. In some embodiments, R8 is substituted acyloxy. In some embodiments, R8 is nitro. In some embodiments, R8 is halogen. In some embodiments, R8 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R8 is substituted C1-C10 aliphatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R8 is substituted C6-C10 aromatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R8 is substituted C6-C10 aralkyl acyl. In some embodiments, R8 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R8 is substituted C6-C10 alkylaryl acyl. In some embodiments, R8 is unsubstituted alkoxy. In some embodiments, R8 is substituted alkoxy. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is substituted aryl. In some embodiments, R8 is unsubstituted C3-C10heterocyclyl. In some embodiments, R8 is substituted C3-C10heterocyclyl. In some embodiments, R8 is unsubstituted heteroaryl, In some embodiments, R8 is unsubstituted C3-C10cycloalkyl. In some embodiments, R8 is substituted C3-C10cycloalkyl. In some embodiments, R8 is —OPO3WY. In some embodiments, R8 is —OCH2PO4WY. In some embodiments, R8 is —OCH2PO4Z. In some embodiments, R8 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R9 is substituted C6-C10 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog is of Formula X or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R7 and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula X is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula X is not the compound wherein:
R2 is hydrogen, R7 and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydrogen;
R2 is hydrogen, R7 and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydroxy;
R2 is hydrogen, R7 and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is methoxy;
R2 is hydroxy, R7 and R9 are hydrogen, R16 is methyl, R19 is hydrogen, and R18 is hydrogen; or
R2 is hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R19 is methyl, and R18 is hydrogen.
In some embodiments, the compound of Formula X is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R9 is substituted C6-C10 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In other embodiments of the invention, the pyrone analogs of the invention are of Formula XI or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XI is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula XI is not the compound wherein:
R2 is hydrogen, R6 is hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R18 is hydrogen, and R19 is hydrogen;
R2 is hydrogen, R6 is hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydroxy;
R2 is hydrogen, R6 is hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is methoxy;
R2 is hydroxy, R7 and R9 are hydrogen, R16 is methyl, R19 is hydrogen, and R18 is hydrogen;
R2 is hydroxy, R7 and R9 are hydrogen, R16 is hydrogen, R19 is methyl, and R18 is hydrogen;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydrogen;
R2 is hydrogen, R6, R7, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydroxy;
R2 is hydroxy, R6, R7, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydrogen; or
R2 is hydroxy, R6, R7, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydroxy.
In some embodiments, the compound of Formula XI is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl. In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aromatic acyl. In some embodiments, R9 is substituted C6-C1 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In other embodiments of the invention, the pyrone analog is of Formula XII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R8, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XII is not the compound wherein
R2 is hydrogen, R6, R8, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydrogen;
R2 is hydrogen, R6, R8, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydroxy; or
R2 is hydroxy, R6, R8, and R9 are hydrogen, R16 is hydrogen, R19 is hydrogen, and R18 is hydrogen.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl, In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R8 is hydrogen. In some embodiments, R8 is hydroxyl. In some embodiments, R8 is carboxaldehyde. In some embodiments, R8 is unsubstituted amine. In some embodiments, R8 is substituted amine. In some embodiments, R8 is unsubstituted C1-C10 alkyl. In some embodiments, R8 is substituted C1-C10 alkyl. In some embodiments, R8 is unsubstituted C2-C10 alkynyl. In some embodiments, R8 is substituted C2-C10 alkynyl. In some embodiments, R8 is unsubstituted C2-C10 alkenyl. In some embodiments, R8 is substituted C2-C10 alkenyl. In some embodiments, R8 is carboxyl. In some embodiments, R8 is unsubstituted carbohydrate. In some embodiments, R8 is substituted carbohydrate. In some embodiments, R8 is unsubstituted ester. In some embodiments, R8 is substituted ester. In some embodiments, R8 is unsubstituted acyloxy. In some embodiments, R8 is substituted acyloxy. In some embodiments, R8 is nitro. In some embodiments, R8 is halogen. In some embodiments, R8 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R8 is substituted C1-C10 aliphatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R8 is substituted C6-C10 aromatic acyl. In some embodiments, R8 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R8 is substituted C6-C10 aralkyl acyl. In some embodiments, R8 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R8 is substituted C6-C10 alkylaryl acyl. In some embodiments, R8 is unsubstituted alkoxy. In some embodiments, R8 is substituted alkoxy. In some embodiments, R8 is unsubstituted aryl. In some embodiments, R8 is substituted aryl. In some embodiments, R8 is unsubstituted C3-C10heterocyclyl. In some embodiments, R8 is substituted C3-C10 heterocyclyl. In some embodiments, R8 is unsubstituted heteroaryl, In some embodiments, R8 is unsubstituted C3-C10cycloalkyl. In some embodiments, R8 is substituted C3-C10cycloalkyl. In some embodiments, R8 is —OPO3WY. In some embodiments, R8 is —OCH2PO4WY. In some embodiments, R8 is —OCH2PO4Z. In some embodiments, R8 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aromatic acyl. In some embodiments, R9 is substituted C6-C1 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In other embodiments of the invention, the pyrone analog is of Formula XIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X is O, S, or NR′ wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
wherein R2 is hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R6, R7, and R9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XIII is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula XIII is not the compound wherein:
R2 is hydroxy, R6, R7, and R9 are hydrogen, n is 2, and a first R18 is 3′-hydroxy, R19 is hydrogen, and a second R18 is 5′-hydroxy; or
R2 is hydroxy, R6, R7, and R9 are hydrogen, n is 1, R19 is hydrogen, and R18 is 3′-hydroxy.
In some embodiments, the compound of Formula XIII is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R6 is hydrogen. In some embodiments, R6 is hydroxyl. In some embodiments, R6 is carboxaldehyde. In some embodiments, R6 is unsubstituted amine. In some embodiments, R6 is substituted amine. In some embodiments, R6 is unsubstituted C1-C10 alkyl. In some embodiments, R6 is substituted C1-C10 alkyl. In some embodiments, R6 is unsubstituted C2-C10 alkynyl. In some embodiments, R6 is substituted C2-C10 alkynyl. In some embodiments, R6 is unsubstituted C2-C10 alkenyl. In some embodiments, R6 is substituted C2-C10 alkenyl. In some embodiments, R6 is carboxyl. In some embodiments, R6 is unsubstituted carbohydrate. In some embodiments, R6 is substituted carbohydrate. In some embodiments, R6 is unsubstituted ester. In some embodiments, R6 is substituted ester. In some embodiments, R6 is unsubstituted acyloxy. In some embodiments, R6 is substituted acyloxy. In some embodiments, R6 is nitro. In some embodiments, R6 is halogen. In some embodiments, R6 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R6 is substituted C1-C10 aliphatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R6 is substituted C6-C10 aromatic acyl. In some embodiments, R6 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R6 is substituted C6-C10 aralkyl acyl. In some embodiments, R6 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R6 is substituted C6-C10 alkylaryl acyl. In some embodiments, R6 is unsubstituted alkoxy. In some embodiments, R6 is substituted alkoxy. In some embodiments, R6 is unsubstituted aryl. In some embodiments, R6 is substituted aryl. In some embodiments, R6 is unsubstituted C3-C10heterocyclyl. In some embodiments, R6 is substituted C3-C10 heterocyclyl. In some embodiments, R6 is unsubstituted heteroaryl, In some embodiments, R6 is unsubstituted C3-C10cycloalkyl. In some embodiments, R6 is substituted C3-C10cycloalkyl. In some embodiments, R6 is —OPO3WY. In some embodiments, R6 is —OCH2PO4WY. In some embodiments, R6 is —OCH2PO4Z. In some embodiments, R6 is —OPO3Z.
In some embodiments, R7 is hydrogen. In some embodiments, R7 is hydroxyl. In some embodiments, R7 is carboxaldehyde. In some embodiments, R7 is unsubstituted amine. In some embodiments, R7 is substituted amine. In some embodiments, R7 is unsubstituted C1-C10 alkyl. In some embodiments, R7 is substituted C1-C10 alkyl. In some embodiments, R7 is unsubstituted C2-C10 alkynyl. In some embodiments, R7 is substituted C2-C10 alkynyl. In some embodiments, R7 is unsubstituted C2-C10 alkenyl. In some embodiments, R7 is substituted C2-C10 alkenyl. In some embodiments, R7 is carboxyl. In some embodiments, R7 is unsubstituted carbohydrate. In some embodiments, R7 is substituted carbohydrate. In some embodiments, R7 is unsubstituted ester. In some embodiments, R7 is substituted ester. In some embodiments, R7 is unsubstituted acyloxy. In some embodiments, R7 is substituted acyloxy. In some embodiments, R7 is nitro. In some embodiments, R7 is halogen. In some embodiments, R7 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R7 is substituted C1-C10 aliphatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R7 is substituted C6-C10 aromatic acyl. In some embodiments, R7 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R7 is substituted C6-C10 aralkyl acyl. In some embodiments, R7 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R7 is substituted C6-C10 alkylaryl acyl. In some embodiments, R7 is unsubstituted alkoxy. In some embodiments, R7 is substituted alkoxy. In some embodiments, R7 is unsubstituted aryl. In some embodiments, R7 is substituted aryl. In some embodiments, R7 is unsubstituted C3-C10heterocyclyl. In some embodiments, R7 is substituted C3-C10 heterocyclyl. In some embodiments, R7 is unsubstituted heteroaryl, In some embodiments, R7 is unsubstituted C3-C10cycloalkyl. In some embodiments, R7 is substituted C3-C10cycloalkyl. In some embodiments, R7 is —OPO3WY. In some embodiments, R7 is —OCH2PO4WY. In some embodiments, R7 is —OCH2PO4Z. In some embodiments, R7 is —OPO3Z.
In some embodiments, R9 is hydrogen. In some embodiments, R9 is hydroxyl. In some embodiments, R9 is carboxaldehyde. In some embodiments, R9 is unsubstituted amine. In some embodiments, R9 is substituted amine. In some embodiments, R9 is unsubstituted C1-C10 alkyl. In some embodiments, R9 is substituted C1-C10 alkyl. In some embodiments, R9 is unsubstituted C2-C10 alkynyl. In some embodiments, R9 is substituted C2-C10 alkynyl. In some embodiments, R9 is unsubstituted C2-C10 alkenyl. In some embodiments, R9 is substituted C2-C10 alkenyl. In some embodiments, R9 is carboxyl. In some embodiments, R9 is unsubstituted carbohydrate. In some embodiments, R9 is substituted carbohydrate. In some embodiments, R9 is unsubstituted ester. In some embodiments, R9 is substituted ester. In some embodiments, R9 is unsubstituted acyloxy. In some embodiments, R9 is substituted acyloxy. In some embodiments, R9 is nitro. In some embodiments, R9 is halogen. In some embodiments, R9 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R9 is substituted C1-C10 aliphatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aromatic acyl. In some embodiments, R9 is substituted C6-C1 aromatic acyl. In some embodiments, R9 is unsubstituted C6-C11 aralkyl acyl. In some embodiments, R9 is substituted C6-C10 aralkyl acyl. In some embodiments, R9 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R9 is substituted C6-C10 alkylaryl acyl. In some embodiments, R9 is unsubstituted alkoxy. In some embodiments, R9 is substituted alkoxy. In some embodiments, R9 is unsubstituted aryl. In some embodiments, R9 is substituted aryl. In some embodiments, R9 is unsubstituted C3-C10heterocyclyl. In some embodiments, R9 is substituted C3-C10 heterocyclyl. In some embodiments, R9 is unsubstituted heteroaryl, In some embodiments, R9 is unsubstituted C3-C10cycloalkyl. In some embodiments, R9 is substituted C3-C10cycloalkyl. In some embodiments, R9 is —OPO3WY. In some embodiments, R9 is —OCH2PO4WY. In some embodiments, R9 is —OCH2PO4Z. In some embodiments, R9 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, compounds of the following Formulae VIII-A, VIII-B, and VIII-C, are disclosed, where each instance of Rc, and Rd is independently hydrogen, —OPO3WY, —OPO3Z, —OCH2OPOWY, or —OCH2OPO3Z, where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassium and Z is calcium, magnesium or iron.
In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is OPO3WY and Rd is hydrogen. In some embodiments, the compound of Formula VIII-A is not the compound wherein R1 is OPO3K2 and Rd is hydrogen.
In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is —OPO3WY and Rd is OPO3WY. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is a mixture of hydrogen and OPO3WY and Rd is OPO3WY. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is hydrogen and Rd is a mixture of hydrogen and —PO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is —OPO3Z and Rd is hydrogen. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, Rd is OPO3Z and Rd is OPO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, Rd is a mixture of hydrogen and —OPO3Z and Rd is OPO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is hydrogen and Rd is a mixture of hydrogen and —OPO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, Rd is —CH2OPO3Z and Rd is hydrogen. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, Rd is —CH2OPO3Z and Rd is —CH2OPO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is a mixture of hydrogen and —CH2OPO3Z and Rd is —CH2OPO3Z. In some embodiments of the invention, for a compound of Formulae VIII-A, VIII-B, or VIII-C, R1 is hydrogen and Rd is a mixture of hydrogen and —CH2OPO3Z.
In some embodiments, the pyrone analog of Formula XIII is of Formula XIV:
In some embodiments the pyrone analog of the invention is of Formula XV or a pharmaceutically/veterinarily acceptable salt thereof:
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XV is not the compound of Formula A:
wherein Rf is hydrogen.
In some embodiments, the compound of Formula XV is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XVI or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R18 and R21 are independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 and R20 are independently hydrogen, C1-C10 alkyl C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z; and
W and Y are independently hydrogen, methyl, ethyl, alkyl carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XVI is not the compound of Formula A:
wherein Rf is hydrogen.
In some embodiments, the compound of Formula XVI is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 or R21 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 or R21 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R20 is hydrogen. In some embodiments, R20 is unsubstituted C1-C10 alkyl. In some embodiments, R20 is substituted C1-C10 alkyl. In some embodiments, R20 is unsubstituted C2-C10 alkynyl. In some embodiments, R20 is substituted C2-C10 alkynyl. In some embodiments, R20 is unsubstituted C2-C10 alkenyl. In some embodiments, R20 is substituted C2-C10 alkenyl. In some embodiments, R20 is unsubstituted carbohydrate. In some embodiments, R20 is substituted carbohydrate. In some embodiments, R20 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R20 is substituted C1-C10 aliphatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R20 is substituted C6-C10 aromatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R20 is substituted C6-C10 aralkyl acyl. In some embodiments, R20 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R20 is substituted C6-C10 alkylaryl acyl. In some embodiments, R20 is unsubstituted aryl. In some embodiments, R20 is substituted aryl. In some embodiments, R20 is unsubstituted C3-C10heterocyclyl. In some embodiments, R20 is substituted C3-C10 heterocyclyl. In some embodiments, R20 is unsubstituted heteroaryl. In some embodiments, R20 is substituted heteroaryl. In some embodiments, R20 is unsubstituted C3-C10cycloalkyl. In some embodiments, R20 is substituted C3-C10cycloalkyl. In some embodiments, R20 is —PO3WY. In some embodiments, R20 is —CH2PO4WY. In some embodiments, R20 is —CH2PO4Z. In some embodiments, R20 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XVII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R18 is hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R20 is hydrogen. In some embodiments, R20 is unsubstituted C1-C10 alkyl. In some embodiments, R20 is substituted C1-C10 alkyl. In some embodiments, R20 is unsubstituted C2-C10 alkynyl. In some embodiments, R20 is substituted C2-C10 alkynyl. In some embodiments, R20 is unsubstituted C2-C10 alkenyl. In some embodiments, R20 is substituted C2-C10 alkenyl. In some embodiments, R20 is unsubstituted carbohydrate. In some embodiments, R20 is substituted carbohydrate. In some embodiments, R20 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R20 is substituted C1-C10 aliphatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R20 is substituted C6-C10 aromatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R20 is substituted C6-C10 aralkyl acyl. In some embodiments, R20 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R20 is substituted C6-C10 alkylaryl acyl. In some embodiments, R20 is unsubstituted aryl. In some embodiments, R20 is substituted aryl. In some embodiments, R20 is unsubstituted C3-C10heterocyclyl. In some embodiments, R20 is substituted C3-C10 heterocyclyl. In some embodiments, R20 is unsubstituted heteroaryl. In some embodiments, R20 is substituted heteroaryl. In some embodiments, R20 is unsubstituted C3-C10cycloalkyl. In some embodiments, R20 is substituted C3-C10cycloalkyl. In some embodiments, R20 is —PO3WY. In some embodiments, R20 is —CH2PO4WY. In some embodiments, R20 is —CH2PO4Z. In some embodiments, R20 is —PO3Z.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XVIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein each instance of R18 and R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4;
t is an integer of 0, 1, 2, 3, or 4; and
W and Y are independently hydrogen, methyl, ethyl, alkyl carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XVIII is not the compound of Formula A:
wherein Rf is hydrogen; and
wherein the compound of Formula XVIII is not the compound of the following formulae:
In some embodiments, the compound of Formula XVIII is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R22 is hydrogen. In some embodiments, R22 is hydroxy. In some embodiments, R22 is carboxaldehyde. In some embodiments, R22 is unsubstituted amine. In some embodiments, R22 is substituted amine. In some embodiments, R22 is unsubstituted C1-C10 alkyl. In some embodiments, R22 is unsubstituted C2-C10 alkynyl. In some embodiments, R22 is substituted C2-C10 alkynyl. In some embodiments, R22 is unsubstituted C2-C10 alkenyl. In some embodiments, R22 is substituted C2-C10 alkenyl. In some embodiments, R22 is carboxyl. In some embodiments, R22 is unsubstituted carbohydrate. In some embodiments, R22 is substituted carbohydrate. In some embodiments, R22 is unsubstituted ester. In some embodiments, R22 is substituted ester. In some embodiments, R22 is unsubstituted acyloxy. In some embodiments, R22 is substituted acyloxy. In some embodiments, R22 is nitro. In some embodiments, R22 is halogen. In some embodiments, R22 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R22 is substituted C1-C10 aliphatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R22 is substituted C6-C10 aromatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R22 is substituted C6-C10 aralkyl acyl. In some embodiments, R22 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R22 is substituted C6-C10 alkylaryl acyl. In some embodiments, R22 is unsubstituted alkoxy. In some embodiments, R22 is substituted alkoxy. In some embodiments, R22 is unsubstituted aryl. In some embodiments, R22 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R22 is substituted C3-C10heterocyclyl. In some embodiments, R22 is unsubstituted heteroaryl. In some embodiments, R22 is substituted heteroaryl. In some embodiments, R22 is unsubstituted C3-C10cycloalkyl. In some embodiments, R22 is substituted C3-C10cycloalkyl. In some embodiments, R22 is —OPO3WY. In some embodiments, R22 is —OCH2PO4WY. In some embodiments, R22 is —OCH2PO4Z. In some embodiments, R22 is —OPO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In some embodiments, t is an integer of 0. In some embodiments, t is an integer of 1. In some embodiments, t is an integer of 2. In some embodiments, t is an integer of 3. In some embodiments, t is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XIX or a pharmaceutically/veterinarily acceptable salt thereof:
wherein each instance of R18 and R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4;
m is an integer of 0, 1, or 2; and
W and Y are independently hydrogen, methyl, ethyl, alkyl carbohydrate, or a cation, and Z is a multivalent cation, and
wherein the compound of Formula XIX is not one of the following compounds:
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R22 is hydrogen. In some embodiments, R22 is hydroxy. In some embodiments, R22 is carboxaldehyde. In some embodiments, R22 is unsubstituted amine. In some embodiments, R22 is substituted amine. In some embodiments, R22 is unsubstituted C1-C10 alkyl. In some embodiments, R22 is unsubstituted C2-C10 alkynyl. In some embodiments, R22 is substituted C2-C10 alkynyl. In some embodiments, R22 is unsubstituted C2-C10 alkenyl. In some embodiments, R22 is substituted C2-C10 alkenyl. In some embodiments, R22 is carboxyl. In some embodiments, R22 is unsubstituted carbohydrate. In some embodiments, R22 is substituted carbohydrate. In some embodiments, R22 is unsubstituted ester. In some embodiments, R22 is substituted ester. In some embodiments, R22 is unsubstituted acyloxy. In some embodiments, R22 is substituted acyloxy. In some embodiments, R22 is nitro. In some embodiments, R22 is halogen. In some embodiments, R22 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R22 is substituted C1-C10 aliphatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R22 is substituted C6-C10 aromatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R22 is substituted C6-C10 aralkyl acyl. In some embodiments, R22 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R22 is substituted C6-C10 alkylaryl acyl. In some embodiments, R22 is unsubstituted alkoxy. In some embodiments, R22 is substituted alkoxy. In some embodiments, R22 is unsubstituted aryl. In some embodiments, R22 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R22 is substituted C3-C10heterocyclyl. In some embodiments, R22 is unsubstituted heteroaryl. In some embodiments, R22 is substituted heteroaryl. In some embodiments, R22 is unsubstituted C3-C10cycloalkyl. In some embodiments, R22 is substituted C3-C10cycloalkyl. In some embodiments, R22 is —OPO3WY. In some embodiments, R22 is —OCH2PO4WY. In some embodiments, R22 is —OCH2PO4Z. In some embodiments, R22 is —OPO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In some embodiments, m is an integer of 0. In some embodiments, m is an integer of 1. In some embodiments, m is an integer of 2.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XX or a pharmaceutically/veterinarily acceptable salt thereof:
wherein each instance of R18 and R22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4;
p is an integer of 0, 1, 2 or 3;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula XX is not one of the following compounds:
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R22 is hydrogen. In some embodiments, R22 is hydroxy. In some embodiments, R22 is carboxaldehyde. In some embodiments, R22 is unsubstituted amine. In some embodiments, R22 is substituted amine. In some embodiments, R22 is unsubstituted C1-C10 alkyl. In some embodiments, R22 is unsubstituted C2-C10 alkynyl. In some embodiments, R22 is substituted C2-C10 alkynyl. In some embodiments, R22 is unsubstituted C2-C10 alkenyl. In some embodiments, R22 is substituted C2-C10 alkenyl. In some embodiments, R22 is carboxyl. In some embodiments, R22 is unsubstituted carbohydrate. In some embodiments, R22 is substituted carbohydrate. In some embodiments, R22 is unsubstituted ester. In some embodiments, R22 is substituted ester. In some embodiments, R22 is unsubstituted acyloxy. In some embodiments, R22 is substituted acyloxy. In some embodiments, R22 is nitro. In some embodiments, R22 is halogen. In some embodiments, R22 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R22 is substituted C1-C10 aliphatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R22 is substituted C6-C10 aromatic acyl. In some embodiments, R22 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R22 is substituted C6-C10 aralkyl acyl. In some embodiments, R22 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R22 is substituted C6-C10 alkylaryl acyl. In some embodiments, R22 is unsubstituted alkoxy. In some embodiments, R22 is substituted alkoxy. In some embodiments, R22 is unsubstituted aryl. In some embodiments, R22 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R22 is substituted C3-C10heterocyclyl. In some embodiments, R22 is unsubstituted heteroaryl. In some embodiments, R22 is substituted heteroaryl. In some embodiments, R22 is unsubstituted C3-C10cycloalkyl. In some embodiments, R22 is substituted C3-C10cycloalkyl. In some embodiments, R22 is —OPO3WY. In some embodiments, R22 is —OCH2PO4WY. In some embodiments, R22 is —OCH2PO4Z. In some embodiments, R22 is —OPO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In some embodiments, p is an integer of 0. In some embodiments, p is an integer of 1. In some embodiments, p is an integer of 2. In some embodiments, p is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XXI or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R18 and R21 are independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.
In some embodiments of the invention, at least one of R187 or R21 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R20 is hydrogen. In some embodiments, R20 is unsubstituted C1-C10 alkyl. In some embodiments, R20 is substituted C1-C10 alkyl. In some embodiments, R20 is unsubstituted C2-C10 alkynyl. In some embodiments, R20 is substituted C2-C10 alkynyl. In some embodiments, R20 is unsubstituted C2-C10 alkenyl. In some embodiments, R20 is substituted C2-C10 alkenyl. In some embodiments, R20 is unsubstituted carbohydrate. In some embodiments, R20 is substituted carbohydrate. In some embodiments, R20 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R20 is substituted C1-C10 aliphatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R20 is substituted C6-C10 aromatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R20 is substituted C6-C10 aralkyl acyl. In some embodiments, R20 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R20 is substituted C6-C10 alkylaryl acyl. In some embodiments, R20 is unsubstituted aryl. In some embodiments, R20 is substituted aryl. In some embodiments, R20 is unsubstituted C3-C10heterocyclyl. In some embodiments, R20 is substituted C3-C10 heterocyclyl. In some embodiments, R20 is unsubstituted heteroaryl. In some embodiments, R20 is substituted heteroaryl. In some embodiments, R20 is unsubstituted C3-C10cycloalkyl. In some embodiments, R20 is substituted C3-C10cycloalkyl. In some embodiments, R20 is —PO3WY. In some embodiments, R20 is —CH2PO4WY. In some embodiments, R20 is —CH2PO4Z. In some embodiments, R20 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XXII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X5 is a C1 to C4 group, optionally interrupted by O, S, NR23, or NR23R23 as valency permits, forming a ring which is aromatic or nonaromatic;
wherein R18 and R21 are independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R23 is independently hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, acyloxy, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, heteroaryl, C5-C10heterocyclyl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation; and Z is a multivalent cation.
In some embodiments of the invention, at least one of R18 or R21 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In some embodiments, R23 is hydrogen. In some embodiments, R23 is unsubstituted C1-C10 alkyl. In some embodiments, R23 is substituted C1-C10 alkyl. In some embodiments, R23 is unsubstituted C2-C10 alkynyl. In some embodiments, R23 is substituted C2-C10 alkynyl. In some embodiments, R23 is unsubstituted C2-C10 alkenyl. In some embodiments, R23 is substituted C2-C10 alkenyl. In some embodiments, R23 is unsubstituted acyloxy. In some embodiments, R23 is substituted acyloxy. In some embodiments, R23 is unsubstituted carbohydrate. In some embodiments, R23 is substituted carbohydrate. In some embodiments, R23 is unsubstituted acyloxy. In some embodiments, R23 is substituted acyloxy. In some embodiments, R23 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R23 is substituted C1-C10 aliphatic acyl. In some embodiments, R23 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R23 is substituted C6-C10 aromatic acyl. In some embodiments, R23 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R23 is substituted C6-C10 aralkyl acyl. In some embodiments, R23 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R23 is substituted C6-C10 alkylaryl acyl. In some embodiments, R23 is unsubstituted alkoxy. In some embodiments, R23 is substituted alkoxy. In some embodiments, R23 is unsubstituted aryl. In some embodiments, R23 is substituted aryl. In some embodiments, R23 is unsubstituted C3-C10heterocyclyl. In some embodiments, R23 is substituted C3-C10heterocyclyl. In some embodiments, R23 is unsubstituted heteroaryl. In some embodiments, R23 is substituted heteroaryl. In some embodiments, R23 is unsubstituted C3-C10cycloalkyl. In some embodiments, R23 is substituted C3-C10cycloalkyl.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments, the pyrone analog of the invention is a compound of Formula XXIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R20 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
Het is a 3 to 10 membered optionally substituted monocyclic or bicyclic heteroaromatic or heteroalicyclic ring system containing 1, 2, 3, 4, or 5 heteroatoms selected from the group of O, S, and N, with the proviso that no two adjacent ring atoms are O or S, wherein the ring system is unsaturated, partially unsaturated or saturated, wherein any number of the ring atoms have substituents as valency permits which are hydrogen, hydroxyl, carboxaldehyde, alkylcarboxaldehyde, imino, C1-C10 alkyl, C1-C10 alkynyl, C1-C10 alkenyl, carboxyl, carbohydrate, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C5-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, heteroaryl, C5-C10heterocyclyl, C5-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.
In some embodiments, R20 is hydrogen. In some embodiments, R20 is unsubstituted C1-C10 alkyl. In some embodiments, R20 is substituted C1-C10 alkyl. In some embodiments, R20 is unsubstituted C2-C10 alkynyl. In some embodiments, R20 is substituted C2-C10 alkynyl. In some embodiments, R20 is unsubstituted C2-C10 alkenyl. In some embodiments, R20 is substituted C2-C10 alkenyl. In some embodiments, R20 is unsubstituted carbohydrate. In some embodiments, R20 is substituted carbohydrate. In some embodiments, R20 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R20 is substituted C1-C10 aliphatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R20 is substituted C6-C10 aromatic acyl. In some embodiments, R20 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R20 is substituted C6-C10 aralkyl acyl. In some embodiments, R20 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R20 is substituted C6-C10 alkylaryl acyl. In some embodiments, R20 is unsubstituted aryl. In some embodiments, R20 is substituted aryl. In some embodiments, R20 is unsubstituted C3-C10heterocyclyl. In some embodiments, R20 is substituted C3-C10 heterocyclyl. In some embodiments, R20 is unsubstituted heteroaryl. In some embodiments, R20 is substituted heteroaryl. In some embodiments, R20 is unsubstituted C3-C10cycloalkyl. In some embodiments, R20 is substituted C3-C10cycloalkyl. In some embodiments, R20 is —PO3WY. In some embodiments, R20 is —CH2PO4WY. In some embodiments, R20 is —CH2PO4Z. In some embodiments, R20 is —PO3Z.
In some embodiments, Het is one of the following formulae:
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog of Formula II is of Formula IV or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
X2 and X4 are independently CR5, O, S, or N;
each instance of R5 is independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R10 and R11 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula IV is not the compound of Formula A:
wherein Rf is hydrogen.
In some embodiments, the compound of Formula IV is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, X2 is CR5.
In other embodiments, X2 is O.
In yet other embodiments, X2 is S.
In further embodiments, X2 is N.
In other embodiments, X4 is CR5.
In some embodiments, X4 is O.
In yet other embodiments, X4 is S.
In some embodiments, X4 is N.
In some embodiments, at least one of X2 or X4 is N.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In various embodiments, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is carboxaldehyde. In some embodiments, R5 is unsubstituted amine. In some embodiments, R5 is substituted amine. In some embodiments, R5 is unsubstituted C1-C10 alkyl. In some embodiments, R5 is substituted C1-C10 alkyl. In some embodiments, R5 is unsubstituted C2-C10 alkynyl. In some embodiments, R5 is substituted C2-C10 alkynyl. In some embodiments, R5 is unsubstituted C2-C10 alkenyl. In some embodiments, R5 is substituted C2-C10 alkenyl. In some embodiments, R5 is carboxyl. In some embodiments, R5 is unsubstituted carbohydrate. In some embodiments, R5 is substituted carbohydrate. In some embodiments, R5 is unsubstituted ester. In some embodiments, R5 is substituted ester. In some embodiments, R5 is unsubstituted acyloxy. In some embodiments, R5 is substituted acyloxy. In some embodiments, R5 is nitro. In some embodiments, R5 is halogen. In some embodiments, R5 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R5 is substituted C1-C10 aliphatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R5 is substituted C6-C10 aromatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R5 is substituted C6-C10 aralkyl acyl. In some embodiments, R5 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R5 is substituted C6-C10 alkylaryl acyl. In some embodiments, R5 is unsubstituted alkoxy. In some embodiments, R5 is substituted alkoxy. In some embodiments, R5 is unsubstituted aryl. In some embodiments, R5 is substituted aryl. In some embodiments, R5 is unsubstituted C3-C10heterocyclyl. In some embodiments, R5 is substituted C3-C10 heterocyclyl. In some embodiments, R5 is unsubstituted heteroaryl, In some embodiments, R5 is unsubstituted C3-C10cycloalkyl. In some embodiments, R5 is substituted C3-C10cycloalkyl. In some embodiments, R5 is —OPO3WY. In some embodiments, R5 is —OCH2PO4WY. In some embodiments, R5 is —OCH2PO4Z. In some embodiments, R5 is —OPO3Z.
In some embodiments, R10 is hydrogen. In some embodiments, R10 is hydroxyl. In some embodiments, R10 is carboxaldehyde. In some embodiments, R10 is unsubstituted amine. In some embodiments, R10 is substituted amine. In some embodiments, R10 is unsubstituted C1-C10 alkyl. In some embodiments, R10 is substituted C1-C10 alkyl. In some embodiments, R10 is unsubstituted C2-C10 alkynyl. In some embodiments, R10 is substituted C2-C10 alkynyl. In some embodiments, R10 is unsubstituted C2-C10 alkenyl. In some embodiments, R10 is substituted C2-C10 alkenyl. In some embodiments, R10 is carboxyl. In some embodiments, R10 is unsubstituted carbohydrate. In some embodiments, R10 is substituted carbohydrate. In some embodiments, R10 is unsubstituted ester. In some embodiments, R10 is substituted ester. In some embodiments, R10 is unsubstituted acyloxy. In some embodiments, R10 is substituted acyloxy. In some embodiments, R10 is nitro. In some embodiments, R10 is halogen. In some embodiments, R10 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R10 is substituted C1-C10 aliphatic acyl. In some embodiments, R10 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R10 is substituted C6-C10 aromatic acyl. In some embodiments, R10 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R10 is substituted C6-C10 aralkyl acyl. In some embodiments, R10 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R10 is substituted C6-C10 alkylaryl acyl. In some embodiments, R10 is unsubstituted alkoxy. In some embodiments, R10 is substituted alkoxy. In some embodiments, R10 is unsubstituted aryl. In some embodiments, R10 is substituted aryl. In some embodiments, R10 is unsubstituted C3-C10heterocyclyl. In some embodiments, R10 is substituted C3-C10heterocyclyl. In some embodiments, R10 is unsubstituted heteroaryl, In some embodiments, R10 is unsubstituted C3-C10cycloalkyl. In some embodiments, R10 is substituted C3-C10cycloalkyl. In some embodiments, R10 is —OPO3WY. In some embodiments, R10 is —OCH2PO4WY. In some embodiments, R10 is —OCH2PO4Z. In some embodiments, R10 is —OPO3Z.
In some embodiments, R11 is hydrogen. In some embodiments, R11 is hydroxyl. In some embodiments, R11 is carboxaldehyde. In some embodiments, R11 is unsubstituted amine. In some embodiments, R11 is substituted amine. In some embodiments, R11 is unsubstituted C1-C10 alkyl. In some embodiments, R11 is substituted C1-C10 alkyl. In some embodiments, R11 is unsubstituted C2-C10 alkynyl. In some embodiments, R11 is substituted C2-C10 alkynyl. In some embodiments, R11 is unsubstituted C2-C10 alkenyl. In some embodiments, R11 is substituted C2-C10 alkenyl. In some embodiments, R11 is carboxyl. In some embodiments, R11 is unsubstituted carbohydrate. In some embodiments, R11 is substituted carbohydrate. In some embodiments, R11 is unsubstituted ester. In some embodiments, R11 is substituted ester. In some embodiments, R11 is unsubstituted acyloxy. In some embodiments, R11 is substituted acyloxy. In some embodiments, R11 is nitro. In some embodiments, R11 is halogen. In some embodiments, R11 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R11 is substituted C1-C10 aliphatic acyl. In some embodiments, R11 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R11 is substituted C6-C10 aromatic acyl. In some embodiments, R11 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R11 is substituted C6-C10 aralkyl acyl. In some embodiments, R11 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R11 is substituted C6-C10 alkylaryl acyl. In some embodiments, R11 is unsubstituted alkoxy. In some embodiments, R11 is substituted alkoxy. In some embodiments, R11 is unsubstituted aryl. In some embodiments, R11 is substituted aryl. In some embodiments, R11 is unsubstituted C3-C10heterocyclyl. In some embodiments, R11 is substituted C3-C10heterocyclyl. In some embodiments, R11 is unsubstituted heteroaryl, In some embodiments, R11 is unsubstituted C3-C10cycloalkyl. In some embodiments, R11 is substituted C3-C10cycloalkyl. In some embodiments, R11 is —OPO3WY. In some embodiments, R11 is —OCH2PO4WY. In some embodiments, R11 is —OCH2PO4Z. In some embodiments, R11 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate 1. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R17 is hydrogen. In some embodiments, R17 is hydroxy. In some embodiments, R17 is carboxaldehyde. In some embodiments, R17 is unsubstituted amine. In some embodiments, R17 is substituted amine. In some embodiments, R17 is unsubstituted C1-C10 alkyl. In some embodiments, R17 is unsubstituted C2-C10 alkynyl. In some embodiments, R17 is substituted C2-C10 alkynyl. In some embodiments, R17 is unsubstituted C2-C10 alkenyl. In some embodiments, R17 is substituted C2-C10 alkenyl. In some embodiments, R17 is carboxyl. In some embodiments, R17 is unsubstituted carbohydrate. In some embodiments, R17 is substituted carbohydrate. In some embodiments, R17 is unsubstituted ester. In some embodiments, R17 is substituted ester. In some embodiments, R17 is unsubstituted acyloxy. In some embodiments, R17 is substituted acyloxy. In some embodiments, R17 is nitro. In some embodiments, R17 is halogen. In some embodiments, R17 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R17 is substituted C1-C10 aliphatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R17 is substituted C6-C10 aromatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R17 is substituted C6-C10 aralkyl acyl. In some embodiments, R17 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R17 is substituted C6-C10 alkylaryl acyl. In some embodiments, R17 is unsubstituted alkoxy. In some embodiments, R17 is substituted alkoxy. In some embodiments, R17 is unsubstituted aryl. In some embodiments, R17 is substituted aryl. In some embodiments, R17 is unsubstituted C3-C10heterocyclyl. In some embodiments, R17 is substituted C3-C10heterocyclyl. In some embodiments, R17 is unsubstituted heteroaryl. In some embodiments, R17 is substituted heteroaryl. In some embodiments, R17 is unsubstituted C3-C10cycloalkyl. In some embodiments, R17 is substituted C3-C10cycloalkyl. In some embodiments, R17 is —OPO3WY. In some embodiments, R17 is —OCH2PO4WY. In some embodiments, R17 is —OCH2PO4Z. In some embodiments, R17 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXIV or Formula XXV or a pharmaceutically/veterinarily acceptable salt thereof:
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
n is an integer of 0, 1, 2, 3, or 4; and
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation.
In some embodiments of the invention, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of r R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W and Y are independently potassium, sodium, or lithium.
In various embodiments, Z is calcium, magnesium or iron.
In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXVI or Formula XXVII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2, R5, W, Y, and Z are as defined for Formula II and R10 and R11 are as defined for Formula IV;
R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula IV is of Formula XXVIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R2, W, Y, and Z are as defined for Formula II and R10 and R11 are as defined for Formula IV;
R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula II is of Formula V or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
X1 and X4 are independently CR5, O, S, or N;
each instance of R5 is independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R12 and R13 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula V is not the compound of Formula A:
wherein Rf is hydrogen.
In some embodiments, the compound of Formula V is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, X1 is CR5.
In other embodiments, X1 is O.
In yet other embodiments, X1 is S.
In further embodiments, X1 is N.
In other embodiments, X4 is CR5.
In some embodiments, X4 is O.
In yet other embodiments, X4 is S.
In some embodiments, X4 is N.
In some embodiments, at least one of X1 or X4 is N.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In various embodiments, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is carboxaldehyde. In some embodiments, R5 is unsubstituted amine. In some embodiments, R5 is substituted amine. In some embodiments, R5 is unsubstituted C1-C10 alkyl. In some embodiments, R5 is substituted C1-C10 alkyl. In some embodiments, R5 is unsubstituted C2-C10 alkynyl. In some embodiments, R5 is substituted C2-C10 alkynyl. In some embodiments, R5 is unsubstituted C2-C10 alkenyl. In some embodiments, R5 is substituted C2-C10 alkenyl. In some embodiments, R5 is carboxyl. In some embodiments, R5 is unsubstituted carbohydrate. In some embodiments, R5 is substituted carbohydrate. In some embodiments, R5 is unsubstituted ester. In some embodiments, R5 is substituted ester. In some embodiments, R5 is unsubstituted acyloxy. In some embodiments, R5 is substituted acyloxy. In some embodiments, R5 is nitro. In some embodiments, R5 is halogen. In some embodiments, R5 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R5 is substituted C1-C10 aliphatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R5 is substituted C6-C10 aromatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R5 is substituted C6-C10 aralkyl acyl. In some embodiments, R5 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R5 is substituted C6-C10 alkylaryl acyl. In some embodiments, R5 is unsubstituted alkoxy. In some embodiments, R5 is substituted alkoxy. In some embodiments, R5 is unsubstituted aryl. In some embodiments, R5 is substituted aryl. In some embodiments, R5 is unsubstituted C3-C10heterocyclyl. In some embodiments, R5 is substituted C3-C10 heterocyclyl. In some embodiments, R5 is unsubstituted heteroaryl, In some embodiments, R5 is unsubstituted C3-C10cycloalkyl. In some embodiments, R5 is substituted C3-C10cycloalkyl. In some embodiments, R5 is —OPO3WY. In some embodiments, R5 is —OCH2PO4WY. In some embodiments, R5 is —OCH2PO4Z. In some embodiments, R5 is —OPO3Z.
In some embodiments, R12 is hydrogen. In some embodiments, R12 is hydroxyl. In some embodiments, R12 is carboxaldehyde. In some embodiments, R12 is unsubstituted amine. In some embodiments, R12 is substituted amine. In some embodiments, R12 is unsubstituted C1-C10 alkyl. In some embodiments, R12 is substituted C1-C10 alkyl. In some embodiments, R12 is unsubstituted C2-C10 alkynyl. In some embodiments, R12 is substituted C2-C10 alkynyl. In some embodiments, R12 is unsubstituted C2-C10 alkenyl. In some embodiments, R12 is substituted C2-C10 alkenyl. In some embodiments, R12 is carboxyl. In some embodiments, R12 is unsubstituted carbohydrate. In some embodiments, R12 is substituted carbohydrate. In some embodiments, R12 is unsubstituted ester. In some embodiments, R12 is substituted ester. In some embodiments, R12 is unsubstituted acyloxy. In some embodiments, R12 is substituted acyloxy. In some embodiments, R12 is nitro. In some embodiments, R12 is halogen. In some embodiments, R12 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R12 is substituted C1-C10 aliphatic acyl. In some embodiments, R12 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R12 is substituted C6-C10 aromatic acyl. In some embodiments, R12 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R12 is substituted C6-C10 aralkyl acyl. In some embodiments, R12 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R12 is substituted C6-C10 alkylaryl acyl. In some embodiments, R12 is unsubstituted alkoxy. In some embodiments, R12 is substituted alkoxy. In some embodiments, R12 is unsubstituted aryl. In some embodiments, R12 is substituted aryl. In some embodiments, R12 is unsubstituted C3-C10heterocyclyl. In some embodiments, R12 is substituted C3-C10heterocyclyl. In some embodiments, R12 is unsubstituted heteroaryl. In some embodiments, R12 is unsubstituted C3-C10cycloalkyl. In some embodiments, R12 is substituted C3-C10cycloalkyl. In some embodiments, R12 is —OPO3WY. In some embodiments, R12 is —OCH2PO4WY. In some embodiments, R12 is —OCH2PO4Z. In some embodiments, R12 is —OPO3Z.
In some embodiments, R13 is hydrogen. In some embodiments, R13 is hydroxyl. In some embodiments, R13 is carboxaldehyde. In some embodiments, R13 is unsubstituted amine. In some embodiments, R13 is substituted amine. In some embodiments, R13 is unsubstituted C1-C10 alkyl. In some embodiments, R13 is substituted C1-C10 alkyl. In some embodiments, R13 is unsubstituted C2-C10 alkynyl. In some embodiments, R13 is substituted C2-C10 alkynyl. In some embodiments, R13 is unsubstituted C2-C10 alkenyl. In some embodiments, R13 is substituted C2-C10 alkenyl. In some embodiments, R13 is carboxyl. In some embodiments, R13 is unsubstituted carbohydrate. In some embodiments, R13 is substituted carbohydrate. In some embodiments, R13 is unsubstituted ester. In some embodiments, R13 is substituted ester. In some embodiments, R13 is unsubstituted acyloxy. In some embodiments, R13 is substituted acyloxy. In some embodiments, R13 is nitro. In some embodiments, R13 is halogen. In some embodiments, R13 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R13 is substituted C1-C10 aliphatic acyl. In some embodiments, R13 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R13 is substituted C6-C10 aromatic acyl. In some embodiments, R13 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R13 is substituted C6-C10 aralkyl acyl. In some embodiments, R13 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R13 is substituted C6-C10 alkylaryl acyl. In some embodiments, R13 is unsubstituted alkoxy. In some embodiments, R13 is substituted alkoxy. In some embodiments, R13 is unsubstituted aryl. In some embodiments, R13 is substituted aryl. In some embodiments, R13 is unsubstituted C3-C10heterocyclyl. In some embodiments, R13 is substituted C3-C10heterocyclyl. In some embodiments, R13 is unsubstituted heteroaryl, In some embodiments, R13 is unsubstituted C3-C10cycloalkyl. In some embodiments, R13 is substituted C3-C10cycloalkyl. In some embodiments, R13 is —OPO3WY. In some embodiments, R13 is —OCH2PO4WY. In some embodiments, R13 is —OCH2PO4Z. In some embodiments, R13 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R17 is hydrogen. In some embodiments, R17 is hydroxy. In some embodiments, R17 is carboxaldehyde. In some embodiments, R17 is unsubstituted amine. In some embodiments, R17 is substituted amine. In some embodiments, R17 is unsubstituted C1-C10 alkyl. In some embodiments, R17 is unsubstituted C2-C10 alkynyl. In some embodiments, R17 is substituted C2-C10 alkynyl. In some embodiments, R17 is unsubstituted C2-C10 alkenyl. In some embodiments, R17 is substituted C2-C10 alkenyl. In some embodiments, R17 is carboxyl. In some embodiments, R17 is unsubstituted carbohydrate. In some embodiments, R17 is substituted carbohydrate. In some embodiments, R17 is unsubstituted ester. In some embodiments, R17 is substituted ester. In some embodiments, R17 is unsubstituted acyloxy. In some embodiments, R17 is substituted acyloxy. In some embodiments, R17 is nitro. In some embodiments, R17 is halogen. In some embodiments, R17 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R17 is substituted C1-C10 aliphatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R17 is substituted C6-C10 aromatic acyl. In some embodiments, R17 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R17 is substituted C6-C10 aralkyl acyl. In some embodiments, R17 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R17 is substituted C6-C10 alkylaryl acyl. In some embodiments, R17 is unsubstituted alkoxy. In some embodiments, R17 is substituted alkoxy. In some embodiments, R17 is unsubstituted aryl. In some embodiments, R17 is substituted aryl. In some embodiments, R17 is unsubstituted C3-C10heterocyclyl. In some embodiments, R17 is substituted C3-C10heterocyclyl. In some embodiments, R17 is unsubstituted heteroaryl. In some embodiments, R17 is substituted heteroaryl. In some embodiments, R17 is unsubstituted C3-C10cycloalkyl. In some embodiments, R17 is substituted C3-C10cycloalkyl. In some embodiments, R17 is —OPO3WY. In some embodiments, R17 is —OCH2PO4WY. In some embodiments, R17 is —OCH2PO4Z. In some embodiments, R17 is —OPO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, R21 is hydrogen. In some embodiments, R21 is hydroxy. In some embodiments, R21 is carboxaldehyde. In some embodiments, R21 is unsubstituted amine. In some embodiments, R21 is substituted amine. In some embodiments, R21 is unsubstituted C1-C10 alkyl. In some embodiments, R21 is unsubstituted C2-C10 alkynyl. In some embodiments, R21 is substituted C2-C10 alkynyl. In some embodiments, R21 is unsubstituted C2-C10 alkenyl. In some embodiments, R21 is substituted C2-C10 alkenyl. In some embodiments, R21 is carboxyl. In some embodiments, R21 is unsubstituted carbohydrate. In some embodiments, R21 is substituted carbohydrate. In some embodiments, R21 is unsubstituted ester. In some embodiments, R21 is substituted ester. In some embodiments, R21 is unsubstituted acyloxy. In some embodiments, R21 is substituted acyloxy. In some embodiments, R21 is nitro. In some embodiments, R21 is halogen. In some embodiments, R21 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R21 is substituted C1-C10 aliphatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R21 is substituted C6-C10 aromatic acyl. In some embodiments, R21 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R21 is substituted C6-C10 aralkyl acyl. In some embodiments, R21 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R21 is substituted C6-C10 alkylaryl acyl. In some embodiments, R21 is unsubstituted alkoxy. In some embodiments, R21 is substituted alkoxy. In some embodiments, R21 is unsubstituted aryl. In some embodiments, R21 is substituted aryl. In some embodiments, R21 is unsubstituted C3-C10heterocyclyl. In some embodiments, R21 is substituted C3-C10heterocyclyl. In some embodiments, R21 is unsubstituted heteroaryl. In some embodiments, R21 is substituted heteroaryl. In some embodiments, R21 is unsubstituted C3-C10cycloalkyl. In some embodiments, R21 is substituted C3-C10cycloalkyl. In some embodiments, R21 is —OPO3WY. In some embodiments, R21 is —OCH2PO4WY. In some embodiments, R21 is —OCH2PO4Z. In some embodiments, R21 is —OPO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In some embodiments, n is an integer of 0. In some embodiments, n is an integer of 1. In some embodiments, n is an integer of 2. In some embodiments, n is an integer of 3. In some embodiments, n is an integer of 4.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog of Formula V is of Formula XXIX or Formula XXX or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula V is of Formula XXXI or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula II is of Formula VI or a pharmaceutically/veterinarily acceptable salt thereof:
wherein X is O, S, or NR′, wherein R′ is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl;
R1, and R2 are independently hydrogen, hydroxyl, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C4-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
X1 and X4 are independently CR5, O, S, or N;
each instance of R5 is independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10alkylaryl acyl, alkoxy, amine, aryl, C3-C10heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R14 and R15 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, amine, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation; and
wherein the compound of Formula VI is not the compound of Formula A:
wherein Rf is hydrogen.
In some embodiments, the compound of Formula VI is not the compound of Formula A wherein Rf is PO3K2.
In some embodiments, X is O.
In other embodiments, X is S.
In yet other embodiments, X is NR′.
In some embodiments, R′ is hydrogen. In some embodiments, R′ is unsubstituted C1-C10 alkyl. In some embodiments, R′ is substituted C1-C10 alkyl. In some embodiments, R′ is unsubstituted C2-C10 alkynyl. In some embodiments, R′ is substituted C2-C10 alkynyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C2-C10 alkenyl. In some embodiments, R′ is substituted C2-C10 alkenyl. In some embodiments, R′ is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R′ is substituted C1-C10 aliphatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aromatic acyl. In some embodiments, R′ is substituted C6-C10 aromatic acyl. In some embodiments, R′ is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R′ is substituted C6-C10 aralkyl acyl. In some embodiments, R′ is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R′ is substituted C6-C10 alkylaryl acyl. In some embodiments, R′ is unsubstituted aryl. In some embodiments, R′ is substituted aryl. In some embodiments, R′ is unsubstituted C3-C10 heterocyclyl. In some embodiments, R′ is substituted C3-C10 heterocyclyl. In some embodiments, R′ is unsubstituted heteroaryl. In some embodiments, R′ is substituted heteroaryl. In some embodiments, R′ is unsubstituted C3-C10cycloalkyl. In some embodiments, R′ is substituted C3-C10cycloalkyl.
In some embodiments, X1 is CR5.
In other embodiments, X1 is O.
In yet other embodiments, X1 is S.
In further embodiments, X1 is N.
In other embodiments, X3 is CR5.
In some embodiments, X3 is O.
In yet other embodiments, X3 is S.
In some embodiments, X3 is N.
In some embodiments, at least one of X1 or X3 is N.
In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxyl. In some embodiments, R1 is optionally substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C1-C10 alkyl. In some other embodiments, R1 is substituted C1-C10 alkyl. In some embodiments, R1 is unsubstituted C2-C10 alkynyl. In some embodiments, R1 is substituted C2-C10 alkynyl. In some embodiments, R1 is unsubstituted C2-C10 alkenyl. In some embodiments, R1 is substituted C2-C10 alkenyl. In some embodiments, R1 is carboxyl. In some embodiments, R1 is unsubstituted carbohydrate. In some embodiments, R1 is substituted carbohydrate. In some embodiments, R1 is unsubstituted ester. In some embodiments, R1 is substituted ester. In some embodiments, R1 is unsubstituted acyloxy. In some embodiments, R1 is substituted acyloxy. In some embodiments, R1 is nitro. In some embodiments, R1 is halogen. In some embodiments, R1 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R1 is substituted C1-C10 aliphatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R1 is substituted C6-C10 aromatic acyl. In some embodiments, R1 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R1 is substituted C6-C10 aralkyl acyl. In some embodiments, R1 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R1 is substituted C6-C10 alkylaryl acyl. In some embodiments, R1 is unsubstituted alkoxy. In some embodiments, R1 is substituted alkoxy. In some embodiments, R1 is unsubstituted amine. In some embodiments, R1 is substituted amine. In some embodiments, R1 is unsubstituted aryl. In some embodiments, R1 is substituted aryl. In some embodiments, R1 is unsubstituted C4-C10heterocyclyl. In some embodiments, R1 is substituted C4-C10heterocyclyl. In some embodiments, R1 is unsubstituted heteroaryl. In some embodiments, R1 is substituted heteroaryl. In some embodiments, R1 is unsubstituted C3-C10cycloalkyl. In some embodiments, R1 is substituted C3-C10cycloalkyl. In some embodiments, R1 is —OPO3WY. In some embodiments, R1 is —OCH2PO4WY. In some embodiments, R1 is —OCH2PO4Z. In some embodiments, R1 is —OPO3Z.
In some embodiments, when R1 is aryl, it is monocyclic. In some embodiments, when R1 is aryl, it is bicyclic. In some embodiments, when R1 is heteroaryl, it is monocyclic. In some embodiments, when R1 is heteroaryl, it is bicyclic.
In various embodiments, R1 is one of the following formulae:
wherein R16 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10 heterocyclyl, heteroaryl, C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
R17 is hydrogen, hydroxy, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, aryl, C3-C10 heterocyclyl, heteroaryl, or C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
each instance of R18 and R21 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z;
R19 is hydrogen, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carbohydrate, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, aryl, C3-C10heterocyclyl, heteroaryl, optionally substituted C3-C10cycloalkyl, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
s is an integer of 0, 1, 2, or 3; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, at least one of R16 and R19 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R17 or R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments, R2 is hydrogen. In some embodiments, R2 is hydroxyl. In some embodiments, R2 is optionally substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C1-C10 alkyl. In some other embodiments, R2 is substituted C1-C10 alkyl. In some embodiments, R2 is unsubstituted C2-C10 alkynyl. In some embodiments, R2 is substituted C2-C10 alkynyl. In some embodiments, R2 is unsubstituted C2-C10 alkenyl. In some embodiments, R2 is substituted C2-C10 alkenyl. In some embodiments, R2 is carboxyl. In some embodiments, R2 is unsubstituted carbohydrate. In some embodiments, R2 is substituted carbohydrate. In some embodiments, R2 is unsubstituted ester. In some embodiments, R2 is substituted ester. In some embodiments, R2 is unsubstituted acyloxy. In some embodiments, R2 is substituted acyloxy. In some embodiments, R2 is nitro. In some embodiments, R2 is halogen. In some embodiments, R2 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R2 is substituted C1-C10 aliphatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R2 is substituted C6-C10 aromatic acyl. In some embodiments, R2 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R2 is substituted C6-C10 aralkyl acyl. In some embodiments, R2 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R2 is substituted C6-C10 alkylaryl acyl. In some embodiments, R2 is unsubstituted alkoxy. In some embodiments, R2 is substituted alkoxy. In some embodiments, R2 is unsubstituted amine. In some embodiments, R2 is substituted amine. In some embodiments, R2 is unsubstituted aryl. In some embodiments, R2 is substituted aryl. In some embodiments, R2 is unsubstituted C4-C10heterocyclyl. In some embodiments, R2 is substituted C4-C10heterocyclyl. In some embodiments, R2 is unsubstituted heteroaryl. In some embodiments, R2 is substituted heteroaryl. In some embodiments, R2 is unsubstituted C3-C10cycloalkyl. In some embodiments, R2 is substituted C3-C10cycloalkyl. In some embodiments, R2 is —OPO3WY. In some embodiments, R2 is —OCH2PO4WY. In some embodiments, R2 is —OCH2PO4Z. In some embodiments, R2 is —OPO3Z.
In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxyl. In some embodiments, R5 is carboxaldehyde. In some embodiments, R5 is unsubstituted amine. In some embodiments, R5 is substituted amine. In some embodiments, R5 is unsubstituted C1-C10 alkyl. In some embodiments, R5 is substituted C1-C10 alkyl. In some embodiments, R5 is unsubstituted C2-C10 alkynyl. In some embodiments, R5 is substituted C2-C10 alkynyl. In some embodiments, R5 is unsubstituted C2-C10 alkenyl. In some embodiments, R5 is substituted C2-C10 alkenyl. In some embodiments, R5 is carboxyl. In some embodiments, R5 is unsubstituted carbohydrate. In some embodiments, R5 is substituted carbohydrate. In some embodiments, R5 is unsubstituted ester. In some embodiments, R5 is substituted ester. In some embodiments, R5 is unsubstituted acyloxy. In some embodiments, R5 is substituted acyloxy. In some embodiments, R5 is nitro. In some embodiments, R5 is halogen. In some embodiments, R5 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R5 is substituted C1-C10 aliphatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R5 is substituted C6-C10 aromatic acyl. In some embodiments, R5 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R5 is substituted C6-C10 aralkyl acyl. In some embodiments, R5 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R5 is substituted C6-C10 alkylaryl acyl. In some embodiments, R5 is unsubstituted alkoxy. In some embodiments, R5 is substituted alkoxy. In some embodiments, R5 is unsubstituted aryl. In some embodiments, R5 is substituted aryl. In some embodiments, R5 is unsubstituted C3-C10heterocyclyl. In some embodiments, R5 is substituted C3-C10 heterocyclyl. In some embodiments, R5 is unsubstituted heteroaryl, In some embodiments, R5 is unsubstituted C3-C10cycloalkyl. In some embodiments, R5 is substituted C3-C10cycloalkyl. In some embodiments, R5 is —OPO3WY. In some embodiments, R5 is —OCH2PO4WY. In some embodiments, R5 is —OCH2PO4Z. In some embodiments, R5 is —OPO3Z.
In some embodiments, R14 is hydrogen. In some embodiments, R14 is hydroxyl. In some embodiments, R14 is carboxaldehyde. In some embodiments, R14 is unsubstituted amine. In some embodiments, R14 is substituted amine. In some embodiments, R14 is unsubstituted C1-C10 alkyl. In some embodiments, R14 is substituted C1-C10 alkyl. In some embodiments, R14 is unsubstituted C2-C10 alkynyl. In some embodiments, R14 is substituted C2-C10 alkynyl. In some embodiments, R14 is unsubstituted C2-C10 alkenyl. In some embodiments, R14 is substituted C2-C10 alkenyl. In some embodiments, R14 is carboxyl. In some embodiments, R14 is unsubstituted carbohydrate. In some embodiments, R14 is substituted carbohydrate. In some embodiments, R14 is unsubstituted ester. In some embodiments, R14 is substituted ester. In some embodiments, R14 is unsubstituted acyloxy. In some embodiments, R14 is substituted acyloxy. In some embodiments, R14 is nitro. In some embodiments, R14 is halogen. In some embodiments, R14 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R14 is substituted C1-C10 aliphatic acyl. In some embodiments, R14 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R14 is substituted C6-C10 aromatic acyl. In some embodiments, R14 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R14 is substituted C6-C10 aralkyl acyl. In some embodiments, R14 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R14 is substituted C6-C10 alkylaryl acyl. In some embodiments, R14 is unsubstituted alkoxy. In some embodiments, R14 is substituted alkoxy. In some embodiments, R14 is unsubstituted aryl. In some embodiments, R14 is substituted aryl. In some embodiments, R14 is unsubstituted C3-C10heterocyclyl. In some embodiments, R14 is substituted C3-C10heterocyclyl. In some embodiments, R14 is unsubstituted heteroaryl. In some embodiments, R14 is unsubstituted C3-C10cycloalkyl. In some embodiments, R14 is substituted C3-C10cycloalkyl. In some embodiments, R14 is —OPO3WY. In some embodiments, R14 is —OCH2PO4WY. In some embodiments, R14 is —OCH2PO4Z. In some embodiments, R14 is —OPO3Z.
In some embodiments, R15 is hydrogen. In some embodiments, R15 is hydroxyl. In some embodiments, R15 is carboxaldehyde. In some embodiments, R15 is unsubstituted amine. In some embodiments, R15 is substituted amine. In some embodiments, R15 is unsubstituted C1-C10 alkyl. In some embodiments, R15 is substituted C1-C10 alkyl. In some embodiments, R15 is unsubstituted C2-C10 alkynyl. In some embodiments, R15 is substituted C2-C10 alkynyl. In some embodiments, R15 is unsubstituted C2-C10 alkenyl. In some embodiments, R15 is substituted C2-C10 alkenyl. In some embodiments, R15 is carboxyl. In some embodiments, R15 is unsubstituted carbohydrate. In some embodiments, R15 is substituted carbohydrate. In some embodiments, R15 is unsubstituted ester. In some embodiments, R15 is substituted ester. In some embodiments, R15 is unsubstituted acyloxy. In some embodiments, R15 is substituted acyloxy. In some embodiments, R13 is nitro. In some embodiments, R13 is halogen. In some embodiments, R13 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R15 is substituted C1-C10 aliphatic acyl. In some embodiments, R15 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R15 is substituted C6-C10 aromatic acyl. In some embodiments, R15 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R15 is substituted C6-C10 aralkyl acyl. In some embodiments, R15 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R15 is substituted C6-C10 alkylaryl acyl. In some embodiments, R15 is unsubstituted alkoxy. In some embodiments, R15 is substituted alkoxy. In some embodiments, R15 is unsubstituted aryl. In some embodiments, R15 is substituted aryl. In some embodiments, R15 is unsubstituted C3-C10heterocyclyl. In some embodiments, R15 is substituted C3-C10heterocyclyl. In some embodiments, R15 is unsubstituted heteroaryl, In some embodiments, R15 is unsubstituted C3-C10cycloalkyl. In some embodiments, R15 is substituted C3-C10cycloalkyl. In some embodiments, R15 is —OPO3WY. In some embodiments, R15 is —OCH2PO4WY. In some embodiments, R15 is —OCH2PO4Z. In some embodiments, R15 is —OPO3Z.
In some embodiments, R16 is hydrogen. In some embodiments, R16 is unsubstituted C1-C10 alkyl. In some embodiments, R16 is substituted C1-C10 alkyl. In some embodiments, R16 is unsubstituted C2-C10 alkynyl. In some embodiments, R16 is substituted C2-C10 alkynyl. In some embodiments, R16 is unsubstituted C2-C10 alkenyl. In some embodiments, R16 is substituted C2-C10 alkenyl. In some embodiments, R16 is unsubstituted carbohydrate. In some embodiments, R16 is substituted carbohydrate. In some embodiments, R16 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R16 is substituted C1-C10 aliphatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R16 is substituted C6-C10 aromatic acyl. In some embodiments, R16 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R16 is substituted C6-C10 aralkyl acyl. In some embodiments, R16 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R16 is substituted C6-C10 alkylaryl acyl. In some embodiments, R16 is unsubstituted aryl. In some embodiments, R16 is substituted aryl. In some embodiments, R16 is unsubstituted C3-C10heterocyclyl. In some embodiments, R16 is substituted C3-C10 heterocyclyl. In some embodiments, R16 is unsubstituted heteroaryl. In some embodiments, R16 is substituted heteroaryl. In some embodiments, R16 is unsubstituted C3-C10cycloalkyl. In some embodiments, R16 is substituted C3-C10cycloalkyl. In some embodiments, R16 is —PO3WY. In some embodiments, R16 is —CH2PO4WY. In some embodiments, R16 is —CH2PO4Z. In some embodiments, R16 is —PO3Z.
In some embodiments, R18 is hydrogen. In some embodiments, R18 is hydroxy. In some embodiments, R18 is carboxaldehyde. In some embodiments, R18 is unsubstituted amine. In some embodiments, R18 is substituted amine. In some embodiments, R18 is unsubstituted C1-C10 alkyl. In some embodiments, R18 is unsubstituted C2-C10 alkynyl. In some embodiments, R18 is substituted C2-C10 alkynyl. In some embodiments, R18 is unsubstituted C2-C10 alkenyl. In some embodiments, R18 is substituted C2-C10 alkenyl. In some embodiments, R18 is carboxyl. In some embodiments, R18 is unsubstituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is substituted carbohydrate. In some embodiments, R18 is unsubstituted ester. In some embodiments, R18 is substituted ester. In some embodiments, R18 is unsubstituted acyloxy. In some embodiments, R18 is substituted acyloxy. In some embodiments, R18 is nitro. In some embodiments, R18 is halogen. In some embodiments, R18 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R18 is substituted C1-C10 aliphatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R18 is substituted C6-C10 aromatic acyl. In some embodiments, R18 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R18 is substituted C6-C10 aralkyl acyl. In some embodiments, R18 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R18 is substituted C6-C10 alkylaryl acyl. In some embodiments, R18 is unsubstituted alkoxy. In some embodiments, R18 is substituted alkoxy. In some embodiments, R18 is unsubstituted aryl. In some embodiments, R18 is substituted aryl. In some embodiments, R18 is unsubstituted C3-C10heterocyclyl. In some embodiments, R18 is substituted C3-C10heterocyclyl. In some embodiments, R18 is unsubstituted heteroaryl. In some embodiments, R18 is substituted heteroaryl. In some embodiments, R18 is unsubstituted C3-C10cycloalkyl. In some embodiments, R18 is substituted C3-C10cycloalkyl. In some embodiments, R18 is —OPO3WY. In some embodiments, R18 is —OCH2PO4WY. In some embodiments, R18 is —OCH2PO4Z. In some embodiments, R18 is —OPO3Z.
In some embodiments, R19 is hydrogen. In some embodiments, R19 is unsubstituted C1-C10 alkyl. In some embodiments, R19 is substituted C1-C10 alkyl. In some embodiments, R19 is unsubstituted C2-C10 alkynyl. In some embodiments, R19 is substituted C2-C10 alkynyl. In some embodiments, R19 is unsubstituted C2-C10 alkenyl. In some embodiments, R19 is substituted C2-C10 alkenyl. In some embodiments, R19 is unsubstituted carbohydrate. In some embodiments, R19 is substituted carbohydrate. In some embodiments, R19 is unsubstituted C1-C10 aliphatic acyl. In some embodiments, R19 is substituted C1-C10 aliphatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aromatic acyl. In some embodiments, R19 is substituted C6-C10 aromatic acyl. In some embodiments, R19 is unsubstituted C6-C10 aralkyl acyl. In some embodiments, R19 is substituted C6-C10 aralkyl acyl. In some embodiments, R19 is unsubstituted C6-C10 alkylaryl acyl. In some embodiments, R19 is substituted C6-C10 alkylaryl acyl. In some embodiments, R19 is unsubstituted aryl. In some embodiments, R19 is substituted aryl. In some embodiments, R19 is unsubstituted C3-C10heterocyclyl. In some embodiments, R19 is substituted C3-C10 heterocyclyl. In some embodiments, R19 is unsubstituted heteroaryl. In some embodiments, R19 is substituted heteroaryl. In some embodiments, R19 is unsubstituted C3-C10cycloalkyl. In some embodiments, R19 is substituted C3-C10cycloalkyl. In some embodiments, R19 is —PO3WY. In some embodiments, R19 is —CH2PO4WY. In some embodiments, R19 is —CH2PO4Z. In some embodiments, R19 is —PO3Z.
In some embodiments, s is an integer of 0. In some embodiments, s is an integer of 1. In some embodiments, s is an integer of 2. In some embodiments, s is an integer of 3.
In various embodiments, W is hydrogen. In various embodiments, W is unsubstituted methyl. In various embodiments, W is substituted methyl. In various embodiments, W is unsubstituted ethyl. In various embodiments, W is substituted ethyl. In various embodiments, W is unsubstituted alkyl. In various embodiments, W is substituted alkyl. In various embodiments, W is unsubstituted carbohydrate. In various embodiments, W is substituted carbohydrate. In various embodiments, W is potassium. In various embodiments, W is sodium. In various embodiments, W is lithium.
In various embodiments, Y is hydrogen. In various embodiments, Y is unsubstituted methyl. In various embodiments, Y is substituted methyl. In various embodiments, Y is unsubstituted ethyl. In various embodiments, Y is substituted ethyl. In various embodiments, Y is unsubstituted alkyl. In various embodiments, Y is substituted alkyl. In various embodiments, Y is unsubstituted carbohydrate. In various embodiments, Y is substituted carbohydrate. In various embodiments, Y is potassium. In various embodiments, Y is sodium. In various embodiments, Y is lithium.
In various embodiments, Z is calcium. In various embodiments, Z is magnesium. In various embodiments, Z is iron.
In some embodiments of the invention, the pyrone analog of Formula VI is of Formula XXXII or Formula XXXIII or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
In some embodiments of the invention, the pyrone analog of Formula VI is of Formula XXXIV or a pharmaceutically/veterinarily acceptable salt thereof:
wherein R16 is hydrogen, —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z;
wherein each instance of R18 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C1-C10 alkyl, C2-C10 alkynyl, C2-C10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C1-C10 aliphatic acyl, C6-C10 aromatic acyl, C6-C10 aralkyl acyl, C6-C10 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, C3-C10 heterocyclic, C3-C10cycloalkyl, —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z; and
n is an integer of 0, 1, 2, 3, or 4.
In some embodiments of the invention, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z, or at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z. In some embodiments, R16 is —PO3WY, —CH2PO4WY, —CH2PO4Z or —PO3Z and at least one of R18 is —OPO3WY, —OCH2PO4WY, —OCH2PO4Z or —OPO3Z.
Each instance of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, W, Y and Z disclosed may be used in any combination in any of the Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, and XXXIV.
The compounds of the invention may be synthesized via several approaches, and the particular synthesis route is chosen depending on the substituent pattern of the desired compound. The routes are illustrated with selected members of the class of compounds of the invention, but can be used for other compounds described herein. Note that Scheme 1 is found at paragraph 222.
In this synthetic route, a benzyl protected ortho-hydroxyphenyl styrylketone 2-A is cyclized to yield a 3-hydroxy flavone using hydrogen peroxide and base. Deprotection via treatment with hydrogen and palladium catalysts yields a 3′-,4′-dihydroxyphenyl 3-hydroxy flavone 2-C. (See Chemical Research in Toxicology, 17(6), 795-804 (2004).)
Another approach to compounds of the invention is via acid catalyzed cyclization of an 1-ortho-hydroxyphenyl-3-aryl-1, 3, propanedione 3-A to yield a flavone analog 3-C, as is illustrated in Scheme 3. Benzyl protection of the dihydroxy substituents on the 3-aryl moiety is shown, but methyl ether protection may also be used. After cyclization is accomplished, the protecting groups are removed from compound 3-B. In the case of benzyl protection, treatment with hydrogen in the presence of a palladium is used. If methyl ether protection is used, treatment of the cyclized protected species analogous to compound 3-B with trimethylsilyl iodide will produce the final product 3-C. (See Chemical Research in Toxicology, 17(6), 795-804 (2004).)
Alternative cyclizations to yield flavone analogs may also be used and is illustrated in Scheme 4. Beta-ketoester 4-A is cyclized with 1, 3, 5, trihydroxybenzene using heat to yield the protected flavone 4-C. Deprotection with trimethylsilyl iodide yields a flavone 4-D. The same intermediate 4-C is obtained by reacting the acetylenic trihydroxybenzene 4-F with compound 4-E to yield the tricyclic intermediate 4-G. Reduction of 4-G with hydrogen over palladium yields 4-C, which can be converted to the flavone 4-D as before. (See Faming Zhuanli Shenquig Gongkai Shuomingshu 1666987 (2005), and Acta Chemica Scandinavica 49(7), 524-9 (1995).)
Key: Substituents described in Table 1 of exemplary compounds are abbreviated as shown herein.
Key: Substituents described in Table 2 of exemplary compounds of Formula D are abbreviated as shown herein.
The synthesis of compound 2-F is shown in Scheme 5. Vinylogous ketone 2-D is cyclized in the presence of hydrogen peroxide and base to form the dibenzyl protected flavonoid 2-E. Hydrogenolysis with hydrogen with palladium catalysis deprotects the benzyl ethers to yield the 3′,4′-dihydroxy phenyl pyrone analog 2-F.
The synthesis of pyrone analog 3-F is accomplished via synthetic steps as shown in Scheme 6. Propanedione 3-D is cyclized under acidic conditions to yield the 3-H dibenzyloxy flavone analog. Deprotection of the benzyl ethers via hydrogenolysis produces pyrone analog 3-F.
The trihydroxy benzene 4-B is condensed with propanedione 4-H to obtain the 3′,4′-dimethoxy phenyl flavone 4-I. Deprotection of the methyl ethers at the 3′ and 4′ positions with trimethylsilyl iodide produces pyrone analog 4-J.
An anesthetic wake up test is used to assess the reversal effect of modulator, PA, on the sedative effects of barbiturates, opioids, and benzodiazepines. This is a single blind, randomized, controlled animal trial. Approximately 48 rodents may be utilized throughout the study. Animals may be reused. However, a washout of 24 hours is required between exposures.
Twelve rodents can be utilized in each portion of this trial. Intravenous barbiturate (e.g. diprivan, pentobarbital, or phenobarbital) anesthesia is induced and titrated to spontaneous but slow respirations and lack of response to painful stimulation. Supplemental oxygen may be delivered. A maximum of 3 doses of intraperitoneal PA may be tested (low, medium, high) along with placebo. Once administered rodents are monitored with the help of stopwatch for time to awakening and return to normal respiratory rate. Once awakened, rodents are tested for criteria including time to withdrawal from painful stimulus and performance on rotarod.
This study may be repeated as a single agent trial with opioids (remifentanyl, fentanyl, morphine, etc) and benzodiazepines (diazepam, midazolam, lorazepam). This study can also be repeated as a multi agent trial utilizing one opioid, one benzodiazepine, and one barbiturate.
Opioids frequently produce adverse CNS side effects in ambulatory settings, providing a rationale for improving opioid analgesia by minimizing adverse effects. Pyrone analogs may activate PgP efflux of pump ligands at the blood brain barrier. In this pilot study, the hypothesis that pyrone analogs can improve the tolerability and safety of oxycodone without impairing analgesia is tested. Healthy subjects (up to approximately 65 individuals) undergoing third molar removal are randomly allocated to receive, for example, 500 mg oral PA or matching placebo at 1 hr prior to surgery. All subjects receive, for example, 10 mg oral oxycodone immediately prior to surgery. Oxycodone concentrations do not differ between groups prior to surgery, at 1 hr, or at 4 hr. Total Nausea and Vomiting Score (TNVS) is calculated for the time from dosing through 24 hr.
All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. It will be apparent to those of skill in the art that variations may be applied without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
This application claims the benefit of U.S. Provisional Application Ser. Nos. 60/953,187, filed on Jul. 31, 2007 and 61/076,584, filed on Jun. 27, 2008, each of which is hereby incorporated by reference in its entirety. This application cross references U.S. Provisional Application Ser. Nos. 60/953,186, filed Jul. 31, 2007; 61/076,612, filed Jun. 27, 2008; 60/953,188, filed Jul. 31, 2007; 61/076,608, filed Jun. 27, 2008; 61/076,591, filed Jun. 27, 2008; 61/076, 578, filed Jun. 27, 2008; and 61/076,587, filed on Jun. 27, 2008, each of which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61076584 | Jun 2008 | US | |
| 60953187 | Jul 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12182323 | Jul 2008 | US |
| Child | 12877343 | US |
