Tigilanol tiglate analogs, phorbol analogs, prodrugs, synthetic methods, and methods of use

Abstract

In one aspect, the disclosure relates to analogs of EBC-46. In one aspect, the analogs are modulators of protein kinase C (PKC). In another aspect, the disclosed compounds can be used in the treatment of solid tumors, HIV / AIDS, and neurodegenerative diseases, as well as in the enhancement of antigen density in antigen-targeted CAR-T and CAR-NK cell immunotherapies. In yet another aspect, the disclosed compounds are selective for individual PKC isoforms, allowing precise targeting of diseases associated with PKC dysfunction. In an alternative aspect, the disclosed compounds are useful as pan-PKC modulators and are not selective. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Description

TIGILANOL TIGLATE ANALOGS, PHORBOL ANALOGS, PRODRUGS, SYNTHETIC METHODS, AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 63 / 636,906, filed April 22, 2024, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under contracts Al 124743 and CA31845 awarded by the National Institutes of Health. The Government has certain rights in the invention.BACKGROUND

[0003] Approximately 39 million people are living with HIV globally. While current antiretroviral therapies (ARTs) can suppress viral loads to undetectable levels in people living with HIV, ART is not a cure as it does not eliminate reservoirs of latently infected cells that chronically resupply the virus. As a result, people living with HIV require lifelong ART treatment, which raises concerns about compliance, resistance, cost, and health issues associated with chronic exposure. While global access to ART is improving, supply has still not met the need. To circumvent the concerns arising from chronic therapies, strategies to cure HIV are being pursued, including gene therapies to remove the HIV-integrated virus, immune therapies to clear infected cells, “block and lock” strategies to silence the latent virus, and “kick and kill” strategies using latency-reversing agents (LRAs) to activate (kick) HIV-infected cells, allowing for their clearance (kill) by the immune system or other approaches that target cells actively expressing HIV proteins.

[0004] “Kick and kill” studies have uncovered several classes of LRAs, including protein kinase C (PKC) modulators, histone deacetylase and bromodomain inhibitors, Toll-like receptor agonists, disulfiram, benzotriazoles, SMAC mimetics, and Tat-mRNA LNPs, as well as LRA combinations that have been reported to exhibit synergistic effects. PKC modulators have shown special promise as LRAs, including a recent report of delayed virologic rebound upon treatment interruption in a humanized mouse model using an analog of bryostatin 1 as the “kick” (LRA) component and natural killer cells as the “kill” component.

[0005] Protein kinase C (PKC) is a family of kinases that regulate fundamental biological processes such as cell growth, apoptosis, RNA transcription, and immune functions as well asmore complex organismal functions such as memory and cognition. The PKC family of isozymes is traditionally divided into three groups - with its eight highly homologous isozymes classified as either conventional (a, pi, pil, y) or novel (5, E, q, 9) and its more distantly related isozymes as atypical ( , i). Although there are many similarities in the structures and biological roles of the many members of this family, specific PKC isozymes have been shown to control distinct downstream cellular pathways. Thus, individual PKC isozymes have been linked to specific diseases such as the involvement of PKC-3 in Parkinson’s disease or the role of PKC-pil as a tumor suppressor in colorectal cancer. Therefore, isoform-selective modulation presents an opportunity for PKC modulators to target specific diseases.

[0006] All PKC isozymes are activated through a sequence of phosphorylations at key regulatory domains, however only the conventional (a, pi, pil, y) and novel (6, E, q, 0) isozymes are activated by the binding of secondary messengers (diacylglycerol) to their C1 domain. In the cytosol, PKCs are large, flexible proteins which undergo significant reorganization and translocation from the cytosol to the cellular membranes upon the binding of its C1 domain (e.g., diacylglycerol, EBC- 46). This translocation event from the cytosol to the cellular membranes is known as the hallmark of ligand-induced PKC activation, and this process can be visualized and quantified through cellular models using fluorophore-tagged PKCs.

[0007] Protein kinase C (PKC) modulators can be activators or formal inhibitors used by way of feedback inhibition pathways, where activation and inhibition pathways can be controlled by the amount of compound used and / or the duration of exposure. Both activators and inhibitors of PCK can be therapeutically relevant. PKC modulators have figured in therapeutic approaches to the treatment of solid tumors, the eradication of HIV / AIDS, the amelioration of neurodegenerative diseases, and the enhancement of antigen density in antigen-targeted CAR-T and CAR-NK cell immunotherapies. Tigilanol tiglate (EBC-46, Stelfonta) is proposed to be an isoform-selective modulator of PKC-p that has been FDA-approved for veterinary use that has been shown to exhibit a cure rate of up to 88% in canine solid tumors. Furthermore, EBC-46 is currently under consideration in human clinical trials for the treatment of melanoma, squamous cell carcinoma, and head and neck solid tumors. In this regard, it has recently been granted orphan drug status for the treatment of soft tissue sarcomas.

[0008] Although some analogs of EBC-46 have been reported using the natural source of tigilanol tiglate. However, some analogs of EBC-46 are inaccessible from natural sources. Production ofthe same would facilitate investigation into the structural basis for EBC-46’s apparent isoform- selective PKC-P activation well as for improved therapeutic activity.

[0009] Despite advances in PKC modulator research, there is still a scarcity of compounds targeting PKC that are potent, efficacious, and selective for individual PKC isoforms. The design and development of variants of PKC modulating compounds would lead to more targeted treatment of diseases associated with PKC dysfunction. These needs and other needs are satisfied by the present disclosure.SUMMARY

[0010] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to analogs of EBC-46. In one aspect, the analogs are modulators of protein kinase C (PKC). In another aspect, the disclosed compounds can be used in the treatment of solid tumors, HIV / AIDS, and neurodegenerative diseases, as well as in the enhancement of antigen density in antigen-targeted CAR-T and CAR-NK cell immunotherapies. In yet another aspect, the disclosed compounds are selective for individual PKC isoforms, allowing precise targeting of diseases associated with PKC dysfunction. In an alternative aspect, the disclosed compounds are useful as pan-PKC modulators and are not selective.

[0011] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the severalviews.

[0013] FIG. 1A shows an overview of EBC-46 synthesis from phorbol (1); FIG. 1 B shows an overview of EBC-46 analog design. It should be noted that a black dot is used for shorthand in some drawings to represent a “wedged” hydrogen (i.e., a hydrogen atom extending from the plane of the page).

[0014] FIG. 2A shows a comparison of the pharmacophoric elements of (S)-diacylacylglycerol, a phorbol diester, and 3-(N-acetylamino)-5-(N-decyl-N-methylamino)benzylalcohol (ADMB); FIG. 2B shows a model of the Membrane-Ligand-PKC ternary complex; FIG. 2C shows the 3D X-ray crystal structure of PDBu bound to the C1b domain of PKC-delta (hydrogen bonds indicated in dashed black lines) (left) and a docking model of EBC-46 bound to the C1 b domain of PKC-5 (right) with key amino acid residues labeled..

[0015] FIG. 3 shows results of an NF-KB activation assay for selected compounds.

[0016] FIGs. 4A-4B show confocal microscopy images of CHO-K1 cells transfected with PKC- GFP and treated with PKC modulators (EBC-46, SUW430, and SUW431). Translocation assessed at 10 min after compound addition.

[0017] FIGs. 5A-5F show evaluation of EBC-46 analogs as LRAs. J-Lat clone 10.6 cells were treated with ascending concentrations of novel tigilanol tiglate analogs for 48 hours. Bryostatin 1 , a natural PKC modulator, served as a positive control. All conditions were completed in three independent biological replicates, each in technical duplicates, resulting in n = 6. The same bryostatin 1 , EBC-46, and SUW400 curves are shown in FIGs. 5A-5D for comparison purposes. Dose curves are separated by ring modifications as follows: (FIG. 5A) B-ring analogs, (FIG. 5B) C-ring analogs derived from 2 (Scheme 2A), (FIG. 5C) C-ring analogs derived from 3 (Scheme 2B), and (FIG. 5D) A-ring analogs. (FIG. 5E) Time course experiment showing EBC-46 and SUW427 (100 nM) over the course of 48 hours and (FIG. 5F) time course experiment showing EBC-46 and SUW427 (250 nM) over the course of 48 hours.

[0018] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.DETAILED DESCRIPTION

[0019] EBC-46 is a PKC modulator approved for veterinary medicine and human use for cancer. Disclosed herein are EBC-46 precursors and derivatives and use of the same as LRAs. In one aspect, when compared to bryostatin 1 , a potent PKC modulator and leading LRA, the disclosed analogs exhibit superior PKC affinities (some remarkably at a picomolar level), unique isoform selectivities (some like EBC-46 and one unprecedented), and notably better functional activity (LRA) in a J-Lat latency reversal model system.

[0020] In one aspect, disclosed herein are compounds of Formula I:Formula I; wherein Ri is a linear or branched C1-C10 alkoxy group, linear or branched C1-C10 alkyl or alkenyl ester optionally substituted with C3-C6 cycloalkyl or heterocycloalkyl group, or a linear or branched siloxy group; wherein R2 is a C1-C10 alkyl group, a C6-C12 alkylaryl or arylalkyl group, or a C3-C6 cycloalkyl or heterocycloalkyl group optionally substituted with a C1-C4 alkyl group; wherein R3 and R4 together form an epoxide, or are both H, or wherein a bond marked by * is a double bond, R4 is absent, and R3 is H; wherein Rs is hydrogen, a linear or branched C1-C10 alkyl or alkenyl group, or is a substituted or unsubstituted benzyloxycarbonyl group; wherein Re is OH or H; wherein R7is a ketone, a C1-C10 linear or branched alkyl or alkenyl ester, a linear or branched siloxy group, or a C6-C10 aryl ester; and wherein the bond marked by * is a double bond or a single bond.

[0021] In another aspect, when Ri is a linear or branched siloxy group, Ri can include one or more alkyl groups bonded to the silicon molecule in the siloxy group. In a further aspect, the one or more alkyl groups can be methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or any combination thereof. In a further aspect, exemplary Ri substituents include, but are not limitedi substituents include, but are not limited to, a tert-butyldimethylsilyl (TBS) ether, a triethylsilyl (TES) ether, a triisopropylsilyl (TIPS) ether, an N-butyl dimethyl silyl ether, a pentamethyl disilyl ether, or a derivative or variant thereof.

[0022] In a further aspect, exemplary R2substituents include, but are not limited to, wderivatives and variants thereof.

[0023] In a further aspect, exemplary R5substituents include, but are not limited to, hydrogen, methyl,derivatives and variants thereof.

[0024] In some aspects, R4is absent and R3is H, or R3and R4together formIn a further aspect, exemplary R7substituents include, but are not limited to,, and derivatives and variants thereof. Additional exemplary R7substituents include, but are not limited to, a tert-butyldimethylsilyl (TBS) ether, a triethylsilyl (TES) ether, a triisopropylsilyl (TIPS) ether, an N-butyl dimethyl silyl ether, a pentamethyl disilyl ether, or a derivative or variant thereof.

[0025] In any of these aspects, the compound can be selected fromsome aspects, compounds may be referred to herein by the names below the structures shown above (e.g. SUW439) or by the number alone (e.g. 439). It is to be understood that SUW439 and 439 are the same compound and that this system of nomenclature applies to all such numbered compounds (e.g. SUW402 and 402 are the same, SUW424 and 424 are the same, and so forth).

[0026] Also disclosed herein are pharmaceutical compositions including a therapeutically effective amount of a disclosed compound or salt. In some aspects, the pharmaceutical compositions can include at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0027] In another aspect, disclosed herein is a method for treating a disease in a subject, such as, for example, a human subject, the method including at least the step of administering a disclosed compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the compound to the subject. In some aspects, the disease can be a neurological disorder, cancer, a cardiovascular disease or disorder, a viral disease, a metabolic disease or disorder, rejection of a transplanted organ, or any combination thereof In another aspect, the neurological disorder can be a mood disorder, bipolar disorder, Parkinson’s disease, or any combination thereof. In still another aspect, the cancer can be colorectal cancer, melanoma, squamous cell carcinoma, a head and neck solid tumor, or any combination thereof. In an aspect, the cardiovascular disease or disorder can be stroke. In still another aspect, the viral disease can be HIV. In one aspect, the metabolic disease or disorder can be diabetes.

[0028] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspectsdescribed herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0029] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0030] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0031] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0032] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0033] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0034] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0035] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions

[0036] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0037] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutically acceptable salt,” “a disease,” or “an alkyl group,” including, but not limited to, mixtures, combinations, or co-occurrence of two or more such pharmaceutically acceptable salts, diseases, or alkyl groups, and the like.

[0038] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about10” is disclosed, then “10” is also disclosed.

[0039] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. 'about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about x’ to ‘y’”, where x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0040] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0041] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or“at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0042] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material. For example, an “effective amount” of anhydride refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired level of conversion of one chemical moiety to a target chemical moiety. The specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the amount and type of reactant to be modified, other functional groups and protecting groups present, further chemical modifications to be performed, and solvent and additives present in the reaction mixture.

[0043] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0044] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).Chemical Definitions

[0045] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0046] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such asnitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0047] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0048] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain ( / .e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0049] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0050] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkylgroups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0051] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0052] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0053] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, — CH2— (methylene), — CH2CH2— , — CH2C(CH3)2CH2— , and — CH2CH2CH2— are non-limiting examples of alkanediyl groups.

[0054] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA1— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0055] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0056] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0057] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can beunsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0058] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0059] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized TT electrons above and below the plane of the molecule, where the TT clouds contain (4n+2) TT electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0060] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0061] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughoutthis specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0062] The terms “amine” or “amino” as used herein are represented by the formula — NA , where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0063] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) and — N(-alkyl)2, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0064] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0065] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or — (A1O(O)C-A2-OC(O))a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0066] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0067] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably andrefer to F, Cl, Br, or I.

[0068] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0069] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0070] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2- b]pyridazinyl, imidazo[1 ,2-a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0071] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1 ,2,3-oxadiazole, 1 ,2,5-oxadiazole and 1 ,3,4-oxadiazole, thiadiazole, including, 1 ,2,3-thiadiazole, 1,2,5-thiadiazole, and 1 ,3,4-thiadiazole, triazole,including, 1 ,2,3-triazole, 1, 3, 4-triazole, tetrazole, including 1 ,2,3,4-tetrazole and 1 ,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1 ,2,4-triazine and 1 ,3,5-triazine, tetrazine, including 1 ,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0072] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1 ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, 2,3-dihydro- 1 ,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1 H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2- b]pyridin-3-yl; and 1 H-pyrazolo[3,2-b]pyridin-3-yl.

[0073] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0074] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula — OH.

[0075] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0076] The term “azide” or “azido” as used herein is represented by the formula — N3.

[0077] The term “nitro” as used herein is represented by the formula — NO2.

[0078] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0079] The term “silyl” as used herein is represented by the formula — SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0080] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A1, — S(O)2A1, — OS(O)2A1, or — OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0081] The term “thiol” as used herein is represented by the formula — SH.

[0082] “R1,” “R2,” “R3,”... “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant ( / .e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded orattached to the second group.

[0083] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0084] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0085] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)o-40R°; -O(CH2)0-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O_4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; - N3; -(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)0_4N(RO)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; - (CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR-, SC(S)SR°; -(CH2)O_4SC(0)R°; -(CH2)O-4C(0)NR02; -C(S)NRO2; -C(S)SR°; -(CH2)O_4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)0-4SSRO; - (CH2)O-4S(0)2R0; -(CH2)O_4S(0)2OR°; -(CH2)0-4OS(O)2RO; -S(O)2NRO2; -(CH2)O-4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2;P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(C1-4 straight or branched alkylene)O- N(R°)2; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o- iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated,or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0086] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -CN, -N3, -(CH2)0- SH, -(CH2)O-2NH2, -straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, - CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0087] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R‘, =NNHC(O)OR‘, =NNHS(O)2R‘, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0088] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, - OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, - S(O)2R+, -S(O)2NR+2, -C(S)NR+2I-C(NH)NR+2, or -N(R+)S(O)2R+; wherein each Rt is independently hydrogen, Ci_6aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rt, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0090] Suitable substituents on the aliphatic group of Rt are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or - NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, trifl ate, mesylate, tosylate, and brosylate.

[0092] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-lnterscience, 1999).

[0093] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a furtheraspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0094] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified ( / .e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0095] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0096] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bondedcombinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0097] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0098] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0099] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-lngold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0100] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36CI, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. I sotopical ly labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0101] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0102] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0103] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.keto form enol form amide form imidic acid formLikewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0104] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0105] In some aspects, a structure of a compound can be represented by a formula:

[0106] which is understood to be equivalent to a formula:

[0107] wherein n is typically an integer. That is, R" is understood to represent five independent substituents, R"a\ R"b\ R' , R"<d\ and R"(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R',(a)is halogen, then R"(b) is not necessarily halogen in that instance.

[0108] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0109] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible nonexpress basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.Pharmaceutical Definitions

[0110] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0111] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0112] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12thedition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta- blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0113] As used herein, “attached” can refer to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, TT-TTinteractions, cation-n interactions, anion-TT interactions, polar TT-interactions, and hydrophobic effects.

[0114] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.

[0115] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as HIV / AIDS, a neurodegenerative disease, and / or a head and neck solid tumor The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of HIV / AIDS, neurodegenerative disease and / or head and neck solid tumor in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e. , arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. T reating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0116] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0117] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease,disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0118] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0119] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0120] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment.It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0121] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0122] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0123] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0124] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0125] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure containrelati vely basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0126] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, nontoxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0127] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acidgroups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0128] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0129] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0130] The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

[0131] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.ASPECTS

[0132] The present disclosure can be described in accordance with the following numbered aspects, which should not be confused with the claims.

[0133] Aspect 1. A compound having Formula I or a pharmaceutically acceptable salt thereof:Formula I; wherein Ri is hydrogen, a linear or branched C1-C10 alkoxy group, linear or branched CICI 0 alkyl or alkenyl ester optionally substituted with C3-C6 cycloalkyl or heterocycloalkyl group, or a linear or branched siloxy group; wherein R2is a C1-C10 alkyl group, a C6-C12 alkylaryl or arylalkyl group, or a C3-C6 cycloalkyl or heterocycloalkyl group optionally substituted with a C1-C4 alkyl group; wherein R3and R4together form an epoxide, or are both H, or wherein a bond marked by * is a double bond, R4is absent, and R3is H; wherein R5is hydrogen, a linear or branched C1-C10 alkyl or alkenyl group, or is a substituted or unsubstituted benzyloxycarbonyl group; wherein R6is OH or H;wherein R? is a ketone, a C1-C10 linear or branched alkyl or alkenyl ester, linear or branched siloxy group, a C1-C10 carbamate, or a C6-C10 aryl ester; and wherein the bond marked by * is a double bond or a single bond.

[0134] Aspect 2. The compound or salt of aspect 1, wherein Ri is selected from

[0135] Aspect s. The compound or salt of aspect 1 or 2, wherein R2 is selected from

[0136] Aspect 4. The compound or salt of any one of aspects 1-3, wherein R3and R4together form

[0137] Aspect 5. The compound or salt of any one of aspects 1 -3, wherein R4is absent and R3 isH.

[0138] Aspect s. The compound or salt of any one of aspects 1-5, wherein Rs is hydrogen, methyl,

[0139] Aspect 7. The compound or salt of any one of aspects 1-5, wherein R6is OH.

[0140] Aspect 8. The compound or salt of any one of aspects 1-7, wherein R6is hydrogen.

[0141] Aspect 9. The compound or salt of any one of aspects 1-8, wherein R? is selected from

[0142] Aspect 10. The compound or salt of any one of aspects 1-9, wherein the bond marked by* is a double bond.

[0143] Aspect 11 . The compound or salt of any one of aspects 1-9, wherein the bond marked by* is a single bond.Aspect 12. The compound of any one of aspects 1-11 , wherein the compound comprises

[0144] Aspect 13. A pharmaceutical composition comprising a therapeutically effective amount of the compound or salt of any one of aspects 1-12.

[0145] Aspect 14. The pharmaceutical composition of aspect 13, further comprising at least one pharmaceutically acceptable excipient, diluent, or carrier.

[0146] Aspect 15. A method for treating a disease or disorder in a subject, the method comprising administering the compound or salt of any one of aspects 1-12 or the pharmaceutical composition of aspect 13 or 14 to the subject

[0147] Aspect 16. The method of aspect 15, wherein the subject is a human.

[0148] Aspect 17. The method of aspect 15 or 16, wherein the disease or disorder comprises a neurological disorder, cancer, a cardiovascular disease or disorder, a viral disease, a metabolic disease or disorder, rejection of a transplanted organ, or any combination thereof.

[0149] Aspect 18. The method of aspect 17, wherein the neurological disorder comprises a mood disorder, bipolar disorder, Parkinson’s disease, or any combination thereof.

[0150] Aspect 19. The method of aspect 17, wherein the cancer comprises colorectal cancer, melanoma, squamous cell carcinoma, a head and neck solid tumor, or any combination thereof.

[0151] Aspect 20. The method of aspect 17, wherein the cardiovascular disease or disorder comprises stroke.

[0152] Aspect 21. The method of aspect 17, wherein the viral disease comprises HIV.

[0153] Aspect 22. The method of aspect 17, wherein the metabolic disease or disorder comprises diabetes.EXAMPLES

[0154] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.gr, amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.Example 1 : Design and Synthesis of EBC-46 Analogs

[0155] Based on a previous pharmacophoric model for PKC modulators, studies on the role of the lipophilic region of PKC modulators in the activation of PKC, and studies on the structureactivity relationship (SAR) of C1-domain ligands of PKC, small changes are expected in the structure of these tigliane compounds to influence their PKC binding affinity and isoformselectivity. Thus, to probe which functional groups of EBC-46 are important for inducing potent and isoform-selective PKC modulation and ultimately to investigate the utility of isoform-selective modulators as HIV latency reversal agents, the present design strategy focuses on making modifications to the lipophilic region, by diversification at the C12 and C13 positions, and to the PKC-binding region by exploring derivatives of its unique B-ring oxidation pattern and the C3 ketone of the A-ring (FIGs. 1 B and 2B).Scheme 1A: Selected B-ring analogs of EBC-46Scheme 1 B: Reactions and conditions for the synthesis of B-ring analogs of EBC-46Scheme 1C: Reactions and conditions for the synthesis of B-ring analogs of EBC-46

[0156] Schemes 1A-1C present reactions and conditions for the synthesis of B-ring analogs of EBC-46. (Scheme 1A) Overview of B-ring analogs of EBC-46. (Note a) Reactions and conditions for synthesis of SUW400 and SUW402 previously reported. (Scheme 1 B) Reactions and conditions for the synthesis of SUW403. (Note b) Vanadyl isopropoxide (0.05 equiv), Yamamoto ligand (0.1 equiv), cumene hydroperoxide (2 equiv), toluene, 0 °C to room temperature. (Scheme 1C) Reactions and conditions for the synthesis of SUW426 and SUW427. (Note c) For SUW426: methyl triflate (6 equiv), 2,6-di-tert-butyl pyridine (10 equiv), CH2CI2. (Note d) For SUW427: 4- methylcarbonate benzyl chloroformate (1 equiv), triethylamine (NEts) (1 equiv), 4- dimethylaminopyridine (DMAP) (1 equiv), CH2CI2, 4 °C.Scheme 2A: Reactions and conditions for the synthesis of C-ring analogs of EBC-46Scheme 2B: Reactions and conditions for the synthesis of C-ring analogs of EBC-46

[0157] Schemes 2A-2B present reactions and conditions for the synthesis of C-ring analogs of EBC-46. (Scheme 2A) C12 analog synthesis. (Note a) For SUW413: 1- methylcyclopropanecarboxylic acid (2.2 equiv), NEt3(4 equiv), 2,4,6-trichlorobenzoyl chloride (2 equiv), DMAP (2.6 equiv), toluene, and 60 °C; then p-toluenesulfonic acid (TsOH) [0.21 M in H2O:acetonitrile (MeCN)]. (Note b) For SUW424: N-methylimidazole (36 equiv), CDI (7 equiv), MeCN; then pyrrolidine; then TsOH (0.21 M in H2O:MeCN). (Note c) For SUW430: lutidinium bistriflimide (0.5 equiv), tert-butyl 2,2,2-trichloro acetimidate (11.6 equiv), fluorobenzene, 40 to 50 °C; then pyridinium p-toluenesulfonate (PPTS) (12 equiv), MeOH:MeCN (5:1 , v / v), 60 °C. (Scheme 2B) Reactions and conditions for the synthesis of C13 C-ring analogs of EBC-46. (Note d) For SUW406: cyclobutanecarboxylic acid (1.8 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (2 equiv), NEt3(3 equiv), DMAP (0.25 equiv), CH2CI2; then TsOH (0.21 M in H2O:MeCN). (Note e) For SUW407: (R)-2-methylbutanoic acid (1.8 equiv), EDC (2 equiv), NEt3(3 equiv), DMAP (0.25 equiv), CH2CI2; then TsOH (0.21 M in H2O:MeCN). (Note f) For SUW421 : N-methylimidazole (32 equiv), CDI (3 equiv), MeCN; then pyrrolidine; then TsOH (0.21 M in H2O:MeCN). (Note g) For SUW428: benzoic acid (3.5 equiv), NEt3(3.5 equiv), DMAP (3.9 equiv), CH2CI2; then PPTS (12 equiv), MeOH:MeCN (5:1 , v / v), 60 °C. (Note h) For SUW431 : 1- napthaleneacetic acid (2 equiv), EDC (2 equiv), NEt3(2.1 equiv), DMAP (0.5 equiv), CH2CI2; then PPTS (12 equiv), MeOH:MeCN (5:1 , v / v), 60°C.Scheme 3: Reactions and conditions for the synthesis of A-ring analogs of EBC-46

[0158] Scheme 3 presents reactions and conditions for the synthesis of A-ring analogs of EBC- 46. (Note a) For SUW422: benzoyl chloride (10 equiv), DMAP (0.5 equiv), pyridine, 50 °C; then p-toluenesulfonic acid (TsOH) (0.105 M in H2O:MeCN), 80 °C. (Note b) For SUW425: senecioic acid (20 equiv), EDC (20.5 equiv), NEt3(23 equiv), DMAP (0.5 equiv), CH2CI2, 40 °C; the TsOH (0.105 M in H2O:MeCN), 80 °C.

[0159] This investigation into the SAR of the B-ring began by exploring the importance of the C5p-hydroxy-C6a,C7a-epoxy functionality that is peculiar to EBC-46 and other phorbol-derived natural products that exhibit potent anti-cancer or anti-HIV activity such as yuanhuacine and gnidimacrin. To investigate the importance of the C5-beta-hydroxyl group and the C6,C7-alpha epoxide independently of each other, a series of B-ring analogs featuring different variations of the oxidation pattern was prepared. SUW400 features a C6,C7 alkene in place of the C6,C7- alpha epoxide. SUW403 lacks oxidation at C5 featuring just the C6,C7-alpha epoxide. SUW402is simply a phorbol diester featuring both the lack of oxidation at C5 and a C6,C7 alkene. The syntheses of SUW400 and SUW402 have already been reported. SUW403 was prepared in one step from SUW402 via Yamamoto epoxidation.

[0160] A C20-methyl ether analog SUW426 was prepared as a negative control tool compound to probe the existence of a PKC-independent pathway for the biological activity of EBC-46. Based on the present pharmacophoric model and the computational modeling of the C1 domain binding site, it is expected that the removal of the C20 alcohol’s ability to function as a hydrogen bond donor while also introducing the steric bulk of the methyl group would make this compound incapable of binding to the C1 domain of PKC. SUW426 was prepared directly from EBC-46 by treatment with excess methyl triflate and 2,6-ditertbutyl pyridine as a hindered base.

[0161] With the possibility that these drugs might have a narrow therapeutic window when administered systemically, a C20-esterase releasable prodrug SUW427 was prepared. This esterase-labile linker successfully expanded the therapeutic window of bryostatin 1 by over 100- fold. This prodrug variant of EBC-46 (SUW427) was prepared directly from EBC-46 and the corresponding benzylic chloroformate.

[0162] This investigation into the SAR of the C-ring consisted of changing the substituents of the C12 and C13 oxygens (Schemes 4-5). Prior work investigating C12 and C13 ester derivatives of EBC-46 revealed that small changes in the lipophilicity of these substituents had profound effects on the isoform-selective activation of PKC and the in vitro and anti-melanoma properties in vivo. C12 analogs were synthesized from 2 which was made using a previously reported synthetic route (Scheme 4).Scheme 5

[0163] Because of the potential of the tiglate ester to act as a Michael acceptor, a more metabolically stable isostere of the C12 tiglate ester featuring a C12 cyclopropane in place of the a, p unsaturation was envisioned. SUW413 was prepared in two steps; first using the mixed Yamaguchi anhydride, generated in situ from the corresponding carboxylic acid and 2,2,2- trichlorobenzoyl chloride to form the C12 ester followed by subsequent acid deprotection of the C5,C20 acetonide.

[0164] Because the C12-hydroxy metabolite of EBC-46 has been identified as a major metabolite of EBC-46, making analogs that featured esterase-resistant groups at this position were envisioned. To mimic the geometry of the tiglate ester, a C12-pyrrolidine carbamate analog (SUW424) was made. In one step, 2, was treated with carbonyl diimidazole (GDI) to form the C12 imidazole carbamate, and the C12 pyrrolidine carbamate was formed rapidly by addition of superstoichiometric pyrrolidine. Subsequent acid deprotection afforded SUW424.

[0165] As another metabolically stable functionality, a C12-tert butyl ether was envisioned as a way of installing a hydrophobic cap on C12 to mimic a “prostratin-like” C-ring without having to do a multistep deoxygenation. SUW430 was prepared in two steps from 2 by first using a noncoordinating acid-base catalyzed tert-butyl etherification61 followed by a mild-acid mediated deprotection of the C5,C20 acetonide.

[0166] The synthesis of C13 analogs began from 3 which was made using a previously reported synthetic route (Scheme 5). The C12 and C13 acetate groups were cleaved to the corresponding diol using cesium methoxide. Selective reinstallation of the C13 acetate using acetic anhydride with no acylation catalyst followed by C12 tiglate esterification and subsequent C13 acetate deprotection yielded the C13 hydroxy C12 tiglate.

[0167] To probe the importance of the chiral ester at C13, an achiral cyclobutanoate ester analog (SUW406) and a diastereomeric (R)-methyl-butyrate ester analog (SUW407) were made. Both compounds were made in two steps from 4 using standard Steglich esterification conditions followed by subsequent acid deprotection of the C5,C20 acetonide.

[0168] The C13 ester carbonyl of phorbol esters and prostratin has been observed to participate in a transannular hydrogen bond with the C9 alcohol40,41. This hydrogen bond plays a role in preorganizing the C13 substituent. Disruption of this intramolecular hydrogen bond in prostratin and DPP, by converting the C13 ester groups to the corresponding C13 ethers, results in compounds with weak PKC binding affinity and poor in vitro activity. To investigate whether the binding affinity of these compounds could be improved by strengthening this hydrogen bond, enhancing the Lewis basicity of the carbonyl by preparing a C13 carbamate was envisioned. SUW421 was prepared using the previously described carbamoylation conditions for the preparation of SUW424 Similarly, as a more nonpolar isostere of SUW421 , a C13 benzoate ester was prepared from 4 using benzoic anhydride. Subsequent acid deprotection of the C5,C20 acetonide afforded SUW428.

[0169] In a previous study on prostratin esters and their ability to activate latent HIV reservoirs in vitro and ex-vivo, the best performing compound featured a napthylacetyl ester at C1311. This compound was >100-fold better at activating HIV reservoirs than prostratin itself. Inspired by this finding, a C13 napthylacetyl group was installed to 4 using standard Steglich conditions. Subsequent acid deprotection of the C5,C20 acetonide afforded SUW431.

[0170] This investigation into the SAR of the A-ring began by exploring ester variants of the C3- alcohol (Scheme 6) - a functional group found in structurally homologous PKC-modulating compounds with potent biological activity.Scheme 6

[0171] The synthesis of C3 analogs began from 5 which was made using a previously reported synthetic route (Scheme 6). Divergent intermediate 6 was prepared from 5 by first protecting the C20 and C4,C5 alcohols with a t-butyldimethylsilyl group and an acetonide, respectively. Subsequent deacetylation of the C12 and C13 acetate esters, selective esterification of the C12 and C13 alcohols, and stereoselective reduction of the C3 ketone with sodium borohydride afforded C3-hydroxy intermediate 6. Because the C6,C7 epoxide was not compatible with the protection and deprotection conditions described above, the A-ring analogs also possess a C6,C7-alkene in the B-ring.

[0172] Gnidimacrin is highly effective at activating latent HIV reservoirs and features a C3-beta benzoate ester. Thus, a C3 benzoate ester was installed by treating 6 with benzoyl chloride in pyridine, and subsequent acidic deprotection of the B-ring protecting groups afforded the final compound, SUW422.

[0173] In a study looking at the HIV-latency reversal activity of various ingenol esters, the C3 senecioate ester of ingenol was identified as the most efficacious compound with the ability to activate latent reservoirs to the same degree as their anti-CD3 / CD28 T-cell positive control. Thus, a 03 senecioate ester was prepared by Steglich esterification of 6, and subsequent acid deprotection of the B-ring protecting groups afford SUW425.

[0174] General Procedures: All reactions were carried out in glassware under ambient atmosphere unless otherwise noted. Reactions were concentrated under reduced pressure using a rotary evaporator unless otherwise noted. Commercial reagents were used as received or purified using the methods indicated herein. Dichloromethane, diethyl ether, dimethylformamide, tetrahydrofuran, and toluene were passed through an alumina drying column (Solv-Tek Inc.) using nitrogen pressure; ethyl acetate and hexanes were obtained from Fisher Scientific. Analytical thin- layer chromatography (TLC) was carried out on 250 pm silica gel 60G plates with fluorescent indicator F254 (EMD Millipore). Plates were visualized with UV light and treated with p- anisaldehyde, ceric ammonium molybdate, or potassium permanganate stain with gentle heating. Flash column chromatography was performed using silica gel (230-400 mesh, grade 60, particle size 40 to 63 pm) purchased from Fischer Scientific. NMR spectra were acquired on a Varian INOVA 600 or Varian 400 or Bruker 400 magnetic resonance spectrometer.1H chemical shifts are reported relative to the residual solvent peak (CDCI3 = 7.26 ppm, de-acetone = 2.05 ppm, CD3OD = 3.31 ppm) as follows: chemical shift (5), multiplicity (app = apparent, b = broad, s =singlet, d = doublet, t = triplet, q = quartet, m = multiplet, or combinations thereof), coupling constant(s) in Hz, integration.13C chemical shifts are reported relative to the residual solvent peak (CDCI3 = 77.16 ppm, d6-acetone = 206.26 ppm, CD3OD = 49.00 ppm). Infrared spectra were acquired on a Nicolet iS 50 FT-IR Spectrometer (ThermoFisher) equipped with an attenuated total reflectance (ATR) assembly. Optical rotations were acquired on a P-2000 Digital Polarimeter (Jasco). High resolution mass spectra (HRMS) were acquired at the Vincent Coates Foundation Mass Spectrometry Laboratory at Stanford.

[0175] Experimental procedures were generally optimized on a small scale, and the results from these optimized procedures are provided below. Reaction procedures were performed by multiple investigators to ensure reproducibility. Characterization data is provided for all isolable compounds. For some steps, the reaction product could be used without chromatographic purification. Because the hazard of new compounds is unknown, all procedures were conducted with full personal protective equipment in a way that avoided exposure.Synthesis Strategy for C-Rinq Analogs

[0176] We directed our molecular editing of the C-ring at variations of the C12 and C13 substituents (Schemes 2A-2B). Since the discovery of phorbol myristate acetate and other phorbol esters, it has been found that changes in the C12 / C13 lipid domain profoundly influence biological activity and potency: Phorbol myristate acetate is a potent tumor promoter, while prostratin (C12-deoxyphorbol-C13-acetate) is not. However, prostratin is an LRA lead and the corresponding prostrati n-C13-naphthyl acetate differing from prostratin by only a naphthyl group is > 130-fold more potent than prostratin as an LRA and is used by clinicians and investigators to estimate HIV reservoirs ex vivo in children and acutely HIV-infected adults. Similarly, prior work investigating C12 and C13 ester derivatives of EBC-46 revealed that small changes in the lipophilicity of these substituents had important effects on the isoform-selective activation of PKC and on antimelanoma and wound-healing activities. We readily synthesized our C12 analogs from 2, which we made using our previously reported synthetic route (Scheme 2A). Because of the potential of the tiglate ester to act as a Michael acceptor or to isomerize, we sought a more metabolically stable C12 isostere featuring a C12 cyclopropane in place of the tiglate-alkene. Toward this end, we prepared SUW413 in two steps: using the mixed Yamaguchi anhydride, generated in situ from the corresponding carboxylic acid and 2,2,2-trichlorobenzoyl chloride, to form the C12 ester followed by subsequent acid deprotection of the C5.C20 acetonide. Because EBC-46 lacking a C12 ester has been identified as a major metabolite (58), we envisioned thatanalogs that featured more esterase-resistant groups at this position would have improved activity. Toward this end, we first targeted the C12-pyrrolidine carbamate analog (SUW424) as it mimics the planar geometry of the tiglate ester but is less hydrolytically labile. In one step, we treated 2 with carbonyl diimidazole (CDI) to form the C12-imidazole carbamate, and the C12- pyrrolidine carbamate was formed rapidly by addition of excess pyrrolidine. Subsequent acid deprotection afforded SUW424. We considered the C12-tert-butyl ether SUW430, incorporating another metabolically stable functionality, as yet unexplored in decades of research on tiglianes, as it would also serve as a hydrophobic cap covering the C12 oxygen and thereby mimicking prostratin, which lacks a C12 oxygen. This tactic would open step-economical access to new “pseudodeoxy” analogs, in which the oxygen is buried in a hydrocarbon environment and would thus avoid the multistep deoxygenation required in our scalable synthesis of prostratin and its analogs from phorbol. This branched ether proved to be one of the first examples of an active phorbol derivative with a non-ester lipid at C12 (vide infra) (60). We prepared SUW430 in two steps from 2 by first using highly effective noncoordinating acid-base-catalyzed tert-butyl etherification followed by a mild acid-mediated deprotection of the C5,C20 acetonide.

[0177] The corresponding synthesis of C13 analogs began from 3, which we made using our previously reported synthetic route (Scheme 2B). We cleaved the C12 and C13 acetate groups to the corresponding diol using cesium methoxide. Chemoselective reinstallation of the C13 acetate using acetic anhydride (with no acylation catalyst) followed by C12-tiglate esterification and subsequent C13-acetate deprotection yielded the C13-hydroxy-C12-tiglate ester 4. To probe the importance of the chiral ester at C13, we sought to make an achiral cyclobutyl ester analog (SUW406) and a diastereomeric (R)-methyl-butyrate ester analog of EBC-46 (SUW407). SUW406 has an achiral near-planar array of carbons analogous to the methylbutyrate ester in EBC-46. SUW407 probes whether the C13 chirality in EBC-46 is important as our pharmacophore model suggests that it would be in contact with the membrane and not the chiral PKC binding domain. We made both compounds in two steps from 4 using standard Steglich esterification conditions followed by subsequent acid deprotection of the C5.C20 acetonide. The C13 ester carbonyl of phorbol esters and prostratin has been observed to participate in a transannular hydrogen bond with the C9 alcohol. This hydrogen bond plays a role in preorganizing the C13 substituent. Disruption of this intramolecular hydrogen bond in prostratin and 12-deoxyphorbol- 13-phenylacetate, by converting the C13 esters to the corresponding C13 ethers, results in compounds with weak PKC binding affinity and poor in vitro activity. To investigate whether the binding affinity of these compounds could be improved by strengthening this hydrogen bond, weincreased the Lewis basicity of the carbonyl by incorporating it into a C13 carbamate. We prepared SUW421 using the previously described carbamoylation / deprotection conditions for the preparation of SUW424. Similarly, we prepared a C13-benzoate ester, as a more nonpolar isostere of SUW421 , from 4 using benzoic anhydride. Subsequent acid deprotection of the C5,C20 acetonide afforded SUW428. In our previous study of prostratin esters and their ability to activate latent HIV reservoirs in vitro and ex vivo, we found that the best performing compound featured a (l-napthyl)acetate ester at C13. This compound was >1 OO-fold better at activating HIV reservoirs than prostratin itself and is now used to measure HIV reservoirs ex vivo in children living with HIV and acutely infected adults. Inspired by this finding, we installed a C13-(1- naphthyl)acetate ester in 4 using standard Steglich conditions. Subsequent acid deprotection of the C5,C20 acetonide afforded SUW431.

[0178] We began our molecular editing of the A-ring by exploring ester variants of the C3 alcohol (Scheme 3) — a functional group found in structurally homologous PKC-modulating compounds with potent biological activity. The synthesis of C3 analogs began from 5, which we made using our previously reported synthetic route (Scheme 3). We prepared intermediate 6 from 5 by first protecting the C20 and C4,C5 alcohols with a t-butyldimethylsilyl group and an acetonide, respectively. Subsequent deacetylation of the C 12, C 13- acetate esters, selective esterification of the C12,C13 alcohols, and stereoselective reduction of the C3 ketone with sodium borohydride afforded the readily derivatizable C3-hydroxy intermediate 7. Because the C6,C7 epoxide was not compatible with the protection and deprotection conditions described above, the A-ring analogs also have a C6,C7 alkene in the B-ring. Given that gnidimacrin is highly effective at activating latent HIV reservoirs and features a C3-[3-benzoate ester, we installed a C3-benzoate ester to mimic the structure of its A-ring by treating 7 with benzoyl chloride in pyridine. Subsequent acid deprotection of the B-ring protecting groups afforded the final compound SUW422. In a study looking at the HIV latency reversal activity of various ingenol esters, the C3-senecioate ester of ingenol was identified as the most efficacious compound with the ability to activate latent reservoirs to the same degree as their anti-CD3 / CD28 T-cell positive control. Thus, we prepared a C3-senecioate ester by Steglich esterification of 7, and subsequent acid deprotection of the firing protecting groups afforded SUW425.Example 2: Characterization of EBC-46 Analogs and IntermediatesSUW403

[0179] To a flame-dried vial equipped with a stir bar was added vanadyl isopropoxide (0.4 mg, 1.7 pmol, 0.05 equiv) from a stock solution. The reaction mixture was cooled to 0°C then ligand 1 (1.9 mg, 3.5 pmol, 0.1 equiv) was added from a stock solution. The reaction mixture was stirred at 0°C for 8 hr. Cumene hydroperoxide (10.6 mg, 69 pmol, 2 equiv) was added directly as a single portion under argon. After stirring for 30 minutes at rt, SUW402 (18.4 mg, 35 pmol, 1 equiv) was added as a solution in toluene (1 ml_). The reaction mixture was stirred at rt for 18 hr. TLC analysis indicated complete consumption of SUW402. The crude reaction mixture was filtered through a pad of Celite and rinsed with DCM (3*10 mL). Purification of the crude residue was accomplished by preparative TLC (50% EtOAc / Hex) to afford SUW403 (7.7 mg, 41% yield) as a colorless oil. Compound purity was established by TLC (one-spot) analysis.

[0180] SUW403 TLC Rf= 0.38 (50% EtOAc / Hex, UV active, purple spot in p-anisaldehyde); FTIR (ATR) 3354 (br), 2924, 2854, 1709, 1669, 1462, 1377, 1259, 1211 , 1074, 1020, 798 cm-1; [a]22D= -50° (c = 0.02, CH2CI2);1H NMR (400 MHz, CDCI3) 6 7.70 (dd, J = 2.6, 1.4 Hz, 1 H), 6.86-6.77 (m, 1 H), 5.46 (d, J = 9.9 Hz, 1 H), 4.24 (app s, 1 H), 3.71-3.60 (m, 2H), 3.38 (s, 1 H), 3.13 (d, J = 6.6 Hz, 1 H), 2.45-2.35 (m, 1 H), 2.22 (s, 1 H), 2.04 (s, 2H), 1.97-1.87 (m, 1H), 1.84-1.81 (m, 3H), 1.81-1.76 (m, 6H), 1.76-1.70 (m, 1H), 1.52-1.41 (m, 2H), 1.33 (d, J = 6.6 Hz, 1H), 1.27 (s, 3H), 1.25 (s, 3H), 1.14 (d, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.83 (d, J = 6.5 Hz, 3H);13C NMR (126 MHz, CDCh, 30 peaks total) 5 208.8, 179.0, 167.6, 163.7, 137.6, 133.2, 128.6, 77.0, 73.2, 65.8, 64.9, 64.3, 61.3, 52.0, 45.8, 41.3, 36.5, 36.2, 36.0, 29.9, 26.7, 26.3, 23.9, 17.4, 16.3, 15.1 , 14.6, 12.4, 11.8, 10.1 ; HRMS calculated for C3oH4309+[M+H]+: 547.2907; found 547.2899.C13-diversifiable intermediate preparation

[0181] To a vial equipped with a stir bar was added 3 (97 mg, 0.186 mmol, 1.0 equiv). A solution of cesium carbonate (155 mg) was prepared in methanol (9.0 mL) and sonicated to dissolution. This basic solution of methanol was added directly to the reaction vessel as a single portion. The reaction mixture was stirred at rt for 18 hours. TLC analysis indicated complete conversion to intermediate SI-1. The reaction was quenched with sat. NH4CI (15 mL), diluted with brine (50 mL), and extracted with EtOAc (3x50 mL) until TLC of the aqueous layer no longer showed product. The resulting intermediate SI-1 was used directly in the next step.

[0182] To a vial equipped with a stir bar was added crude residue SI-1 followed by anhydrous THF (2 mL). Acetic anhydride (1.0 mL) and triethylamine (1.0 mL) were added directly each as one portion. The reaction was stirred at rt for 1 hour. TLC analysis indicated complete consumption of SI-1. The reaction was quenched with methanol (1 mL) and diluted with brine (20 mL). The aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-1 was used directly in the next step.

[0183] To a flame dried vial equipped with a stir bar was added tiglic acid (136 mg), triethylamine (0.35 mL), and trichlorobenzoyl chloride (0.31 g) followed by anhydrous toluene (3.5 mL). This mixture was stirred vigorously at rt for 2 hours. Monoester SI-2 (222 mg, 0.464 mmol, 1 .0 equiv) was dissolved in anhydrous toluene (4.0 mL) in a separate vial equipped with a stir bar. Thesubstrate solution was added to the previously described solution of in situ generated mixed anhydride in one portion followed by addition of DMAP (147 mg). The reaction mixture was stirred at rt for 2 hours. TLC analysis indicated complete consumption of monoester SI-2. The reaction was diluted with EtOAc (100 ml_) and washed with sat. NH4CI (50 ml_), water (50 ml_), sat. NaHCCh (50 mL), and brine (50 ml_). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-3 was used directly in the next step.

[0184] To a vial equipped with a stir bar was added crude tiglate SI-3. A solution of cesium carbonate (300 mg) was prepared in methanol (18.0 mL) and sonicated to dissolution. This basic solution of methanol was added directly to the reaction vessel as a single portion. The reaction mixture was stirred at rt for 18 hours. TLC analysis indicated complete conversion to intermediate 4. The reaction was quenched with sat. NH4CI (15 mL), diluted with brine (50 mL), and extracted with EtOAc (3*50 mL) until TLC of the aqueous layer no longer showed product. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 2x12 cm) affording diversifiable intermediate 4 (50.0 mg, 52% yield over 4 steps, 85% average yield). Compound purity was established by TLC (one spot) analysis.

[0185] SI-1 TLC Rr = 0.26 (50% Acetone / Hex, UV active, dark green spot in p-anisaldehyde); Sl- 2 TLC Rf = 0.21 (50% EtOAc / Hex, UV active, green spot in p-anisaldehyde); SI-3 TLC Rf= 0.55 (50% EtOAc / Hex, UV active, green spot in p-anisaldehyde); 4 TLC Rf= 0.20 (50% EtOAc / Hex, UV active, green spot in p-anisaldehyde). FTIR (ATR) 3461 (br), 2978, 2931 , 2865, 1704, 1689, 1648, 1457, 1375, 1259, 1223, 1088, 1022, 922, 881 , 831, 739, 669 air1; [a]24D= 25° (c = 0.40, CH2CI2);1H NMR (400 MHz, CDCI3) 6 7.59 (dd, J = 2.6, 1.3 Hz, 1 H), 6.86 (qq, J = 7.0, 1.3 Hz, 1 H), 4.85 (d, J = 9.4 Hz, 1 H), 4.73 (s, 1 H), 4.11 (s, 1 H), 3.98 (d, J = 13.0 Hz, 1 H), 3.81 (app p, J = 2.3 Hz, 1 H), 3.58 (d, J = 12.9 Hz, 1 H), 3.32 (s, 1 H), 3.05 (s, 1H), 2.98 (d, J = 7.5 Hz, 1 H), 2.06 (s, 1 H), 1.92 (dq, J = 9.4, 6.6 Hz, 1 H), 1.82-1.79 (m, 6H), 1.78 (dd, J = 2.9, 1.3 Hz, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.21 (s, 3H), 1.11 (d, J = 7.5 Hz, 1 H), 1.05 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H);13C NMR (126 MHz, CDCI3, 28 peaks total) 6 205.8, 170.4, 160.5, 138.7, 134.7, 128.3, 101.4, 87.9, 77.9, 72.6, 68.5, 66.2, 65.7, 61.2, 61.1, 50.9, 45.8, 37.0, 34.8, 28.3, 24.8, 22.4, 22.3, 17.5, 16.9, 14.7, 12.2, 10.1 ; HRMS calculated for C28H39C [M+H]+: 519.2589; found 519.2579.SUW406 preparation (esterification and deprotection)

[0186] In a flame-dried vial, EDC (23.7 mg, 123 pmol, 2 equiv), triethylamine (25.8 pL, 185 pmol, 3 equiv), cyclobutanecarboxylic acid (11.1 mg, 111 pmol, 1.8 equiv), and DMAP (1.9 mg, 15.4 pmol, 0.25 equiv) were dissolved in anhydrous DCM (1.0 mL) and sonicated until homogeneous. In a separate flame-dried vial, 4 (32.0 mg, 61.7 pmol, 1 equiv) was dissolved in anhydrous THF (1.0 mL) and the DCM solution of activated acid was added directly in one portion. The reaction was stirred at rt for 34 hours. TLC analysis indicated complete consumption of 4 and conversion to cyclobutane ester SI-4. The reaction was quenched with methanol (0.5 mL) and diluted with brine (5 mL) and sat. NaHCOs (5 mL). The aqueous layer was extracted with EtOAc (3*10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-4 was used directly in the next step.

[0187] In a vial equipped with a stir bar, the crude residue SI-4 was dissolved in 2 mL TsOH in MeCN (0.21 M). The reaction was stirred at rt for 18 hours. TLC analysis indicated complete consumption of SI-4. The reaction was quenched with sat. NaHCOs (5 mL) and diluted with brine (5 mL). The aqueous layer was extracted with EtOAc (3x10 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (30-70% EtOAc / Hex, 1 xio cm) affording SUW406 (20.0 mg, 58%, 2 steps) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0188] TLC Rr = 0.41 (70% EtOAc / Hex, UV active, green spot in p-anisaldehyde); FTIR (ATR) 3404 (br), 2952, 2925, 2870, 1709, 1377, 1255, 1155, 1134, 1074, 1022, 980, 930, 802, 731 cnr1; [a]25D= -14° (c = 0.40, CH2CI2);1H NMR (400 MHz, CDCI3) 6 7.73 (app s, 1 H), 6.82 (qq, J = 7.0, 1.5 Hz, 1 H), 6.04 (br s, 1 H), 5.45 (d, J = 9.9 Hz, 1 H), 4.24 (s, 1 H), 4.09 (app p, J = 2.8 Hz, 1 H), 3.95 (br s, 1 H), 3.89-3.79 (m, 2H), 3.67 (s, 1 H), 3.28 (s, 1 H), 3.22 - 3.11 (m, 2H), 2.44 - 2.13 (m, 5H), 2.03 - 1.87 (m, 3H), 1.82 (app s, 3H), 1.81 - 1.77 (app d, J = 7.1 Hz, 3H), 1.76 (dd, J =2.9, 1.3 Hz, 3H), 1.31 (d, = 6.6 Hz, 1 H), 1.26 (s, 3H), 1.22 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 30 peaks total) 6 210.1 , 177.8, 167.7, 164.9, 137.8, 133.6, 128.6, 77.4,76.9, 72.6, 71.6, 65.7, 65.4, 64.7, 61.9, 49.1 , 46.0, 38.1 , 36.2, 36.2, 26.7, 24.92, 24.91 , 23.7, 18.5, 17.3, 15.2, 14.6, 12.3, 9.9; HRMS calculated for C30H4IOI0+[M+H]+: 561.2700; found 561.2688.SUW407 preparation (esterification and deprotection)

[0189] In a flame-dried vial, EDC (20.4 mg, 106 pmol, 2 equiv), triethylamine (22.3 pL, 160 pmol, 3 equiv), (R)-2-methylbutanoic acid (9.8 mg, 96 pmol, 1.8 equiv), and DMAP (1.6 mg, 13 pmol, 0.25 equiv) were dissolved in anhydrous DCM (1.0 mL) and sonicated until homogeneous. In a separate flame-dried vial, 4 (27.6 mg, 53.2 pmol, 1 equiv) was dissolved in anhydrous THF (1.0 mL) and the DCM solution of activated acid was added directly in one portion. The reaction was stirred at rt for 32 hours. TLC analysis indicated complete consumption of 4 and conversion to methyl butanoate ester SI-5. The reaction was quenched with methanol (0.5 mL) and diluted with brine (5 mL) and sat. NaHCOs (5 mL). The aqueous layer was extracted with EtOAc (3*10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-5 was used directly in the next step.

[0190] In a vial equipped with a stir bar, the crude residue SI-5 was dissolved in MeCN (1 mL). TsOH in water (0.42 M, 1 mL) was added (final TsOH concentration of 0.21 M). The reaction was stirred at rt for 18 hours. TLC analysis indicated complete consumption of SI-5. The reaction was quenched with sat. NaHCCh (5 mL) and diluted with brine (5 mL). The aqueous layer was extracted with EtOAc (3*10 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (30-70% EtOAc / Hex, 1 x10 cm) affording SUW407 (14.4 mg, 48%, 2 steps) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0191] TLC Rf = 0.43 (70% EtOAc / Hex, UV active, green spot in p-anisaldehyde); FTIR (ATR) 3402 (br), 2963, 2925, 2880, 1711 , 1459, 1379, 1340, 1327, 1257, 1195, 1155, 1131, 1076, 1024, 978, 933, 802, 730 cnr1; [a]25D= -15° (c = 0.20, CH2CI2);1H NMR (400 MHz, CDC ) 5 7.74 (dd, J = 2.7, 1.4 Hz, 1 H), 6.82 (qq, J = 7.0, 1.5 Hz, 1 H), 6.06 (br s, 1 H), 5.44 (d, J = 9.9 Hz, 1 H), 4.24 (d, J = 3.1, 1 H), 4.08 (app p, J = 2.6, 1 H), 3.90 (dd, J = 12.5, 5.8 Hz, 1 H), 3.86 (d, J = 3.2 Hz, 1 H), 3.80 (dd, J = 12.5, 5.8 Hz, 1 H), 3.58 (d, J = 1.1 Hz, 1 H), 3.29 (s, 1 H), 3.19 (d, J = 6.7 Hz, 1 H), 2.41 (app sex, J = 6.9 Hz, 1 H), 2.15 (dd, J= 8.0, 6.0 Hz, 1 H), 1.97 (dq, J = 10.0, 6.5 Hz, 1 H), 1.83 (t, J = 1.2 Hz, 3H), 1.79 (dd, 7.1 , 1.0 Hz, 3H), 1.77 (dd, J = 2.9, 1.3 Hz, 3H), 1.64-1.75 (m, 1 H), 1.41-1.52 (m, 1 H), 1.29 (d, J = 6.7 Hz, 1 H), 1.27 (s, 3H), 1.24 (s, 3H), 1.19 (d, J = 7.0 Hz, 3H), 0.90 (t, J = 7.5 Hz, 3H), 0.87 (d, J = 6.3 Hz, 3H);13C NMR (126 MHz, CDCh, 30 peaks total) 5210.1 , 179.3, 167.7, 164.9, 137.8, 133.6, 128.6, 77.3, 76.8, 72.5, 71.8, 65.7, 65.4, 64.7, 61.8,49.1, 46.1 , 41.2, 36.4, 36.2, 26.6, 26.5, 23.9, 17.4, 16.3, 15.3, 14.6, 12.4, 11.8, 9.9; HRMS calculated for C30H43OK / [M+H]+: 563.2856; found 563.2849.SUW413 preparation (esterification and deprotection)

[0192] To a 2-dram vial was added cyclopropyl acid (12.7 mg, 0.127 mmol, 2.2 equiv) followed by anhydrous toluene (0.5 ml_). Triethylamine (32 pL, 0.230 mmol, 4 equiv) was added in one portion followed by 2,4,6-trichlorobenzoyl chloride (18 pL, 0.115 mmol, 2 equiv). This mixture was stirred vigorously at rt for 2 hours. In a separate vial, 2 (30.0 mg, 0.0576 mmol, 1 equiv) was dissolved in anhydrous toluene (0.5 mL). The substrate solution was added to the previously described solution of in situ generated mixed anhydride in one portion followed by addition of DMAP (18.3 mg, 0.150 mmol, 2.6 equiv). The reaction mixture was stirred at 60 °C for 18 hr. TLC analysis indicated complete consumption of 2. The reaction was diluted with sat. NaHCCh (10 mL) and extracted with DCM (3x10 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-6 was used directly in the next step.

[0193] In a vial equipped with a stir bar, the crude residue SI-6 was dissolved in MeCN (1 mL). Tosic acid monohydrate (67.0 mg, 0.352 mmol, 6.11 equiv) in water (0.3 mL) was added to the reaction mixture in one portion. The reaction mixture was stirred at rt for 18 hr. TLC analysis indicated complete consumption of the starting material. The reaction was quenched with sat. NaHCCh (10 mL) and extracted with DCM (3*10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20%-60% EtOAc / Hex, 3x10 cm) affording SUW413 (12.0 mg, 37% over 2 steps) as a white solid. Compound purity was established by TLC (one spot) analysis. Prior to use in biological studies, a sample of SUW413 was further purified by preparative HPLC.

[0194] TLC Rf= 0.27 (60% EtOAc / Hex, UV active, green spot in p-anisaldehyde); FTIR (ATR) 3411 (br), 2961 , 2925, 2854, 1716, 1458, 1379, 1322, 1261 ,1159, 1086, 1026, 802, 669 cm’1; [a]24D= 18° (c = 0.05, CH2CI2);1H NMR (400 MHz, CDCI3) 5 7.73 (dd, J = 2.6, 1.5 Hz, 1 H), 5.37 (d, J = 9.9 Hz, 1 H), 4.23 (s, 1H), 4.06 (app p, J = 2.8 Hz, 1 H), 3.88 (d, J = 12.5 Hz, 1H), 3.79 (d, J = 12.5 Hz, 1 H), 3.28 (s, 1 H), 3.16 (d, J = 6.6 Hz, 1 H), 2.38 (app sex, J = 6.9 Hz, 1 H), 1.88 (dq, J = 10.0, 6.6 Hz, 1 H), 1.77 (dd, J = 2.6, 1.5 Hz, 3H), 1.75-1.68 (m, 1 H), 1.51-1.39 (m, 1 H), 1.28 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 1.18 (d, J = 3.7 Hz, 2H), 1.13 (d, J = 7.0 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H), 0.71 - 0.64 (m, 2H);13C NMR (126 MHz, CDCI3, 30 peaks total) 6210.1 , 179.0, 175.5, 164.9, 133.7, 77.4, 77.4, 72.5, 71.8, 65.6, 65.4, 64.7, 61.8, 49.1 , 46.0, 41.3, 36.2, 36.2, 26.7, 26.4, 23.9, 19.7, 18.6, 17.3, 16.9, 16.6, 16.3, 15.2, 11.8, 9.9; HRMS calculated for C3oH42NaOw+[M+Na]+: 585.2676; found: 585.2666.SUW422 preparation (TBS protection)

[0195] To a one-neck, round-bottom flask was added intermediate 5 (2.70 g, 5.8 mmol, 1.0 equiv) followed by anhydrous DMF (58.0 mL). Imidazole (1.58 g, 23.25 mmol, 4.0 equiv) was added as single portion followed by TBS-CI (2.6 g, 17.44 mmol, 3.0 equiv). The reaction was stirred at 0 °C and allowed to warm to room temperature for 20 minutes. TLC analysis indicated complete consumption of intermediate 5. The reaction was quenched with methanol (5 mL) and diluted with sat. NH4CI (50 mL) and diluted with brine (250 mL). The aqueous layer was extracted with EtOAc(2*150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Residual DMF was removed by azeotroping with heptane (2x100 mL). The resulting intermediate SI-7 was used directly in the next step.

[0196] To a 500 mL round-bottom flask equipped with a stir bar was added crude intermediate SI-7. Anhydrous acetone (65 mL) and PPTS (1 .46g, 5.8 mmol) were added to the reaction mixture each as one portion. The reaction mixture was sonicated for five minutes to dissolve the PPTS. Afterwards, dimethoxypropane (130 mL) was added directly as a single portion. The flask was equipped with a Vigreux condenser and an argon balloon, and the reaction mixture was heated to 60 °C for 2 hr. TLC analysis indicated complete consumption of intermediate SI-7. The reaction was quenched with sat. NaHCO3(100 mL) and diluted with brine (250 mL). The aqueous layer was extracted with EtOAc (2x250 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-30% Et2O / Hex, 3x13 cm) affording 4,5-acetonide 6 as a white foam (2.5g, 62% yield over 2 steps). Compound purity was established by TLC (one spot) analysis.

[0197] SI-7 TLC Rr = 0.84 (75% EtOAc / Hex, UV active, green spot in p-anisaldehyde); 6 TLC Rf = 0.95 (20% EtOAc / Et2O, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3384 (br), 2957, 2922, 2852, 1740, 1716, 1663, 1464, 1377, 1261 , 1230, 1090, 1020, 838, 800 cm’1; [a]24D= 80° (c = 0.02, CH2CI2);1H NMR (400 MHz, CDCI3) 5 7.56 (dd, J = 2.3, 1 .4 Hz, 1 H), 5.80 (dd, J = 6.7, 1.6 Hz, 1 H), 5.74 (br s, 1 H), 5.46 (d, J = 10.2 Hz, 1 H), 4.88 (d, J= 1.5 Hz, 1H), 4.21-4.12 (m, 2H), 3.13 (app p, J = 2.9 Hz, 1H), 2.80 (app t, J = 6.0 Hz, 1 H), 2.11 (s, 3H), 2.10 (s, 3H), 1.94 (dq, J =10.4, 6.4 Hz, 1H), 1.77 (dd, J = 3.1 , 1.4 Hz, 3H), 1.53 (s, 3H), 1.50 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H), 1.14 (d, J = 5.3 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H);13C NMR (126 MHz, CDCI3, 33 peaks total) 5 204.8, 173.9, 171.1 , 158.1 , 141.5, 133.6, 133.3, 110.1 ,84.5, 77.3, 75.2, 74.6, 66.7, 66.0, 55.1 , 44.8, 39.3, 36.4, 26.9, 26.5, 26.0 (3 peaks), 25.4, 24.3, 21.2, 21.2, 18.6, 18.4, 14.7, 10.6, -5.16, -5.22.SUW422 preparation (acetate removal and methyl butyration)

[0198] To a vial equipped with a stir bar was added 6 (623 mg, 1.00 mmol, 1.0 equiv). A solution of cesium carbonate (128 mg) was prepared in methanol (9.5 mL) and sonicated to dissolution. This basic solution of methanol was added directly to the reaction vessel as a single portion. The reaction mixture was stirred at rt for 18 hours. TLC analysis indicated complete conversion to intermediate SI-8. The reaction was quenched with sat. NH4CI (25 mL), diluted with brine (75 mL), and extracted with EtOAc (3x100 mL) until TLC of the aqueous layer no longer showed product. The resulting intermediate SI-8 was used directly in the next step.

[0199] In a flame-dried vial, EDC (396 mg, 2.06 mmol, 2.05 equiv), triethylamine (300 pL, 2.12 pmol, 2.1 equiv), (S)-2-methylbutanoic acid (220 uL, 2.02 mmol, 2.0 equiv), and DMAP (25 mg, 202 pmol, 0.2 equiv) were dissolved in anhydrous DCM (5.0 mL) and sonicated until homogeneous. In a separate vial equipped with a stir bar, the crude diol SI-8 was dissolved in anhydrous DCM (5.0 mL) and the DCM solution of activated acid was added directly in one portion. The reaction was stirred at rt for 1 hour. TLC analysis indicated complete consumption of SI-8 and conversion to methyl butanoate SI-9. The reaction was quenched with methanol (5 mL) and diluted with brine (50 mL) and 1 M HCI (1.0 mL). The aqueous layer was extracted with DCM (3x50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-9 was used directly in the next step.

[0200] To a flame dried vial equipped with a stir bar was added tiglic acid (333 mg, 3.33 mmol, 3.3 equiv), triethylamine (0.840 ml_, 6.06 mmol, 6.0 equiv), and trichlorobenzoyl chloride (0.470 mL, 1.56 mmol, 3.0 equiv) followed by anhydrous toluene (10.0 mL). This mixture was stirred vigorously at rt for 2 hours. Crude monoester SI-9 was dissolved in anhydrous toluene (2.0 mL) in a separate vial equipped with a stir bar. The substrate solution was added to the previously described solution of in situ generated mixed anhydride in one portion followed by addition of DMAP (382 mg, 3.13 mmol, 3.1 equiv). The reaction mixture was stirred at rt for 2 hours. TLC analysis indicated complete consumption of monoester SI-9. The reaction was diluted with EtOAc (200 mL) and washed with sat. NH4CI (100 mL), water (2x100 mL), sat. NaHCCh (100 mL), and brine (100 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-10 was used directly in the next step.

[0201] In a vial equipped with a stir bar, the crude residue SI-10 was dissolved in MeOH (10.0 mL). Sodium borohydride (120 mg, 3.17 mmol, 3.1 equiv) was added directly to the vial as a single portion. The reaction was stirred at rt for 15 minutes. TLC analysis indicated complete consumption of diester SI-10. The reaction was diluted with water (50 mL) and brine (50 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-30% Et2O / Hex, 2x12 cm) affording C3-alcohol 7 as a white foam (426 mg, 60% yield over 4 steps, 88% average yield per step). Compound purity was established by TLC (one spot) analysis.

[0202] SI-8 TLC F% = 0.24 (20% EtOAc / Et2O, UV active, blue spot in p-anisaldehyde); SI-9 TLC Rr = 0.28 (40% Et2O / Hex, UV active, blue spot in p-anisaldehyde); SI-10 TLC Rf= 0.67 (40% Et2O / Hex, UV active, blue spot in p-anisaldehyde); 7 TLC Rf= 0.51 (40% Et2O / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3410 (br), 2956, 2929, 2856, 1714, 1651 , 1462, 1381 , 1255, 1207, 1190, 1153, 1085, 1065, 1012, 974, 893, 837, 777, 735 erm1; [a]24D= 25° (c = 0.40, CH2CI2);1H NMR (400 MHz, CDCI3) 6 6.82 (dq, = 7.1, 1.5 Hz, 1 H), 5.86-5.77 (m, 3H), 5.51 (d, J = 9.9 Hz, 1 H), 4.77 (d, J = 1.6 Hz, 1 H), 4.24 (d, J = 12.1 , 1 H), 4.19 (d, J = 12.9 Hz, 1 H), 4.13 (d, J = 12.2 Hz, 1 H), 3.08-3.00 (m, 2H), 2.37 (app sex, J = 7.0 Hz, 1 H), 1 .90 (dq, J = 9.8, 6.5 Hz, 1 H), 1.83 (s, 3H), 1.82-1.78 (m, 4H), 1.77-1.70 (m, 1 H), 1.68 (dd, J = 3.1 , 1.5 Hz, 3H), 1.52 (s, 3H), 1.49-1.39 (m, 1 H), 1.33 (s, 3H), 1.18 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H), 1.09 (d, J = 5.7 Hz, 1 H), 0.99 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H);13C NMR (101 MHz, CDCh, 39 peaks total) 6 179.0, 167.6, 140.0, 137.4, 134.6, 133.4, 128.8, 127.5, 108.2, 93.5, 81.4, 77.9, 77.7, 74.2, 67.3, 65.8, 56.5, 45.8, 41.3, 39.7, 36.5, 27.0, 26.7, 26.3, 26.3, 26.1(3 peaks), 24.4, 18.6, 18.5, 16.3, 14.7, 14.6, 13.5, 12.4, 11.8, -5.10, -5.12; HRMS calculated for C39H6iO9Si+[M+H]+: 701.4085; found: 701.4082.SUW422 preparation (benzoylation and deprotection)

[0203] To a flame-dried vial equipped with a stir bar was added 7 (49.1 mg, 69.8 pmol, 1 equiv) followed by distilled pyridine (1.0 mL). Benzoyl chloride (81 pL, 698 pmol, 10 equiv) was added directly as a single portion followed by DMAP (4.3 mg, 35 pmol, 0.5 equiv). The reaction was sealed with a Teflon cap and heated to 50 °C for 3 hours. TLC analysis indicated complete consumption of 7. The reaction was quenched with sat. NaHCCh (10 mL) and diluted with brine (10 mL). The aqueous layer was extracted with EtOAc (3*20 mL). The combined organic layers were dried over Na2SC>4, filtered, concentrated, and azeotroped with heptane (3x50 mL) to remove pyridine. Purification was accomplished by silica gel flash column chromatography (5- 15% ether / Hex, 1 x10 cm) affording benzoate SI-11 (35.4 mg, 63%) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0204] SI-11 TLC Rf = 0.78 (20% Et2O / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3398 (br), 2961 , 2925, 2857, 1716, 1458, 1381 , 1259, 1068, 837, 700, 669 cm'1; [a]23D= 20° (c = 0.07, CH2CI2);1H NMR (400 MHz, CDCI3) 3 8.18-8.14 (m, 2H), 7.60-7.55 (m, 1 H), 7.48-7.42 (m, 2H), 6.82 (dq, J = 7.0, 1 .5 Hz, 1 H), 6.00-5.95 (m, 2H), 5.92-5.80 (m, 1 H), 5.52 (d, J = 9.8 Hz, 1 H), 4.76 (d, J = 1.5 Hz, 1 H), 4.28 (app d, J = 12.7 Hz, 1 H), 4.21 (app d, J = 12.7 Hz, 1 H), 3.16 (dt, J = 3.7, 2.0 Hz, 1H), 3.04 (app t, J = 6.1 Hz, 1 H), 2.39 (app sex, J = 7.0 Hz, 1 H), 2.03-1.94 (m, 1 H), 1.86-1.82 (m, 3H), 1.80 (app d, J = 7.1 , 3H), 1.79-1.71 (m, 1H), 1.64-1.60 (m, 3H), 1.52-1.40 (m, 1 H), 1.34 (s, 3H), 1.22 (s, 3H), 1.19 (s, 3H), 1.14 (d, J = 7.3 Hz, 3H), 1.11 (d, J = 5.6 Hz, 1 H), 1.08 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H);13C NMR (126 MHz, CDCI3, 46 peaks total) 6 179.0, 167.6, 166.6, 140.2, 137.4, 134.2, 133.4, 130.8, 130.2 (2 peaks), 130.1, 128.8, 128.7, 128.6 (2 peaks), 108.3, 94.1, 82.0, 78.0, 77.7, 74.3, 67.2, 65.8, 57.2, 45.9, 41.3, 39.5, 36.6,26.9, 26.7, 26.4, 26.3, 26.2 (3 peaks), 24.4, 18.7, 18.6, 16.3, 15.1 , 14.6, 13.6, 12.4, 11.8, -5.0, - 5.1 ; HRMS calculated for C46H66NaOioSi+[M+Na]+: 829.4323; found 829.4304.

[0205] To a vial equipped with a stir bar was added SI-11 (35.4 mg, 43.9 pmol, 1 equiv) followed by MeCN (1.8 mL). TsOH in water (0.42 M, 0.6 mL) was added (final TsOH concentration of 0.105 M). The reaction mixture was stirred at 80 °C for 30 minutes. TLC analysis indicated complete consumption of SI-11. The reaction with quenched with sat. NaHCCh (5 mL) and diluted with brine (5 mL). The aqueous layer was extracted with EtOAc (3*10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-60% EtOAc / Hex, 1 x10 cm) affording SUW422 (20.4 mg, 71 %) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0206] SUW422 TLC Rf= 0.26 (50% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3419 (br), 2964, 2925, 2878, 1712, 1452, 1377, 1318, 1261 , 1154, 1120, 1070, 1026, 976, 934, 881 , 804, 712, 669, 652 cm’1; [a]25D= -32° (c = 0.22, CH2CI2);1H NMR (400 MHz, CDCI3) 6 8.13-8.09 (m, 2H), 7.64-7.58 (m, 1 H), 7.51-7.44 (m, 2H), 6.81 (dq, J = 7.1, 1.5 Hz, 1 H), 6.00 (app d, J = 1.8 Hz, 1 H), 5.73 (app d, J = 5.2 Hz, 1 H), 5.73 (br s, 1 H), 5.46 (d, J = 10.1 Hz, 1 H), 5.41 (app d, J = 1.4 Hz, 1 H), 4.57 (s, 1 H), 4.28 (d, J = 12.1 Hz, 1 H), 4.21 (d, J = 12.1 , 1 H), 3.25 (app t, J = 5.3 Hz, 1 H), 3.25 (br s, 1H) 3.04 (app dt, J = 4.0, 2.1 Hz, 1 H), 2.37 (app sex, J = 6.9 Hz, 1 H), 2.20-2.09 (m, 1 H), 1.84-1.81 (m, 3H), 1.81-1.76 (m, 6H), 1.76-1.67 (m, 1 H), 1.50-1.39 (m, 1 H), 1.21 (s, 3H), 1.18 (s, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 1.01 (d, J = 5.4 Hz, 1 H), 0.93 (t, 7.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 37 peaks total) 5 179.1 , 168.9, 167.7,139.4, 137.4, 134.0, 133.1 , 132.1 , 130.3 (2 peaks), 129.9, 129.4, 128.8, 128.7 (2 peaks), 89.3, 80.7, 80.5, 77.8, 68.7, 65.38, 65.36, 57.9, 44.7, 41.3, 38.7, 36.9, 26.3, 26.1 , 23.9, 17.1 , 16.3, 15.1 , 14.5, 14.0, 12.4, 11.8; HRMS calculated for C37H48NaOio+[M+Na]+: 675.3098; found 675.3130.SUW425

[0207] In a vial equipped with a stir bar was added senecioic acid (64 mg, 0.64 mmol, 20 equiv), triethylamine (0.10 mL, 0.72 mmol, 23 equiv) and EDC (130 mg, 0.68 mmol, 20.5 equiv) followed by DCM (1 .36 mL). In a separate flame-dried vial equipped with a stir bar was added 7 (23.5 mg, 0.033 mmol, 1 equiv). A portion of the pre-activated acid solution (0.50 mL) was transferred to the vial of 7 in one portion. DMAP (8 mg, 0.064 mmol, 0.5 equiv) was added directly to the reaction mixture as a single portion. The reaction was stirred at 40 °C for 5 hr. TLC analysis indicated complete consumption of 7. The reaction mixture was cooled to rt and quenched with methanol (0.10 mL) and diluted with NH4CI (20 mL) and brine (15 mL). The aqueous layers were extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.

[0208] To a vial equipped with a stir bar was added crude SI-12. 1 mL of a stock solution of TsOH in 3:1 MeCN: H2O (0.10 M) was added to the vial directly as a single portion. The reaction mixture was stirred at 80 °C for 30 minutes. TLC analysis indicated complete consumption of SI-12. The reaction with quenched with sat. NaHCCh (10 mL) and diluted with brine (15 mL). The aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-60% EtOAc / Hex, 1 *7 cm) affording SUW425 (9 mg, 43% yield over 2 steps) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0209] SUW425 TLC Rf= 0.30 (35% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3415 (br), 2964, 2925, 2878, 1712, 1649, 1456, 1379, 1257, 1146, 1074, 975, 883, 803, 734, 669, 651 crrr1; [a]25D= -84° (c = 0.36, CH2CI2);1H NMR (400 MHz, CDCh) 3 6.80 (dq, J = 7.1 , 1.6 Hz, 1 H), 5.91 (app d, J = 1.8 Hz, 1 H), 5.86 (app p, J = 1.3 Hz, 1 H), 5.71 (d, J = 5.2 Hz, 1 H), 5.68 (br s, 1H), 5.43 (d, J = 10.1 Hz, 1 H), 5.22 (app d, J = 1.5 Hz, 1 H), 4.47 (s, 1H), 4.25 (d, J = 12.1 Hz, 1 H), 4.17 (d, J = 12.1 Hz, 1 H), 3.27 (t, J = 5.3 Hz, 1 H), 3.19 (s, 1 H), 3.00-2.94 (m,1 H), 2.37 (app sex, = 6.9 Hz, 1 H), 2.20 (d, J = 1.3 Hz, 3H), 2.13 (dq, J = 10.1, 6.6 Hz, 1 H), 1.92 (d, J = 4.9 Hz, 3H), 1.83-1.80 (m, 3H), 1.79 (dd, J= 7.2, 1.3 Hz, 3H), 1.77-1.70 (m, 1H), 1.69-1.67 (m, 3H), 1.49-1.41 (m, 1H), 1.22 (s, 3H), 1.18 (s, 3H), 1.12 (d, J= 7.1 Hz, 3H), 1.02-0.98 (m, 3H), 0.93 (t, J = 7.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 35 peaks total) 5 179.1 , 168.8, 167.7, 160.8, 139.3, 137.4, 133.0, 131.6, 130.2, 128.8, 115.3, 87.6, 80.5, 78.0, 77.5, 77.4, 68.8, 65.4, 57.8, 44.7, 41.3, 38.7, 36.9, 27.9, 26.3, 26.1 , 23.9, 20.8, 17.1 , 16.3, 15.2, 14.5, 13.8, 12.4, 11.8; HRMS calculated for C35H5IOIO+[M+H]+: 631.3482; found 631.3472.

[0210] To a flame-dried vial equipped with a stir bar was added EBC-46 (3.0 mg, 5.3 pmol, 1 equiv). DMAP (0.6 mg, 5.3 pmol, 1 equiv) and triethylamine (0.5 mg, 5.3 pmol, 1 equiv) were added directly as a single portion. Chloroformate 1 (0.6 mg, 2.6 pmol, 0.5 equiv) was added as a single portion from a freshly prepared stock solution. The reaction was stirred at 4 °C for 2 hr at which point another 0.5 equiv chloroformate was added. The reaction was stirred at 4 °C for 16 hr. TLC analysis indicated complete consumption of EBC-46. The reaction was quenched with MeOH (50 pL) and diluted with NH4CI (15 mL) and brine (15 mL). The aqueous layer was extracted with EtOAc (2*30 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10- 30% EtOAc / Hex, 1 *10 cm) affording SUW427 as a colorless oil (2.1 mg, 52% yield). Compound purity was established by TLC (one spot) analysis.

[0211] SUW427 TLC Rf= 0.67 (50% EtOAc / Hex, UV active, dark blue spot in p-anisaldehyde); FTIR (ATR) 3388 (br), 2960, 2922, 2852, 1765, 1712, 1259, 1084, 1018, 798 cm ’1; [a]21D= -30° (c = 0.03, CH2CI2);1H NMR (400 MHz, CDCI3) 67.71 (dd, J = 2.6, 1 .5 Hz, 1 H), 7.44-7.39 (m, 2H), 7.21-7.16 (m, 2H), 6.86-6.78 (m, 1 H), 5.44 (d, J = 9.9 Hz, 1 H), 5.17 (d, J = 12.1 Hz, 1H), 5.13 (d, J = 12.1 Hz, 1 H), 4.84 (d, J = 11.8 Hz, 1 H), 4.27 (s, 1 H), 4.08 (app t, J = 2.8 Hz, 1 H), 4.03 (d, J =11.9 Hz, 1 H), 3.90 (s, 3H), 3.18 (d, J = 6.0 Hz, 1 H), 3.18 (s, 1 H), 2.39 (app sex, J = 7.0 Hz, 1 H), 2.02-1.92 (m, 1H), 1.82 (app t, J = 1.4 Hz, 3H), 1.79 (app d, J = 7.1 , 3H), 1.77-1.68 (m, 4H), 1.51- 1.41 (m, 1 H), 1.26 (s, 3H), 1.24 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.86 (d, = 6.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 40 peaks total) 6 209.7, 179.1 , 167.6, 164.6, 155.0, 154.2, 151.4, 137.8, 133.6, 133.1 , 129.9 (2 peaks), 128.6, 121.4 (2 peaks), 77.4, 76.8, 72.4, 69.9, 69.3, 68.8, 65.6, 65.0, 60.3, 55.6, 48.9, 46.0, 41.3, 36.2, 36.0, 26.8, 26.3, 23.8, 17.4, 16.3, 15.2, 14.6, 12.4, 11.8, 9.9; HRMS calculated for C40H5IOI5+[M+H]+: 771.3223; found 771.3214.

[0212] To a flame-dried vial equipped with a stir bar was added 4 (22 mg, 0.042 mmol, 1 equiv) followed by DCM (0.75 mL). Triethylamine (20 pL, 0.142 mmol, 3.5 equiv) was added followed by benzoic anhydride (25 mg, 0.142 mmol, 3.5 equiv) and DMAP (13 mg, 0.155 mmol, 3.9 equiv). The reaction was stirred at rt for 2 hr. TLC analysis indicated complete consumption of 4. The reaction was quenched MeOH (0.5 mL). The reaction diluted with NH4CI (25 mL) and water (25 mL). The aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-13 was used directly in the next step.

[0213] In a vial equipped with a stir bar, the crude residue SI-13 was dissolved in a PPTS MeOH:MeCN stock solution (64 mg PPTS in 3 mL 5:1 MeOH:MeCN). The reaction was stirred at 60 °C for 6 hr. TLC analysis indicated complete consumption of intermediate SI-13. The reaction was diluted with brine (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-70% EtOAc / Hex, 1 x7 cm) affording SUW428 as a white solid (15.6 mg, 63% yield over 2 steps). Compound purity was established by TLC (one spot) analysis.

[0214] SI-13 TLC Rr = 0.86 (80% EtOAc / Hex, UV active, green spot in p-anisaldehyde); SUW428 TLC Rf= 0.43 (80% EtOAc / Hex, UV active, dark blue spot in p-anisaldehyde); FTIR (ATR) 3404 (br), 2976, 2927, 2866, 1699, 1452, 1379, 1325, 1284, 1250, 1117, 1070, 1024, 714 erm1; [a]23D= -62° (c = 0.20, CH2CI2);1H NMR (600 MHz, CDCI3) 6 8.02 (d, J = 7.8, 2H), 7.77 (app s, 1 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 2H), 6.85-6.80 (m, 1H), 5.61 (d, J = 9.8 Hz, 1 H), 4.26 (s, 1 H), 4.13 (app p, J = 2.7 Hz, 1H), 3.90 (d, J = 12.6 Hz, 1 H), 3.81 (d, J = 12.5 Hz, 1H), 3.32 (s, 1 H), 3.26 (d, J = 6.7 Hz, 1 H), 2.08-2.01 (m, 1 H), 1.82 (app s, 3H), 1.80 (app d, J = 7.1 Hz, 3H), 1.78 (app d, J = 2.0 Hz, 3H), 1.48 (d, J = 6.7 Hz, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 32 peaks total) 6 210.1 , 168.6, 167.6, 164.9, 137.9, 133.9, 133.7, 130.2 (2 peaks), 129.5, 128.7 (2 peaks), 128.6, 77.4, 77.0, 72.5, 71.8, 66.5, 65.4, 64.7, 61.8, 49.1 , 46.2, 36.4, 36.3, 27.2, 23.9, 17.4, 15.4, 14.6, 12.4, 9.9; HRMS calculated for C32H38OIO+[M+H]+: 583.2538; found 583.2530.SUW430 preparation (tertbutylation)

[0215] To a flame dried vial equipped with a stir bar was added 2 (25 mg, 0.048 mmol, 1 equiv) followed by fluorobenzene (0.15 mL). The acid catalyst (lutidinium bistriflimide) was prepared according to the literature (J. Org. Chem. 2021 , 86, 6, 4877-4882) as a solution in lutidine. The acid catalyst stock solution (0.18 mL, 0.15 M, 0.026 mmol, 0.5 equiv) was added directly as a single portion followed by tert-butyl 2,2,2-trichloro acetimidate (0.25 mL, 1 .221 g / mL, 11.6 equiv). The headspace of the reaction vessel was displaced with argon and the reaction was stirred at 40 °C for 24 hr. TLC analysis indicated partial consumption of 2 and formation of a nonpolar product. The reaction was then stirred at 50 °C for an additional 48 hr. TLC analysis indicated more formation of a nonpolar product. The reaction mixture was filtered through a silica plug (0.5 cm x4.0 cm). The plug was washed with DCM (2x10 mL) followed by EtOAc (2x5 mL). Purification was accomplished by silica gel flash column chromatography (10-40% Et2O / Hex, 1 x7 cm)affording SI-14 as a white solid (8.0 mg, 29% yield). Compound purity was established by TLC (one spot) analysis.

[0216] TLC Rr= 0.21 (40% Et2O / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3348 (br), 2962, 2924, 2854, 1714, 1462, 1377, 1088, 1055, 827, 766, 669 cm’1; [a]23D= 26° (c = 0.10, CH2CI2);1H NMR (400 MHz, CDCI3) 5 7.64 (app s, 1 H), 6.10 (s, 1H), 4.13 (s, 1 H), 3.99 (d, J = 12.8 Hz, 1 H), 3.99 (app s, 1 H), 3.80 (d, J = 8.7 Hz, 1 H), 3.58 (d, J = 12.8 Hz, 1H), 3.30 (s, 1 H), 3.11 (d, J = 7.2 Hz, 1 H), 3.00 (s, 1 H), 2.44 (app sex, J = 6.9 Hz, 1H), 1.83 - 1.68 (m, 5H), 1.51 (s, 3H), 1.48 (s, 3H), 1.29 (s, 6H), 1.21 (s, 9H), 1.17 (d, J = 7.2 Hz, 1 H), 0.99 (d, J = 6.8 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H);13C NMR (126 MHz, CDCI3, 32 peaks total) 5206.5, 178.6, 162.1, 133.7, 101.2, 76.5, 73.6, 72.8, 68.8, 67.1, 65.9, 65.5, 60.5, 49.4, 48.4, 41.8, 36.3, 35.3, 29.9, 28.7 (3 peaks), 26.7, 26.3, 24.9, 23.9, 22.4, 18.0, 16.8, 16.1 , 12.0, 10.1 ; HRMS calculated for C32H49C [M+H]+: 577.3371 ; found 577.3365.SUW430 preparation (deprotection)

[0217] In a vial equipped with a stir bar, SI-14 (7.3 mg, 0.013 mmol, 1 equiv) was dissolved in 5:1 MeOH:MeCN (0.5 mL). PPTS (37 mg, 0.15 mmol, 12 equiv) was added directly as a single portion. The reaction mixture was stirred at 60 °C for 20 hr. TLC analysis indicated complete consumption of SI-14. The reaction was quenched with NaHCCh (10 mL) and diluted with brine (10 mL). The aqueous layer was extracted with EtOAc (2*10 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-60% EtOAc / Hex, 1 x7 cm) affording SUW430 as a white solid (4.7 mg, 69% yield). Compound purity was established by TLC (one spot) analysis.

[0218] TLC Rf = 0.18 (75% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3398 (br), 2958, 2920, 2850, 1716, 1464, 1086, 1020, 800, 669 cm’1; [a]23D= 19° (c = 0.10, CH2CI2);1H NMR (600 MHz, CDCI3) (5 7.76 (dd, J = 2.6, 1.4 Hz, 1 H), 6.13 (s, 1 H), 4.21 (s, 1 H),4.01 (app t, J = 2.8 Hz, 1 H), 3.88 (d, J = 12.4 Hz, 1 H), 3.79 (d, J = 8.8 Hz, 1 H), 3.78 (d, J = 12.4 Hz, 1 H), 3.26 (s, 1 H), 3.11 (d, J = 7.2 Hz, 1 H), 2.43 (app sex, J = 7.1 Hz, 1 H), 1.76 (dd, J = 3.8, 1.9 Hz, 3H), 1.75-1.68 (m, 1 H), 1.52-1.44 (m, 1 H), 1.25 (s, 3H), 1.24 (s, 3H), 1.19 (s, 9H), 1.16 (d, J = 7.2 Hz, 1 H), 1.00 (d, J = 6.6 Hz, 3H), 0.95 (td J = 7.4, 3H);13C NMR (126 MHz, CDCI3, 29 peaks total) 6210.6, 178.9, 165.7, 133.5, 77.3, 76.6, 73.8, 72.7, 72.2, 67.2, 65.8, 65.0, 61.9, 49.5, 48.6, 42.0, 36.3, 35.8, 28.9 (3 peaks), 27.0, 26.5, 24.1 , 18.1, 16.9, 16.4, 12.2, 10.1.SUW431

[0219] To a flame-dried vial equipped with a stir bar was added 2-(napthalen-1-yl) acetic acid (16 mg, 0.085 mmol, 2 equiv) followed by toluene (0.33 ml_), triethylamine (12 pL, 0.089 mmol, 2.1 equiv), and EDC (16 mg, 0.085 mmol, 2 equiv). The acid mixture was stirred for 5 min. at rt. To a separate flame-dried vial equipped with a stir bar was added 4 (22 mg, 0.042 mmol, 1 equiv). The solution of pre-activated acid was transferred to the vial of 4 in one portion. DMAP (6 mg, 0.049 mmol, 0.5 equiv) was added directly to the reaction mixture as a single portion. The reaction was stirred for 90 min. at rt. TLC analysis indicated complete consumption of 4. The reaction mixture was quenched with NH4CI (25 ml_). The aqueous layer was extracted with EtOAc (2x25 ml_). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI- 15 was used directly in the next step.

[0220] In a vial equipped with a stir bar, the crude residue SI-15 was dissolved in a PPTS MeOH:MeCN stock solution (66 mg PPTS in 3 mL 5:1 MeOH:MeCN). The reaction was stirred at 60 °C for 6 hr. TLC analysis indicated complete consumption of intermediate SI-15. The reaction was diluted with brine (25 mL). The aqueous layer was extracted with EtOAc (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-33% EtOAc / Hex, 1 x7 cm) affording SUW431 as a white solid (13.8 mg, 50% yield over 2 steps). Compound purity was established by TLC (one spot) analysis.

[0221] SI-15 TLC Rf= 0.72 (50% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); SUW431 TLC Rf= 0.20 (66% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3421 (br), 2959, 2924, 2855, 1709, 1456, 1259, 1155, 1074, 1024, 785, 669 cm’1; [a]24D= -17° (c = 0.50, CH2CI2);1H NMR (400 MHz, CDCI3) 5 8.01-7.96 (m, 1 H), 7.87-7.83 (m, 1 H), 7.81-7.76 (m, 1 H), 7.70 (app s, 1 H), 7.56-7.51 (m, 1 H), 7.51-7.46 (m, 1H), 7.42-7.39 (m, 2H), 6.88-6.80 (m, 1 H), 5.51 (d, J = 10.0 Hz, 1 H), 4.19 (s, 1 H), 4.14 (d, J = 5.2 Hz, 1H), 4.14 (br s, 1H), 4.02 (app p, J = 2.8 Hz, 1 H), 3.84 (d, J = 12.5 Hz, 1 H), 3.75 (d, J = 12.5 Hz, 1 H), 3.18 (s, 1 H), 3.12 (d, J = 6.6 Hz, 1 H), 1.99-1.91 (m, 1 H), 1.88-1.84 (m, 3H), 1.82 (dd, J = 7.1 , 1.2 Hz, 3H), 1.75 (dd, J = 2.9, 1.3 Hz, 3H), 1.17 (s, 3H), 0.87 (d, J = 6.5 Hz, 3H), 0.80 (s, 3H);13C NMR (101 MHz, CDCh, 37 peaks total) 5210.0, 174.1 , 167.8, 164.8, 137.9, 133.9, 133.6, 132.2, 129.8, 128.8, 128.5, 128.4, 128.3, 126.6, 125.9, 125.5, 124.1 , 77.3, 76.6, 72.5, 71.5, 66.4, 65.2, 64.6, 61.8, 49.0, 45.8, 39.2, 36.0, 35.9, 26.6, 23.2, 17.1 , 15.2, 14.6, 12.4, 9.9; HRMS calculated for C37H430IO+[M+H]+: 647.2851 ; found 647.2838.SUW421

[0222] To a flame-dried vial equipped with a stir bar was added 4 (20 mg, 0.039 mmol, 1 equiv) and anhydrous MeCN (2 mL). N-methylimidazole (0.10 ml_, 1.25 mol, 32 equiv) followed by carbonyldiimidazole (21 mg, 0.129 mmol, 3 equiv). The reaction was stirred at rt for 18 hr. TLC analysis indicated complete consumption of 4 and formation of SI-16. Pyrrolidine (1.0 mL, dried over sieves) was added directly as a single portion. The reaction was stirred at rt for another 18 hr. TLC analysis indicated complete consumption of SI-16. The reaction mixture was diluted with EtOAc (20 mL) and washed with NaHCO3(20 mL) followed by NH4CI (20 mL) and brine (20 mL). The organic layer was dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-17 was used directly in the next step.

[0223] To a vial equipped with a stir bar was added crude SI-17 followed by MeCN (4 mL). TsOH in water (0.42 M, 4.0 mL) was added (final TsOH concentration of 0.21 M). The reaction mixture was stirred at rt for 15 hr. TLC analysis indicated complete consumption of SI-17. The reactionwith quenched with sat. NaHCCh (20 mL) and diluted with brine (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by HPLC (method) affording SUW421 (3 mg, 14%) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0224] SI-16 TLC Rr= 0.05 (70% Et2O / Hex, UV active, red spot in p-anisaldehyde); SI-17 TLC Rf= 0.29 (70% Et2O / Hex, UV active, blue spot in p-anisaldehyde); SUW421 TLC Rf= 0.30 (75% EtOAc / Hex, UV active, blue spot in p-anisaldehyde);1H NMR (600 MHz, CDCI3) 5 7.74 (s, 1 H), 6.86-6.78 (m, 1 H), 6.82 (br s, 1 H) 5.55 (d, J = 9.9 Hz, 1 H), 4.23 (s, 1 H), 4.07 (app p, J = 2.9 Hz, 1 H), 3.88 (d, J = 12.5 Hz, 1 H), 3.79 (d, J = 12.5 Hz, 1 H), 3.49 (dt, J = 11.8, 6.2 Hz, 1 H), 3.36 (dt, J = 11.7, 6.3 Hz, 2H), 3.30 (s, 1 H), 3.22 (dt, J = 12.6, 6.3 Hz, 1 H), 3.16 (d, J = 6.7 Hz, 1 H), 1.96 (dq, J = 10.1 , 6.6 Hz, 1 H), 1.93-1.84 (m, 4H), 1.83 (s, 3H), 1.78-1.74 (m, 3H), 1.44 (d, J = 6.7 Hz, 1 H), 1.25 (s, 3H), 1.25 (s, 3H), 0.88 (d, J = 6.5 Hz, 3H);13C NMR (126 MHz, CDCI3, 30 peaks total) 5 210.3, 167.8, 165.4, 155.6, 137.5, 133.4, 128.7, 78.1 , 77.2, 72.5, 71.9, 65.6, 65.5, 64.7, 61.6, 49.2, 46.4, 46.2, 45.9, 36.6, 36.3, 26.7, 25.8, 25.0, 24.0, 17.5, 15.4, 14.6, 12.4, 9.9; FTIR (ATR) 3332 (br), 2925, 1707, 1682, 1441 , 1410, 1255, 1130, 1076, 1024, 669 cm’1; [a]24D= -21 ° (c = 0.50, CH2CI2); HRMS calculated for C30H42NC [M+H]+: 576.2808; found 576.2798.SUW424

[0225] To a flame-dried vial equipped with a stir bar was added 2 (18 mg, 0.035 mmol, 1 equiv) and 1 :1 anhydrous MeCN: DCM (1.0 mL). N-methylimidazole (0.10 mL, 1.25 mol, 36 equiv) followed by carbonyldiimidazole (39 mg, 0.24 mmol, 7 equiv). The reaction was stirred at rt for 18 hr. TLC analysis indicated complete consumption of 2 and formation of SI-18. Pyrrolidine (1.0 mL, dried over sieves) was added directly as a single portion. The reaction was stirred at rt for 1 hr. TLC analysis indicated complete consumption of SI-18. The reaction mixture was diluted with EtOAc (50 mL) and washed with NH4CI (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-19 was used directly in the next step.

[0226] To a vial equipped with a stir bar was added crude SI-19 followed by MeCN (4 mL). TsOH in water (0.42 M, 4.0 mL) was added (final TsOH concentration of 0.21 M). The reaction mixture was stirred at rt for 15 hr. TLC analysis indicated complete consumption of SI-19. The reaction with quenched with sat. NaHCO3(20 mL) and diluted with brine (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (0-30% EtOAc / ether, 1 x7 cm) affording SUW424(4 mg, 20% yield over 2 steps, note 1) as a white foam. Compound purity was established by TLC (one spot) analysis.

[0227] Note 1 : The poor yield is presumably due to not loading all the compound onto the silica gel column because toluene was used for loading.

[0228] SI-18 TLC Rf= 0.05 (70% Et2O / Hex, UV active, red spot in p-anisaldehyde); SI-19 TLC Rf= 0.31 (70% Et2O / Hex, UV active, blue spot in p-anisaldehyde); SUW424 TLC Rf= 0.35 (75% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3411 (br), 2959, 2924, 2876, 1703, 1455, 1415, 1261 , 1095, 1022, 669 cm’1; [a]23D= -40° (c = 0.06, CH2CI2);1H NMR (400 MHz, CDCI3) 5 7.75 (dd, J = 2.6, 1.4 Hz, 1 H), 5.26 (d, J = 9.9 Hz, 1 H), 4.23 (s, 1 H), 4.06 (app p, J = 2.7 Hz, 1H), 3.88 (d, J = 12.5 Hz, 1 H), 3.80 (d, J = 12.5 Hz, 1H), 3.39 (br d, J = 6.6 Hz, 2H), 3.30 (br d, J = 8.5 Hz, 2H), 3.29 (s, 1 H), 3.16 (d, J = 6.7 Hz, 1H), 2.41 (app sex, J = 7.0 Hz, 1 H), 1.96-1.81 (m, 5H), 1.80-1.70 (m, 4H), 1.53-1.41 (m, 1 H), 1.26 (d, J = 2.5 Hz, 3H), 1.25 (s, 3H), 1.15 (d, J = 7.0 Hz, 3H), 0.97-0.93 (m, 3H), 0.92 (d, J = 3.3 Hz, 3H);13C NMR (126 MHz, CDCI3, 30 peaks total) 5210.2, 179.1, 165.2, 154.9, 133.5, 125.7, 77.6, 72.5, 71.9, 65.7, 65.5, 64.7, 61.8, 49.2, 46.6, 46.4, 46.0, 41.3, 36.2, 36.1 , 26.6, 26.3, 25.8, 25.1 , 23.9, 17.3, 16.3, 15.3, 11.8, 9.9; HRMS calculated for C3OH44NOIO+[M+H]+: 578.2960; found 578.2956.

[0229] Chemicals: Methyl triflate (Oakwood); di-tBu pyridine (Acres, 97%); DCM (freshly distilled).

[0230] To a flame-dried vial equipped with a stir bar was added EBC-46 (9 mg, 0.016 mmol, 1 equiv) and anhydrous DCM (0.70 ml_). 2,6-ditertbutyl pyridine (20 mg, 0.16 mmol, 10 equiv) was added directly as a single portion. The reaction mixture was cooled to 4 °C and methyl tritiate (17 pL, 6.0 equiv) was added directly as a single portion. The reaction was allowed to warm to rt and stirred for 18 hr. TLC analysis indicated about 75% consumption of EBC-46 and formation of a new nonpolar product. The reaction mixture was diluted with NaHCOs (10 ml_). The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (20-50% EtOAc / hexane, 1 x7 cm) affording SUW426 (6 mg, 67% yield) as a white solid. Compound purity was established by TLC (one spot) analysis.

[0231] SUW426 TLC Rf = 0.54 (70% EtOAc / Hex, UV active, blue spot in p-anisaldehyde); FTIR (ATR) 3398 (br), 2963, 2922, 2854, 1711 , 1458, 1377, 1257, 1072, 1018, 800, 669 cm’1; [a]23D= -50° (c = 0.05, CH2CI2);1H NMR (600 MHz, CDCI3) 6 7.70 (app s, 1 H), 6.81 (dq, J = 7.1 , 1.6 Hz, 1 H), 5.45 (d, J = 9.9 Hz, 1 H), 4.27 (d, J = 2.8 Hz, 1 H), 4.19-4.14 (m, 1 H), 4.00 (d, J = 11.4 Hz, 1 H), 3.76 (br d, J = 3.6 Hz, 1 H), 3.70 (s, 1H), 3.42 (s, 3H), 3.34 (d, J = 11.4 Hz, 1 H), 3.17 (d, J = 6.5 Hz, 1 H), 3.15 (s, 1 H), 2.39 (app sex, J = 7.0 Hz, 1 H), 1.97 (dq, J = 9.9, 6.6 Hz, 1 H), 1.82 (app s, 3H), 1.81-1.78 (m, 3H), 1.78-1.70 (m, 4H), 1.50-1.42 (m, 1 H), 1.25 (s, 3H), 1.24 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H);13C NMR (126 MHz, CDCI3, 31 peaks total) 5 209.6, 178.9, 167.6, 164.3, 137.7, 133.5, 128.6, 77.4, 74.3, 72.7, 70.0, 65.7, 64.5, 61.9, 60.0, 48.9, 46.0, 41.3, 36.4, 35.9, 29.9, 26.7, 26.3, 23.9, 17.4, 16.3, 15.2, 14.6, 12.4, 11.8, 9.9; HRMS calculated for C3I H440IO+[M+H]+: 577.3007; found 577.3003.Example 3: Biological Evaluation of EBC-46 Analogs

[0232] With a diverse library of compounds bearing unique functionalities on the A, B, and C rings, how these modifications affect PKC activation and downstream functional activity was explored (Scheme 7). Because binding to the C1 domain of PKC is a prerequisite to PKC-pathway involvement, evaluation of the biological activity of these compounds began with a cell-free competitive binding assay against tritiated phorbol-12,13-dibutyrate (3H-PDBu) for representative conventional (PKC- I) and novel (PKC-5) isoforms of PKC. This assay is conducted with phosphatidyl serine vesicles in solution which mimic the cellular membrane and play a critical role in the binding of small molecules to the C1-domain (Table 1). NF-KB activation is shown in Table 2. y |

[0233] EBC-46 showed potent binding for both isoforms of PKC (1.4 nM for beta, 3.2 nM for delta) with a modest 2-fold selectivity for beta over delta (FIG. 3). SUW400, which features a C6,C7 alkene in place of the C6,C7-a-epoxide, had nearly identical binding affinity and selectivity compared to EBC-46. SUW403, the des-C5-hydroxy analog of EBC-46 showed approximately a 5-fold decrease in potency while retaining a similar isoform selectivity for PKC-p over PKC-5. This finding suggests that the C5-beta-hydroxyl group might improve the potency C6,C7-a-epoxy tiglianes. SUW426 has a methyl ether attached to the C20 oxygen atom, which is the atom that inserts the deepest inside the narrow C1-domain binding pocket. As anticipated, this added steric bulk in combination with removing C20 oxygen’s ability to serve as a hydrogen bond donor (FIGs. 2B-2C) completely killed its binding affinity for PKC.

[0234] SUW422, featuring the C3-beta benzoate ester akin to gnidimacrin, had nearly identical binding potency and selectivity to EBC-46. Similarly, the C3 senecioate ester analog SUW425 had binding affinity and selectivity that was approximately the same as EBC-46. Although the introduction of these large ester groups significantly changes the pharmacophoric region, this functional group, typically found in ingenane and daphnane type natural products, was also compatible with compounds that have the tigliane skeleton.

[0235] Modifications to the C12 and C13 positions of the C-ring, the region that is putatively embedded in the cell membrane during PKC activation, proved to be crucial for potent and selective binding to PKC (FIG. 3). SUW407, which features the diastereomeric C13 (R)- methylbutyrate ester, showed similar binding affinities for both PKC- and PKC-5. This finding suggests that the chirality of this small ester is inconsequential to binding and selectivity. SUW406, featuring a C13 cyclobutanoate ester, showed a similar binding affinity for PKC- compared with EBC-46, but with a moderate four-fold selectivity over PKC-5. This suggests that the relatively inexpensive cyclobutanoic acid might be a useful substitute for the enantiomerically- enriched (S)-methylbutyric acid. SUW413, which features an achiral alpha-cyclopropyl ester, showed very similar binding affinity for both PKC-p and PKC-5 compared to SUW406. This finding suggests that the alpha-cyclopropanated ester might be able to serve as a more stable surrogate for the alpha, beta-unsaturated tiglate ester found in EBC-46. SUW431 , featuring the naphthylacetate ester, had exceptionally increased PKC-binding potency and less selectivity with ~20-fold increased binding for PKC-P (79 pM) and a 30-fold increased binding for PKC-5 (110 pM). Interestingly, SUW431 has approximately 10-fold greater affinity for PKC- 5 than that reported for the exemplary analog from the prostratin series (SUW013).

[0236] SUW424 and SUW421, featuring pyrrolidine carbamates at the C12 and C13 positions respectively, showed relatively weak binding to PKC-P (~25 nM), but significantly increased selectivity over PKC-5 (6-fold and 10-fold respectively). It was hypothesized that this >10-fold decrease in potency was due to the increased polarity of the carbamate functional group, relative to the esters found on EBC-46, making the lipophilic region less favorable to embed into plasma membrane. Therefore, SUW428 was made as a more non-polar isostere of the pyrrolidine carbamate. Gratifyingly, this compound retained >12-fold selectivity for PKC-P over PKC-b while restoring the potency to single digit nanomolar levels for PKC-P (5.1 nM). Considering that SUW431 , featuring an aryl lipid separated from its C13 carbonyl by a methylene spacer, was unselective (1.4-fold for PKC- ), this finding suggests that the conformationally-restricted arrangement of the aryl group of SUW428 might be responsible for the observed PKC-p-selective mode of binding.

[0237] Surprisingly, SUW430, featuring a C12 tert-butyl ether, showed nearly identical binding affinity for PKC- (1 .5 nM) as EBC-46, but with 40-fold selectivity over PKC-b (60 nM). This compound was the most PKC- selective binder in this series. The isoform-selective binding of this C12 ether is inexplicable, but this finding is currently being investigated.

[0238] Next, in the evaluation of this series of EBC-46 analogs, an NF-kB reporter assay was conducted as a high throughput method for screening compounds simultaneously for their ability to get into cells and activate PKC (FIG. 3). It was observed that the performance of the analogs in this assay was strongly correlated with their performance in the cell-free binding assay.

[0239] In this assay, EBC-46 showed approximately a 2.5-fold increase in luminescence relative to the DMSO control at 500 nM and 1500 nM. The desoxy B-ring analogs (SUW400 and SUW403) and the C-ring analogs with a similar polarity and configuration of the EBC-46 esters (SUW406, SUW407, and SUW413) all showed comparable activity at these concentrations. Interestingly, the C20 methyl ether (SUW426) had mild activity in this assay. This compound functions as a negative control for PKC-pathways. Therefore, this finding might suggest that there are other nonCi -domain dependent pathways that are activated by these drugs. As expected, the less potent C12 and C13 carbamate analogs (SUW424 and SUW421) had poor activity in this assay comparable to the negative control (SUW426). The A-ring analogs (SUW422 and SUW425) both activated NF-kB, but there was some divergence in their activity in this functional assay. SUW425 showed activity like EBC-46 (~2.5-fold change at 1500 nM) while SUW422 was moderately less effective at all concentrations tested. The prodrug variant of EBC-46 (SUW427) showed similaractivity to EBC-46 at all concentrations. This compound is expected to have less toxicity in vivo and thus a larger therapeutic window for systemic distribution than the parent compound?. SUW431 , the hyperpotent napthylacetyl ester of EBC-46, had the best overall activity in this assay. Although this compound displayed an inverse dose response past 50 nM, this compound displayed greater NF-kB activation (3-fold change) than EBC-46 at only 50 nM (30-fold lower). The inverse-dose relationship is putatively due to PKC downregulation because of overactivation4,6. Interestingly, the PKC-P selective binders (SUW428 and SUW430) were also great performers in this assay. SUW428 was mildly less effective than EBC-46 at 1500 nM, while SUW430 performed better than EBC-46 at both 500 and 1500 nM despite having the same binding affinity for PKC- and 20-fold weaker affinity for PKC-5.Preclinical Evaluation: Cell-Free PKC Binding Assay

[0240] Production of PKC Isoforms: Agar stabs of DH5-alpha (high copy) bacterial cells, containing plasmids for expression of mammalian PKC-5 (Plasmid #: 178856) and PKC- (Plasmid #112265) fused to EGFP under constitutive mammalian promoters CAG and CMV, respectively, were purchased from Addgene. Upon receipt, these stabs were incubated at 37 °C in 5% CO2 for 24 hours to allow sufficient bacterial growth. Following incubation, a sterile pipette tip was utilized to streak bacteria onto LB agar plates that are positive for their respective antibiotic. For bacteria containing Plasmid #: 178856, bacteria were streaked onto CellPro™ LB (Lennox) + Ampicillin 100 pg / mL while bacteria containing Plasmid #: 112265 was streaked onto CellPro™ LB (Miller) + Kanamycin 50 pg / mL and incubated for 24 hours at 37 °C in 5% CO2 in order to isolate single colonies of bacteria. Single, isolated bacterial colonies were selected utilizing a sterile pipette tip and placed in polypropylene culture tubes with vented stoppers containing 2 mL of LB Broth Miller (Catalog No. BP1426-500) and the respective antibiotic for each plasmid at the recommended concentration of 100ug / ml for ampicillin and 50ug / ml for kanamycin. Following inoculation, these liquid cultures were placed on a shaker at 37 °C at 225 rpm for 24 hours. The next day, the plasmids were sequestered and purified from the bacteria utilizing the Thermo Scientific™ GeneJET Plasmid Miniprep Kit (Catalog No. K0502).

[0241] PKC-fi / PKC-5 Plasmid Purification: To sequester and purify plasmid from each culture tube, bacteria was resuspended in culture and transferred to sterile 1 .7 mL microcentrifuge tubes with 1 mL of bacteria placed into each tube. To harvest the bacteria, microcentrifuge tubes were placed in a microcentrifuge and spun at 8000 rpm for 2 minutes at room temperature. Note that all subsequent centrifugations were performed in a tabletop microcentrifuge at room temperature.Following centrifugation, the supernatant was decanted and 250 pL of Resuspension solution was added to the pelleted cells and vortexed. Afterwards, 250 pL of Lysis Solution was added to the resuspended bacterial cells and tubes were inverted 4-6 times and allowed to incubate for no more than 5 minutes to avoid denaturation of the plasmid DNA. After lysing the bacterial cells, 350 pL of Neutralization Solution was immediately added and tubes were inverted 4-6 times. Tubes were then centrifugated for 5 minutes at 14,000 rpm to pellet the cell debris and chromosomal DNA. The supernatant was then carefully aspirated using a pipette, taking care not to distribute the white precipitate of cell and DNA debris and transferred to the GeneJET spin columns, provided in the Miniprep Kit. The spin columns were subsequently centrifugated for 1 minute, the flow-through was discarded, and the column was placed back into the same collection tube. 500 pL of Wash Solution, diluted with 96% ethanol, was added to the column, and the column was centrifugated for 1 minute at 14,000 rpm. The flow-through was discarded and the column was placed back into the same collection tube. This wash process was repeated a second time, after which the spin columns were centrifugated for an additional 1 minute to ensure all residual Wash solution was removed from the plasmids. The GeneJET spin columns were then transferred to new 1.7 mL microcentrifuge tubes, and 50uL of Elution Buffer was added to the center of the spin column to allow optimal elution of the plasmid DNA. Before centrifugating for 2 minutes, the columns were allowed to incubate for 2 minutes at room temperature. Following centrifugation, the spin columns were discarded, and the purified plasmid was stored at -20 °C. A Thermo Scientific NanoDrop One UV-Vis Spectrophotometer was used to quantify the concentration of plasmid sequestered in each microcentrifuge and verify its purity, using the ratio of absorbance at 260 and 280 nm. A ratio of ~1.8 is accepted as pure.

[0242] PKC-fi / PKC-5 Plasmid Transfection of A549 Cells'. 3 * 105A549 cells were seeded to about 70-90% confluency in 35 mm glass bottom dishes with 20 mm micro-well #1.5 cover glass in DMEM ((4.5 g / L glucose, 10% FBS (30 min at 56 °C), and 1% Pen-Strep-Glutamine (100 X, 50 mg / mL)). For each dish, two 1.7 mL polypropylene microcentrifuge tubes were prepared. One tube contained 125 pL of Opti-MEMTM Medium and 7.5 pL of LipofectamineTM 3000 Reagent while the second tube contained 120 pL of Opti-MEMTM Medium, 2.5 pg of plasmid DNA, and 5 pL of P3000TM Reagent. The 125 pL of diluted plasmid DNA was ultimately added to the 1.7 mL polypropylene microcentrifuge tube containing the diluted LipofectamineTM 3000 Reagent and allowed to incubate for 10-15 minutes at room temperature. Following the incubation period, the entire volume of DNA-lipid complex was added to its respective dish and allowed to incubate for -24 hours at 37 °C in 5% CO2. Following incubation, supernatant was aspirated and replacedwith 1.5 mL of DM EM ((4.5 g / L glucose, 10% FBS (30 min at 56 °), and 1% Pen-Strep-Glutamine (100 X, 50 mg / mL)), and cells were allowed to rest for ~12 hours.

[0243] PKC-(3 / PKC-5 Translocation: Prior to cell imaging at 37 °C, culture media was aspirated and replaced with 900 pL of Ringer’s solution. After locating the appropriate cells expressing EGFP under the confocal laser scanning fluorescence microscope using the 488-nm argon excitation laser, continuous scanning was initiated. After which, 100 pL of compound was added to the respective dish at a 10 times higher concentration to achieve the desired final concentration for translocation observation, and cells were scanned for 30 minutes.

[0244] PKC Binding Assay Protocol: The protein kinase C (PKC) affinity of EBC-46 and EBC-46 analogs was determined via competition with 3H-phorbol-12,13-dibutyrate (3H-PDBu) as described below. This procedure entails a glass-fiber filtration method to determine bound radioligand. One assay = One compound per sheet with positive / negative control.

[0245] Preparation of 3H-PDBu solution: 3H-PDBu (American Radiolabeled Chemicals, Inc.; 1 mCi / mL acetone solution; specific activity: 20 pCi / mmol) was diluted with DMSO to a final concentration of 500 nM.

[0246] Preparation of phosphatidylserine (PS) vesicles: Per two assays, 3.5 mg phosphatidylserine (140 pL) (Avanti Polar Lipids, porcine, 25 mg / mL CHCL solution) was concentrated by removing chloroform under reduced pressure. The phosphatidylserine residue was resuspended in freshly prepared PKC binding assay buffer (3.5 mL), capped, and then thoroughly mixed by alternating between sonicating and vortexing, in 10 second intervals for 1 minute or until a cloudy white mixture (Branson Sonifier 250, power = 2, 50% duty cycle). The resulting cloudy white mixture (1 mg / mL) was stored on ice until use.

[0247] Preparation of PKC binding assay buffer. Per two assays, to a 50 mL polypropylene tube was added Tris-HCI (pH 7.4, 1 M, 1.5 mL), KCI (1 M, 3 mL), CaCI2(0.1 M, 35 pL), and bovine serum albumin (BSA, 60 mg, Sigma-Aldrich). This mixture was diluted to 30 mL with deionized H2O and mixed gently. The buffer was stored on ice until use.

[0248] Preparation of PKC isoform solution: Per two assays, PKC isoform solution was prepared by dissolving a 4 pg aliquot of the indicated recombinant human PKC isoform (Invitrogen) into 26.5 mL of PKC binding assay buffer (this amount is sufficient for two assays). The diluted PKC was stored on ice for immediate use.

[0249] "Master Mix" Solution: To the PKC-isoform solution was added 3.3 mL of 1 mg / mL PS vesicles solution, and 0.150 mL of 500 nM 3H-PDBu solution were added. The resulting solution was vortexed to mix and stored on ice.

[0250] Preparation of analog compound dilutions: Compound dilutions were prepared with filtered DMSO by serially diluting from a chosen "high" concentration (15000 nM) by factors of 2 or ^2. For each analog compound, fourteen concentrations were used to define the inhibition curve with the ^2 dilutions done for concentrations in the middle of the curve (i.e. for SUW400, the analog concentrations used were 15000 nM, 7500 nM, 3750 nM, 1875 nM, 938 nM, 469 nM, 332 nM, 235 nM, 117 nM, 59 nM, 29 nM, 15 nM, 7 nM).

[0251] PKC Binding Assay Protocol: Triplicate data points were obtained for each analog concentration. For each data point, 280 pL of "Master Mix" Solution and 20 pL of analog compound at a specified concentration were added to a polypropylene tube. Non-specific 3H- PDBu binding was assessed in triplicate by substitution of the analog compound with unlabeled PDBu (20 pL of a 75 pM stock, assay concentration: 5 pM).

[0252] Maximal 3H-PDBu binding was assessed in triplicate by substitution of the analog compound with 20 pL DMSO. Samples were prepared by first adding master mix to the test tubes and leaving them in an ice-water-cooled test-tube rack (Note 1). Compounds were added to the master-mix filled test tubes in triplicate at 4 °C, vortexed prior to storage, and then the tubes were returned to storage in the 4 °C ice water-cooled test-tube rack until all samples for one sheet were ready for incubation. Using a partially water-filled thermal block incubator (Note 2), the complete assay solutions were placed directly in the incubator at 37 °C for 5 min, and then cooled in the ice-water cooled test-tube rack for at least 10 min prior to filtration on the harvester.

[0253] Using a Brandel Harvester, the assay contents from each polypropylene tube were vacuum-filtered through polyethylenimine-soaked filters, washed with rinsing buffer (3X) and dried first under vacuum for 5 min. Following harvesting, the sample filter disks are removed immediately after all samples are done harvesting and suspended in scintillation tubes with scintillation fluid. Subsequently, samples are read on the scintillation counter the same day.

[0254] The resulting filters had circular perforations for each data point, which were removed with forceps and placed in a scintillation vial. Scintillation vials were filled with Bio-Safe II scintillation fluid (5 ml_) and measured for radioactivity using a Beckman LS 6000SC scintillation counter.

[0255] Counts per minute (cpm) were averaged for each triplicate dilution. The data were plotted - cpm vs. log(concentration) - using PrismR by GraphPad Software and an IC50 was determined using that program’s built-in one-site competition least squares regression function. Ki values were calculated using the equation: Ki = IC50 / (1 + ([3H-PDBu] I Kd)). The Kd of 3H-PDBu for PKC isoforms was measured separately via saturation binding experiments.

[0256] Note 1 : Master mix is carefully dispensed in the bottom half of the test tubes without touching the walls of the test tube with the outside of the pipet tip. The outside of the tip is wiped off with a chemwipe between tubes. This prevents big droplets on the interior walls that are otherwise seemingly impossible to avoid.

[0257] Note 2: One of our incubation blocks had a defect in the way that it was manufactured such that it did not evenly contact the incubator’s heating mantle. This resulted in one half of our samples being ~5 degrees colder than the other half. We replaced this defective heating block. We also started adding water to the wells of the heating blocks so that the samples have uniform heating contact.

[0258] With a diverse library of compounds bearing unique functionalities on the A-, B-, and Curings (Scheme 4), we began to explore how these modifications affect PKC binding (Table 1), NF- KB activation (Table 2), cell permeation and PKC translocation (FIGs. 4A-4B), and latency reversal in J-Lat cells (FIGs. 5A-5F). Because binding to the C1 domain of PKC is a prerequisite to PKC pathway involvement, our evaluation of the biological activity of these compounds began with a cell-free competitive binding assay against tritiated phorbol-12,13-dibutyrate (3H-PDBu) using representative conventional (PKC- -I) and novel (PKC-5) isoforms of PKC. We conducted this assay with phosphatidyl serine vesicles in solution that mimic the cellular membrane and play a critical role in the binding of small molecules to the PKC C1 domain (Table 1).

[0259] EBC-46 showed potent binding to the two isoforms of PKC (1 .4 nM for PKC-P and 3.2 nM for PKC-5) with modest 2-fold selectivity for PKC-P over PKC-5 (Table 1). SUW400, which features a C6,C7 alkene in place of the C6,C7-a epoxide and is a readily accessible analog, had nearly identical binding affinity and selectivity compared to EBC-46, suggesting that the B-ring epoxide is not critical to PKC binding as predicted by our in silico modeling (FIG. 2C) and suggesting that this more accessible compound might be clinically useful. SUW403, the des- C5- hydroxy analog of EBC-46, showed an approximately 5-fold decrease in potency while retaining similar isoform selectivity for PKC-P over PKC-5, suggesting that C5-OH plays a role in PKC binding, in line with our modeling studies. SUW402, a phorbol diester featuring the esters found on EBC-46, showed highly potent binding to both tested isoforms of PKC (0.12 nM for PKC-p and 0.44 nM for PKC-5). SUW426 has a C20 methoxy group in place of C20-OH, a hydrogen bond donor and pharmacophoric group that inserts deeply into the narrow C1 domain binding pocket. As anticipated from our modeling studies, the added steric bulk of SUW426, in combination with its inability to serve as a C20 hydrogen bond donor (FIGs. 2B-2C), resulted in an approximately 250-fold decrease in PKC binding affinity, thus serving as a tool compound to explore non-PKC effects. SUW422, featuring a hydrolytically stable C3-p-benzoate ester akin to gnidimacrin, had nearly identical binding potency and selectivity to EBC-46, in line with our pharmacophore model. Similarly, the C3-senecioate ester analog (SUW425) had binding affinity and selectivity that was approximately the same as EBC-46. While C3 esters are typically found in biologically active ingenanes and daphnanes, our modeling and data indicate that it also applies to our analogs. Modifications to the C12 and C13 positions of the C-ring, the region that, on the basis of our modeling and subsequent X-ray analyses, is putatively embedded in the cell membrane during PKC activation, proved to be crucial for potent and selective binding to PKC (Table 1). In line with our modeling, SUW407, which features the diastereomericC13-(R)-methylbutyrate ester, showed similar binding affinities for both PKC-P and PKC-5. This finding suggests that the chirality of this small ester is inconsequential to extracellular PKC binding and selectivity as expected from its membrane microenvironment. SUW406, featuring a pseudoplanar achiral C13-cyclobutanoate ester akin to the EBC-46 chiral butanoate, showed a similar binding affinity to PKC-p compared to EBC-46 with moderate 4-fold selectivity over PKC-5. This suggests that the relatively inexpensive pseudoplanar five-carbon cyclobutanoic acid ester might be a useful surrogate for the chiral (S)-methylbutyric acid ester of EBC-46. SUW413, which features an achiral a- cyclopropyl ester, showed very similar binding affinity to both PKC-P and PKC-5 compared to SUW406. This finding suggests that the a-cyclopropyl ester might serve as a more stablesubstitute for the a,[3-unsaturated tiglate ester found in EBC-46. SUW431 , featuring C13-(1- naphthyl)acetate ester), had exceptionally increased PKC binding potency with ~20-fold stronger binding for PKC-P (79 pM) and 30-fold stronger binding for PKC-6 (110 pM) when compared to EBC-46. SUW431 has approximately 10-fold greater affinity to PKC- 6 than that reported for the exemplary analog from the prostratin series (SUW013). SUW424 and SUW421 , featuring pyrrolidine carbamates at the C12 and C13 positions, respectively, showed relatively weak binding to PKC-[3 (~25 nM) but increased selectivity over PKC-6 (6-and 10-fold, respectively). We hypothesized that this >10-fold decrease in potency is due to the increased polarity of the carbamate functional group, relative to the esters found on EBC-46, making the lipophilic region less effective in embedding in a membrane. Therefore, we made SUW428 as a less polar isostere of the pyrrolidine carbamate. In support of our hypothesis, this compound retained >12-fold selectivity for PKC-p over PKC-6 while restoring the potency to single-digit nanomolar levels for PKC-P (5.1 nM). Considering that SUW431 , featuring an aryl lipid separated from its C13 carbonyl by a methylene spacer, was unselective (1.4-fold for PKC-P), this finding suggests that the conformationally restricted arrangement of the aryl group of SUW428 might be responsible for the observed PKC-p-selective mode of binding. Unexpectedly, SUW430, featuring a C12 tertbutyl ether, showed nearly identical binding affinity to PKC-p (1.5 nM) as EBC-46 with 40-fold selectivity over PKC-6 (60 nM). This unprecedentedly selective compound, incorporating a nonester lipid at C12, was the most PKC-P-selective binder in this series and opens a new approach to achieve isoform selectivity as would be desired for various therapeutic indications.PKC-GFP Translocation Assay

[0260] Because the extracellular binding of ligands to the C1 domain of PKC is necessary but not sufficient for their cellular permeation and intracellular PKC activation, we tested EBC-46, our most potent analog (SUW431), and our most isoform-selective analog (SUW430) in a translocation assay using PKC-p and PKC-6 proteins fused to green fluorescent protein (GFP). Using confocal microscopy, this assay allows us to visualize, in real time, cell permeation and the ligand-induced translocation of specific PKC isoforms from the cytosol to the membranes of the cell — the hallmark of PKC activation. All three of these compounds were able to quickly enter cells and effectively translocate PKC-3 at 500 nM and PKC-6 at 1500 nM in CHO-K1 cells within 10 min, confirming that these compounds can permeate cellular membranes as well as access and activate both PKC isoforms (FIGs. 4A-4B). In alignment with past studies on the activation of PKC in CHO-K1 cells, we observed strong plasma membrane translocation of PKC-p (FIG. 4A). SUW431 induced strong perinuclear and plasma membrane translocation of PKC-6, while EBC-46 and SUW430 selectively induced perinuclear translocation of PKC-6 (FIG. 4B). This nuclear membrane- biased translocation profile of PKC-6 in CHO-K1 cells resembles that of 12- deoxyphorbol-13-phenylacetate — a prostratin derivative that exhibits potent HIV latency reversal in vitro and ex vivo.NF-KB Activation Assay

[0261] As a high-throughput method of screening compounds for their ability to get into cells and activate immunological pathways related to HIV latency reversal, we conducted an NF-KB reporter assay using A549 cells stably integrated with a secreted embryonic alkaline phosphatase reporter under the control of a promoter fused to five NF-KB binding sites (Table 2). We assessed NF-KB activation 24 hours after compound addition, and we observed that the performance of our analogs in this assay was strongly correlated with their performance in the cell-free binding assay (Tables 1-2). At 50 nM, EBC-46 and most of our analogs displayed minimal activation of NF-KB relative to the dimethyl sulfoxide (DMSO) control. However, at 50 nM, the highly potent C13-(1- napthyl)acetate ester of EBC-46 (SUW431) and the phorbol diester (SUW402) induced approximately three times the basal level of NF-KB activation indicated by our DMSO negative control. However, in line with the ability of potent PKC activators to induce feedback inhibition mechanisms, we observed that SUW431 and SUW402 also exhibited strong activation of N F-KB at higher concentrations but with an inverse dose response. At 500 nM, EBC-46 induced ~2.5 times the basal level of NF-KB activation. SUW426, the C20-methyl-ether analog of EBC-46, did not exhibit NF-KB activation at either concentration tested in this assay, consistent with its design as a negative control. As expected, the less potent C12,C13-carbamate analogs (SUW424 and SUW421) had minimal activity in this assay at 50 and 500 nM. Compared to EBC-46, both A-ring analogs (SUW422 and SUW425) had similar binding affinities for PKC-P and PKC-6, yet they exhibited minimal NF-KB activation at both 50 and 500 nM. The lack of functional activity from SUW422 and SUW425 in the NF-KB assay could be a result of poor cell membrane permeability or poor hydrolytic stability of these compounds under the assay conditions, suggesting that cell- free PKC binding affinity is necessary but not sufficient for PKC activation. The desoxy-B-ring analogs (SUW400 and SUW403) and the C-ring analogs with similar esters to EBC-46 (SUW406, SUW407, and SUW413) all demonstrated comparable activity to EBC-46 at 50 and 500 nM. The prodrug variant of EBC-46 (SUW427) also showed similar activity to EBC-46 at both concentrations. This is substantial because we expect this compound to have different biophysical properties than EBC-46 and potentially a larger therapeutic window for systemic distribution as was observed with the prodrug of bryostatin 1. SUW428, one of the more PKC-p-selectiveanalogs, was less effective at inducing NF-KB activation than EBC-46 at 500 nM, which is in line with it having approximately three times lower affinity for PKC-P compared to EBC-46. Although SUW430 has the same binding affinity as SUW428 for PKC-b (~20x weaker than EBC-46), it has the same affinity as EBC-46 for PKC- , and it performed comparably to EBC-46 at both concentrations in the NF-KB assay.

[0262] Because SUW402 and SUW431 are potent activators of NF-KB, we used an enzyme- linked immunosorbent assay to measure their ability to up-regulate inflammatory cytokine production (tumor necrosis factor-a and interleukin-8). We stimulated A549 cells with SUW402 and SUW431 at the same concentrations used in the NF-KB activation assay: 500 and 50 nM. SUW402 did not produce detectable levels of tumor necrosis factor-a at either concentration, while SUW431 produced minimal amounts (8.4 pg / mL) at 500 nM, an amount close to the assay’s lowest detectable limit of 3.5 pg / mL. At 500 or 50 nM, both SUW402 and SUW431 produced only modest levels of interleukin-8, a 15 to 25% increase relative to the DMSO negative control. These enzyme-linked immunosorbent assay results suggest that potent up-regulation of NF-KB corresponds with minimal up-regulation of inflammatory cytokine expression in this cell line.

[0263] Cell Maintenance: Human A549 lung carcinoma cells were passaged when about 90% confluency was reached (approximately every three days). With each passage, media was aspirated from the cell layer, which was then washed with PBS. Following aspiration of the PBS, cells were detached from the culture flask with 0.25% GibcoTM Trypsin-EDTA and transferred to a 50ml_ conical tube, which was volumed up with complete pre-warmed DMEM ((4.5 g / L glucose, 10% FBS (30 min at 56 °C), and 1% Pen-Strep-Glutamine (100 X, 50 mg / mL)). This conical tube was spun down at 1800 rpm for 3 minutes, the supernatant was removed, and cells were resuspended in fresh, pre-warmed DMEM. To count cells, 10 pL of resuspended cells were added to a sterile microcentrifuge tube and mixed with 10 pL of trypan blue after which 10 pL of the mixture was pipetted into a Countess chamber slide. A Countess™ 3 Automated Cell Counter was subsequently utilized to determine cell viability and concentration. 1 106cells were seeded with each passage into a T75 culture flask, and cells were incubated at 37 °C in 5% CO2.

[0264] NF-KB Assay Protocol: Human A549 lung carcinoma cells, stably integrated with a secreted embryonic alkaline phosphatase (SEAP) reporter, allows the activity of the NF-KB pathway to be monitored. The SEAP reporter is under control of the interferon p (I FN-p) minimal promoter, which is fused to five NF-KB binding sites.

[0265] 5 x 104A549 cells were plated on Corning® 96 Well TC-Treated Microplates (CLS3595) in 180 l of pre-warmed DMEM (4.5 g / l glucose, 10% heat-inactivated FBS (30 min at 56 °), and 1% Pen-Strep-Glutamine (100 X, 50 mg / mL)). Note that if cells were grown in media containing FBS that is not heat-inactivated, media will contain alkaline phosphatase. In this case, all supernatant must thoroughly be aspirated from the cell pellet obtained after centrifugation before resuspending cells in media containing heat inactivated FBS for plating. Following incubation at 37 °C in 5% CO? for approximately 24 hours to allow for cell adherence onto the 96 well plate, 1.8 pL of each compound dissolved in DMSO, was added in quadruplicate to their respective wells to achieve a final compound concentration of 1500 nM, 500 nM, and 50 nM. 1.8uL of DMSO was added to wells as negative controls while wells treated with EBC-46 served as positive controls. 24 hours following compound addition, 180 pL of QUANTI-BlueTM Solution (medium containing QB buffer and QB Reagent for detection and quantification of alkaline phosphatase) were added into wells on a new clear flat-bottom 96-well plate. 20 pL of supernatant of either SEAP-expressing cells incubated with compound or SEAP-expressing cells incubated with DMSO were added to the wells in the new 96-well plate containing QUANTI-BlueTM Solution. Supernatant and QUANTI-BlueTM Solution were incubated at 37 °C in 5% CO2 for approximately an hour and a half. Following incubation, optical density (OD) at 630nm was measured for each well using a BioTek Synergy H1 microplate reader under normal read speed and with a delay of 100msec.J-Lat HIV Latency Reversal Assay

[0266] Having shown that our lead compounds bind cell-free PKC isoforms, enter cells, translocate PKCGFP fusion proteins, and activate NF-KB transcription factors, we next set out to determine whether our analogs were capable of reversing HIV from latency. We performed in vitro assays using T lymphocyte J-Lat clone 10.6, which contains a latent near full-length replication incompetent integrated HIV DNA genome . J-Lat 10.6 lacks two viral genes, env and nef, which encode for the envelope protein and an accessory protein, respectively, and thus cannot initiate a spreading HIV infection. The integrated HIV provirus also encodes a GFP reporter gene, allowing latency reversal to be measured by quantification of GFP expression. Bryostatin 1 is a naturally occurring PKC modulator that is commonly used in HIV latency reversal studies because of its effectiveness and hence served as our positive control. In this latency reversal assay, we quantified GFP expression 48 hours after compound addition and observed bryostatin 1 to be maximally effective at concentrations of 40 nM or higher with latency reversal in 12% of cells (FIGs. 5A-5F). Given the efficacy of bryostatin 1 as an LRA, EBC-46 and many of its analogs tested in this J-Lat assay induced latency reversal in >90% of cells. SUW400, a structurallysimplified analog of EBC-46, performed similarly, inducing maximal latency reversal of >90% of cells at a concentration of 250 nM, supporting the notion that the C6,C7-a epoxide of EBC-46 does not play an essential role in its membrane permeability or functional activity related to HIV latency reversal. SUW431 , featuring the C13-napthylacetate, was the most effective HIV latency reversal agent, inducing latency reversal in 90% of cells at a concentration of just 40 nM (FIG. 5C). All other analogs with B-ring (SUW403), C-ring (SUW406, SUW407, SUW413, SUW428, and SUW430), and A-ring modifications (SUW422 and SUW425) strongly induced HIV latency reversal (in 80 to 90% of cells) but required a higher dose than EBC-46 before we detected reversal activity (FIGs. 5A-5F). SUW427, an esterase-releasable prodrug of EBC-46, also performed similarly to EBC-46 with a maximum efficacy of latency reversal in >90% of cells at a dose of 250 nM. Notably, in a time course study of this prodrug’s activity, we observed that it demonstrated a time-dependent response as expected for a prodrug. At a concentration of 100 nM, prodrug SUW427 had a clear delayed HIV latency reversal in J-Lat 10.6 cells, achieving comparable HIV latency reversal ability to EBC-46 at the same concentration (FIG. 5E). At a concentration of 250 nM, SUW427 almost converged with its parent compound at all time points and reached maximal latency reversal (FIG. 5F). The gradual release of EBC-46 from its prodrug form provides an alternative mode of administration that avoids the bolus effect associated with rapid drug administration. SUW426, the C20-methyl-ether analog of EBC-46, did not produce latency reversal at any tested concentration (FIG. 5A). This is consistent with its lack of activity in the NF-KB activation assay and its design as a negative control as it is structurally similar to EBC- 46 but unable to bind to the C1 domain of PKC at the concentrations used in this assay as it lacks a complete pharmacophore.Example 4: Additional Synthetic Schemes

[0267] In some experiments, rather than proceeding to a final step as shown in Scheme 8 below, intermediate compounds such as 2 were synthesized and alternate synthetic protocols were followed to produce additional compounds.Example 5: Discussion

[0268] On the basis of our function-oriented synthesis approach and guided by our pharmacophore model for C1 -domain PKC modulators and related SAR studies of their PKC modulation, we leveraged our scalable, sustainable, and step-economical synthesis of EBC-46 (11 steps, 17% overall yield from naturally abundant phorbol) to design, prepare, and evaluate 15 analogs of EBC-46. Our synthesis provides unique and scalable access to EBC-46 and its analogs, many of which are not accessible from the rare natural source endemic to a small rainforest region of northeastern Australia. We examined structural variations at pharmacophoric hotspots in the A-, B-, and C-rings, including a prodrug analog (SUW427) and a negative control (SUW426). Several analogs exhibited binding affinities to PKC-p and PKC-b isoforms that are comparable to bryostatin 1 and EBC-46, and two (SUW402 and SUW431) exhibited remarkable affinities in the picomolar range. Several analogs (SUW421 , SUW424, SUW428, and SUW430) showed PKC isoform selectivities substantially different from EBC-46 (2.3x preference for PKC- P) with selectivities ranging from a 6x to 40x preference for binding PKC-P over PKC-6, representing unprecedented selectivities and progress nearing the long-sought goal of PKC isoform-selective modulation. These function-oriented synthesis results underscore the fact that nature’s compounds are great leads but are not evolved or optimized for human therapeutic indications.

[0269] Complementing our evaluation of the affinities of our compounds in cell-free PKC isoform binding assays and the ability of our compounds to enter cells and activate PKC in PKC-GFP translocation assays, we next conducted an NF-KB reporter assay in A549 cells as a high- throughput method of screening compounds for functional activity relevant to latency reversal. We observed that the performance of our analogs in this assay was strongly correlated with their performance in both the cell-free binding assay and in vitro J-Lat latency reversal assay. All thetested compounds (excluding the non-PKC binding negative control compound SUW426) induced HIV expression from latency in J-Lat cells, and, of particular consequence with respect to “kick and kill’’ approaches, the maximum level of latency reversal achieved with these compounds (>90%) greatly exceeds that induced by bryostatin 1 (12%), a leading LRA taken into a clinical trial but dosed too low to detect activity. Although some analogs have remarkable isoform- selective affinity to PKC-p, these highly selective activators showed less potent activity in the in vitro NF-KB reporter assay and the J-Lat latency reversal assay, suggesting that activation of PKC-5 is more important than activation of PKC-P for HIV latency reversal, an observation in line with previous work. Notably, SUW431 represents an ultrapotent latency reversal agent that effectively activates latent HIV at substantially lower concentrations than EBC-46, and structurally simplified analogs of EBC-46 (e.g., SUW400) demonstrate the potential for more synthetically accessible derivatives of EBC-46, such as unexplored C-ring derivatives of SUW400, to have superior functional activities.

[0270] Notably, SUW133 (a simplified bryostatin 1 analog with a wider therapeutic window than its parent compound) was capable of delaying rebound when administered alone to HIV-infected, ART-treated humanized mice and was even more effective when natural killer cells were also introduced as a “kill” arm, resulting in 40% of the animals not rebounding in vivo after ART discontinuation for the duration of the study. Given this recent success and the strong in vitro efficacy of EBC-46 and its highly accessible analogs identified in the current study, these new molecules are potentially superior lead compounds as LRAs for “kick and kill” approaches to HIV eradication. Although EBC-46 is Food and Drug Administration approved for treating cancers using a direct injection into solid tumors, the compatibility of EBC-46 and its analogs in a systemic drug administration approach has not yet been explored but is warranted by these studies. Future in vivo studies will be necessary to investigate the utility of EBC-46 and its analogs as effective LRAs for the “kick and kill” approach toward HIV eradication. This study shows that readily accessible EBC-46 analogs are notably more effective as LRAs in vitro than bryostatin 1, a lead LRA, strongly warranting their further in vivo study in “kick and kill” approaches to HIV eradication.Example 6: Siloxy CompoundsSUW429 preparation (silylation and deprotection)

[0271] To a flame dried vial equipped with a stir bar was added 2 (28.5 mg, 0.055 mmol, 1 equiv) and DMF (0.5 ml_). TBSCI (66.0 mg, 0.438 mmol, 8 equiv) and imidazole (37.3 mg, 0.547 mmol, 10 equiv) were added directly as solids. The reaction mixture was sonicated until homogenous. The headspace of the reaction vessel was displaced with argon and the reaction was stirred at 70 °C for 36 hr. TLC analysis indicated consumption of 2 and formation of SI-20. The reaction was quenched with NH4CI (10 mL). The aqueous layer was extracted with ether (10 mL). The organic layer was washed with water (10 mL) to remove DMF. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was azeotroped with heptane (2x50 mL) to remove residual DMF. The resulting intermediate SI-20 was transferred to a new vial with DCM and concentrated. Crude SI-20 was used directly in the next step.

[0272] To a vial containing crude SI-20 equipped with a stir bar was added MeCN (1.5 mL). TsOH in water (0.42 M, 0.5 mL) was added (final TsOH concentration of 0.105 M). The reaction mixture was stirred at rt for 24 hr. TLC analysis indicated complete consumption of SI-20. The reaction was quenched with sat. NaHCOs (15 mL) and diluted with brine (15 mL). The aqueous layer was extracted with EtOAc (2x15 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-50% EtOAc / Hex, 1x7 cm) affording SUW429 as a white solid (17.5 mg, 54% yield over 2 steps). Compound purity was established by TLC (one spot) analysis.

[0273] SUW429 TLC Rf= 0.33 (60% EtOAc / Hex, UV active, blue spot in p-anisaldehyde);1H NMR (400 MHz, CDCI3) 0 7.75 (dd, J = 2.8, 1.5 Hz, 1H), 5.99 (s, 1 H), 4.22 (d, J = 2.8 Hz, 1 H), 4.05-3.99 (m, 1 H), 3.92-3.83 (m, 2H), 3.88 (d, J = 12.4 Hz, 1H), 3.79 (d, J = 12.4 Hz, 1 H), 3.53 (s, 1 H), 3.26 (s, 1 H), 3.15 (d, J = 6.7 Hz, 1 H), 2.42 (app sex, J = 7.0 Hz, 1 H), 2.16 (br s), 1.82- 1.69 (m, 5H), 1.52-1.41 (m, 1 H), 1.25 (s, 3H), 1.22-1.16 (m, 7H), 1.00 (d, J = 6.5 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (s, 9H), 0.14 (s, 3H), -0.01 (s, 3H);13C NMR (126 MHz, CDCI3, 31 peakstotal) 5 210.3, 179.0, 165.3, 133.5, 77.8, 77.4, 72.5, 72.0, 67.7, 65.7, 64.8, 61.7, 49.2, 49.0, 41.7, 36.2, 35.9, 26.6, 26.2, 25.9 (3 peaks), 24.0, 18.2, 17.4, 16.9, 16.0, 12.0, 9.9, -4.2, -5.7; HRMS calculated for C3iH5iO9Si+[M+H]+: 595.3297; found 595.3291 ; FTIR (ATR) 3359 (br), 2956, 2924, 2852, 1716, 1661 , 1464, 1259, 1082, 1020, 798, 669 cm'1; [a]23D= 9° (c = 0.04, CH2CI2).

[0274] Protected SUW429: HRMS calculated for C34H55O9Si+[M+H]+: 635.3610; found 635.3603;FTIR (ATR) 3410 (br), 2958, 2922, 2852, 1716, 1462, 1377, 1225, 1082, 835, 744, 669 crtr1;[a]23D= 42 (C = 0.10, CH2CI2).SUW433 preparation (acetate deprotection, monoacetylation, and TBS protection)

[0275] To a vial equipped with a stir bar was added 3 (105 mg, 0.202 mmol, 1.0 equiv). A solution of cesium carbonate (55 mg) was prepared in methanol (4 mL) and sonicated to dissolution. This basic solution of methanol was added directly to the reaction vessel as a single portion. The reaction mixture was stirred at rt for 16 hours. TLC analysis indicated complete conversion to intermediate SI-1. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-1 was transferred to a new vial with DCM / EtOAc and concentrated. Crude SI-1 was used directly in the next step.

[0276] To a vial containing crude SI-1 equipped with a stir bar was added anhydrous THF (2 mL). Acetic anhydride (1.0 mL) and triethylamine (1.0 mL) were added directly each as one portion. The reaction was stirred at rt for 1 hour. TLC analysis indicated complete consumption of SI-1. The reaction was quenched with methanol (1 mL) and diluted with NH4CI (5 mL) and brine (5 mL). The aqueous layer was extracted with DCM (2x10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-2 was transferred to a new vial with DCM and concentrated. Crude SI-2 was used directly in the next step.

[0277] To a vial containing crude SI-2 equipped with a stir bar was added DMF (1 mL). Imidazole (165 mg) and TBS-CI (304 mg) were added sequentially as solids as single portions. Theheadspace of the vial was evacuated with argon. The reaction was sealed with a Teflon cap and heated to 70 °C for 20 hours. TLC analysis indicated complete consumption of SI-2 (the TLC plate must be placed under high vacuum for 3 minutes to remove DMF before running). The reaction was quenched with NH4CI (20 ml_). The aqueous layer was extracted with EtOAc (20 mL). The organic layer was dried over Na2SC>4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (5-30% EtOAc / Hex, 1x7 cm) affording intermediate SI- 21 as a white solid (72.8 mg, 61% yield over 3 steps). Compound purity was established by TLC (one spot) analysis.

[0278] Diol TLC Rf = 0.26 (50% Acetone / Hex, UV active, dark green spot in p-anisaldehyde); monoacetate TLC Rf = 0.21 (50% EtOAc / Hex, UV active, dark green spot in p-anisaldehyde); protected 433 TLC Rf = 0.56 (40% EtOAc / Hex, UV active, blue / black spot in p-anisaldehyde);1H NMR (400 MHz, CDCI3) 6 7.59 (dd, J = 2.7, 1.4 Hz, 1 H), 5.64 (s, 1 H), 4.09 (s, 1 H), 3.97 (app t, J = 2.7 Hz, 1 H), 3.94 (d, J = 12.9 Hz, 1 H), 3.88 (d, J = 9.1 Hz, 1 H), 3.57 (d, J = 12.9 Hz, 1 H), 3.12 (d, J = 6.7 Hz, 1 H), 2.96 (s, 1H), 2.11 (s, 3H), 1.77-1.69 (m, 4H), 1.48 (s, 3H), 1.45 (s, 3H), 1.25 (d, J = 5.6 Hz, 1 H), 1.23 (s, 3H), 1.22 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.86 (s, 9H), 0.11 (s, 3H), 0.00 (s, 3H).;13C NMR (101 MHz, CDCh, 31 peaks total) 5 206.4, 173.2, 161.9, 133.7, 101.2, 77.7, 77.0, 72.8, 68.7, 68.0, 65.8, 65.6, 60.3, 49.4, 48.6, 36.4, 35.1 , 25.9 (4 peaks), 25.0, 24.1 , 22.3, 21.3, 18.2, 17.2, 15.7, 10.1 , -4.3, -5.5; HRMS calculated for C27H46NO9Si+[M+NH4]+: 556.2942; found 556.4421.SUW433 preparation (acetonide deprotection)

[0279] To a vial equipped with a stir bar was added SI-21 (17.0 mg, 28.7 pmol, 1 equiv). A solution of PPTS (65 mg) was prepared in methanol (1 mL). This acidic solution of methanol was added directly to the reaction vessel as a single portion. The reaction was sealed with a Teflon cap and heated to 60 °C for 6 hours. TLC analysis indicated complete consumption of SI-21. The reactionwas quenched with sat. NaHCOs (10 mL). The aqueous layer was extracted with EtOAc (2x10 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10- 65% EtOAc / Hex, 1x7 cm) affording SUW433 as a white solid (10.4 mg, 66% yield). Compound purity was established by TLC (one spot) analysis.

[0280] SUW433 TLC Rf= 0.17 (30% Acetone / Hex, UV active, dark blue spot in p-anisaldehyde);1H N MR (400 MHz, CDCI3) <5 7.74 (dd, J = 2.6, 1.4 Hz, 1 H), 5.71 (s, 1H), 4.21 (app d, J = 3.1 Hz, 1 H), 4.01 (app t, J = 2.9 Hz, 1 H), 3.92-3.83 (m, 3H), 3.78 (dd, J = 12.4, 6.0 Hz, 1 H), 3.53 (d, J = 1.1 Hz, 1H), 3.26 (s, 1 H), 3.15 (d, J = 6.6 Hz, 1 H), 2.17 (dd, J = 7.9, 6.0 Hz, 1H), 2.12 (s, 3H), 1.79-1.71 (m, 4H), 1.26 (d, J = 6.6 Hz, 1 H), 1.23 (s, 3H), 1.20 (s, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), 0.01 (s, 3H).;13C NMR (126 MHz, CDCI3, 28 peaks total) 5210.2, 173.3, 165.3, 133.4, 77.7, 77.4, 72.5, 71.9, 68.0, 65.6, 64.8, 61.8, 49.3, 48.7, 36.2, 35.5, 26.0, 25.9 (3 peaks), 24.0, 21.4, 18.3, 17.1, 15.8, 9.9, -4.3, -5.5.SUW434 preparation (deacetylation, esterification, and acetonide deprotection)

[0281] To a vial equipped with a stir bar was added SI-21 (13.2 mg, 22.3 pmol, 1.0 equiv). A solution of cesium carbonate (20 mg) was prepared in methanol (1 mL) and sonicated to dissolution. This basic solution of methanol was added directly to the reaction vessel as a single portion. The reaction mixture was stirred at rt for 20 hours. TLC analysis indicated complete conversion to intermediate SI-22. The reaction was quenched with sat. NH4CI (5 mL). The aqueous layer was extracted with EtOAc (2x5 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI- 22 was transferred to a new vial with DCM and concentrated. Crude SI-22 was used directly in the next step.

[0282] To a flame dried vial equipped with a stir bar was added 1 -naphthylacetic acid (8.7 mg), triethylamine (11.3 mg), and trichlorobenzoyl chloride (10.9 mg) followed by anhydrous toluene (0.5 mL). This mixture was stirred at rt for 2 hours. Crude SI-22 was dissolved in anhydrous toluene in a separate vial equipped with a stir bar. The substrate solution was added to the previously described solution of in situ generated mixed anhydride in one portion followed by addition of DMAP (6 mg). The reaction mixture was stirred at 4 °C for 18 hours. TLC analysis indicated incomplete consumption of SI-22, so another 2 equivalents of activated acid were prepared as previously described. This second portion of in situ generated mixed anhydride was added to the reaction as a single portion. The reaction mixture was stirred at 4 °C for another 18 hours. TLC indicated complete consumption of SI-22. The reaction was quenched with sat. NaHCC (10 mL). The aqueous layer was extracted with EtOAc (2x10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-23 was transferred to a new vial with DCM and concentrated. Crude SI-23 was used directly in the next step.

[0283] To a vial containing crude SI-23 equipped with a stir bar was added MeCN (0.750 mL). TsOH in water (0.42 M, 0.750 mL) was added (final TsOH concentration of 0.21 M). The reaction was stirred at rt for 48 hours. TLC analysis indicated complete consumption of SI-23. The reaction was quenched with sat. NaHCOa (10 mL). The aqueous layer was extracted with EtOAc (2x10 mL). Solid NaCI (1 g) was added to the aqueous layer during each EtOAc extraction to remove product from the aqueous layer. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (5- 25% Acetone / Benzene, 0.5x7 cm) affording SUW434 as a colorless oil (9.3 mg, 61 % yield over 3 steps). Compound purity was established by TLC (one spot) analysis.

[0284] 12-tbs 13-OH TLC Rf = 0.30 (40% EtOAc / Hex, UV active, blue / black spot in p- anisaldehyde); Protected 434 TLC Rf = 0.25 (50% Ether / Hex, UV active, blue / black spot in p- anisaldehyde); SUW434 TLC Rf = 0.35 (30% Acetone / Toluene, UV active, blue / black spot in p- anisaldehyde);1H NMR (500 MHz, CDCI3) 5 7.96 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 7.9 Hz, 1 H), 7.72 (app s, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.4 Hz, 1 H), 7.46- 7.38 (m, 2H), 5.71 (s, 1H), 4.18 (d, J = 2.9 Hz, 1 H), 4.15 (d, J = 15.3 Hz, 1 H), 4.09 (d, J = 15.4 Hz, 1 H), 3.98 (s, 1 H), 3.89-3.80 (m, 3H), 3.75 (dd, J = 12.5, 5.5 Hz, 1 H), 3.48 (s, 1 H), 3.16 (s, 1 H), 3.07 (d, J = 6.7 Hz, 1 H), 2.11 (app t, J = 7.2 Hz, 1 H), 1.75 (app s, 3H), 1.74-1.66 (m, 1 H), 1.08 (s, 3H), 1 .06 (d, J = 6.7 Hz, 1 H), 0.96 (d, J = 6.4 Hz, 3H), 0.82 (s, 9H), 0.73 (s, 3H), -0.06 (s, 3H), -0.13 (s, 3H);13C NMR (126 MHz, CDCI3, 38 peaks total) 5210.2, 173.9, 165.3, 134.0, 133.4,132.1 , 129.4, 129.0, 128.6, 128.6, 126.9, 126.2, 125.6, 123.7, 77.6, 77.3, 72.5, 71.9, 68.5, 65.5, 64.6, 61.7, 49.2, 48.8, 39.9, 36.1 , 35.5, 26.4, 25.8 (3 peaks), 23.3, 18.2, 17.2, 15.9, 9.9, -4.5, - 5.9.; HRMS calculated for CssHsiOgS [M+H]+: 679.3297; found 679.3298.SUW432 preparation (silylation and deprotection)

[0285] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DMF (1.0 mL). TBSCI (60.3 mg, 0.40 mmol, 9.8 equiv) and imidazole (27.2 mg, 0.40 mmol, 9.8 equiv) were added directly as solids. The reaction mixture was sonicated until homogenous. The reaction was stirred at 70 °C for 24 hours. TLC analysis indicated consumption of SI-24 and formation of SI-25. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-25 was transferred to a new vial with DCM and concentrated. Crude SI-25 was used directly in the next step.

[0286] To a vial containing crude SI-25 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4 (2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-25 and formation of SUW432. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 1.5x16 cm) affording SUW432 as a colorless solid (18.2 mg, 87% yield). Compound purity was established by TLC (one spot) analysis.

[0287] 1H NMR (400 MHz, CDCI3) 6 7.60 (dd, J = 2.5, 1 .4 Hz, 1 H), 5.66 (dd, J = 5.8, 1.2 Hz, 1 H),5.45 (s, 1 H), 4.07-3.95 (m, 2H), 3.92 (d, J = 9.4 Hz, 1 H), 3.21 (m, 2H), 2.53 (d, J = 19.3 Hz, 1 H),2.46 (d, J = 18.9 Hz, 1 H), 2.12 (s, 3H), 2.11-2.08 (m, 1 H), 1.94 (dq, J = 13.3, 7.0 Hz, 1 H), 1.77(dd, J= 3.0, 1.4 Hz, 3H), 1.21 (s, 3H), 1.21 (s, 3H), 1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 5.1 Hz, 1 H) 0.88 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H);13C NMR (126 MHz, CDCI3, 28 peaks total) 5 209.4, 173.6, 161.3, 140.5, 132.8, 129.7, 78.6, 77.5, 73.8, 68.2, 67.9, 56.4, 46.1 , 39.1 , 38.7, 35.9, 25.9 (3 peaks total), 25.4, 24.2, 21.4, 18.3, 16.9, 15.2, 10.2, -4.3, -5.4; HRMS calculated for C28H48NO7Si+[M+NH4]+: 538.3200; found 538.3193.SUW435 preparation (silylation and deprotection)

[0288] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DMF (1.0 ml_). pentamethylsilyl chloride (66.7 mg, 0.40 mmol, 9.8 equiv) and imidazole (27.2 mg, 0.40 mmol, 9.8 equiv) were added directly as solids. The reaction mixture was sonicated until homogenous. The reaction was stirred at rt °C for 2 hours. TLC analysis indicated consumption of SI-24 and formation of SI-26. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-26 was transferred to a new vial with DCM and concentrated. Crude SI-26 was used directly in the next step.

[0289] To a vial containing crude SI-26 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4(2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-26 and formation of SUW435. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 1.5x16 cm) affording SUW435 as a colorless solid (19.0 mg, 88% yield). Compound purity was established by TLC (one spot) analysis.

[0290] 1H NMR (400 MHz, CDCI3) 6 7.60 (dd, J = 2.3, 1.4 Hz, 1 H), 5.66 (app d, J = 5.8 Hz, 1 H), 5.48 (s, 1H), 4.07-3.94 (m, 2H), 3.88 (d, J = 9.4 Hz, 1 H), 3.23-3.18 (m, 2H), 2.53 (d, J = 19.3 Hz, 1H), 2.45 (d, = 18.9 Hz, 1 H), 2.13 (s, 3H), 1.95-1.87 (m, 1 H), 1.78 (dd, J= 2.9, 1.4 Hz, 3H), 1.21 (s, 3H), 1.18 (s, 3H), 0.99 (d, J = 6.1 Hz, 3H), 0.99 (d, J = 6.1 Hz, 1 H) 0.23 (s, 3H), 0.18 (s, 3H), 0.06 (s, 9H);13C NMR (126 MHz, CDCI3, 27 peaks total) 5 209.3, 173.6, 161.3, 140.4, 132.8, 129.8, 78.5, 77.7, 73.8, 68.3, 67.8, 56.5, 46.1 , 39.1 , 38.7, 36.0, 25.5, 24.2, 21.5, 16.8, 15.2, 10.2, 0.4, -0.8, -2.2 (3 peaks); HRMS calculated for C27H48NO7Si2+[M+NH4]+: 554.2969; found 554.2962.SUW436 preparation (silylation and deprotection)

[0291] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DMF (1.0 mL). 1 -(trimethylsilyl)imidazole (56.1 mg, 0.408 mmol, 9.8 equiv) was added directly. The reaction was stirred at rt for 2 hours. TLC analysis indicated consumption of SI-24 and formation of SI-27. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-27 was transferred to a new vial with DCM and concentrated. Crude SI-27 was used directly in the next step.

[0292] To a vial containing crude SI-27 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4(2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-27 and formation of SUW436. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 1.5x16 cm) affording SUW436 as a colorless solid (17.1 mg, 89% yield). Compound purity was established by TLC (one spot) analysis.

[0293] 1H NMR (500 MHz, CDCh) 6 7.57 (dd, = 2.6, 1.3 Hz, 1 H), 5.66 (dd, J = 5.9, 2.1 Hz, 1 H), 5.48 (s, 1 H), 4.02 (d, J = 13.0 Hz, 1 H), 3.96 (d, J = 13.0 Hz, 1 H), 3.90 (d, J = 9.5 Hz, 1 H), 3.23 (app t, J = 5.6 Hz, 1 H), 3.19 (app t, J = 2.9 Hz, 1 H), 2.66 (s, 1H), 2.55 (d, J = 19.0 Hz, 1 H), 2.45 (d, J = 19.0 Hz, 1 H), 2.11 (s, 3H), 1.94 (dq, J = 9.4, 6.5 Hz, 1 H), 1.74 (dd, J = 3.0, 1.3 Hz, 3H), 1.20 (s, 3H), 1.20 (s, 3H), 1.00 (d, J = 5.2 Hz, 1 H), 0.97 (d, = 6.5 Hz, 3H), 0.10 (s, 9H);13C NMR (126 MHz, CDCh, 25 peaks total) 6 209.4, 173.5, 161.3, 140.4, 132.8, 129.7, 78.4, 77.3, 73.8, 68.2, 67.8, 56.4, 45.9, 39.2, 38.7, 35.9, 25.5, 24.2, 21.4, 16.8, 15.0, 10.2, 0.2 (3 peaks); HRMS calculated for C25H42NO7Si+[M+NH4]+: 496.2731 ; found 496.2725SUW437 preparation (silylation and deprotection)

[0294] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DCM (1.0 mL). 2,6-lutidine (6.4 mg, 0.060 mmol, 1.5 equiv) and triethylsilyl trifluoromethanesulfonate (15.9 mg, 0.0602 mmol, 1.5 equiv) were added directly. The reaction was stirred at rt for 10 minutes. TLC analysis indicated consumption of SI-24 and formation of SI- 28. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SC>4, filtered, and concentrated. The resulting intermediate SI-28 was transferred to a new vial with DCM and concentrated. Crude SI-8 was used directly in the next step.

[0295] To a vial containing crude SI-28 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4(2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-28 and formation of SUW437. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 1.5x16 cm) affording SUW437 as a colorless solid (19.4 mg, 93% yield). Compound purity was established by TLC (one spot) analysis.

[0296] 1H NMR (500 MHz, CDCI3) 6 7.59 (app s, 1 H), 5.66 (app d, J = 5.6 Hz, 1 H), 5.45 (s, 1 H), 4.03 (d, J = 13.0 Hz, 1 H), 3.98 (d, J = 11.7 Hz, 1 H), 3.95 (d, J = 9.3 Hz, 1 H), 3.23-3.19 (m, 2H), 2.54 (d, J = 19.1 Hz, 1 H), 2.46 (d, J = 18.9 Hz, 1 H), 2.31 (s, 1 H), 2.12 (s, 3H), 1.94 (dq, J = 13.0, 7.3 Hz, 1 H), 1 .76 (app s, 3H), 1.21 (s, 6H), 1 .01 (d, J = 6.5 Hz, 3H), 0.99 (d, J = 5.2 Hz, 1 H), 0.96 (t, J = 8.0, 9H), 0.60 (q, J = 7.9 Hz, 6H);13C NMR (126 MHz, CDCI3, 28 peaks total) 5 209.4, 173.6, 161.4, 140.5, 132.7, 129.7, 78.5, 77.2, 73.8, 68.2, 68.0, 56.4, 46.1 , 39.1 , 38.7, 36.0, 25.4, 24.2, 21.4, 16.8, 15.2, 10.2, 7.0 (3 peaks), 5.0 (3 peaks); HRMS calculated for C28H48NO7Si+[M+NH4]+: 538.3200; found 538.3194.SUW439 preparation (silylation and deprotection)

[0297] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DMF (1.0 mL). n-butyldimethylsilyl chloride (24.1 mg, 0.160 mmol, 4 equiv) and imidazole (10.9 mg, 0.160 mmol, 4 equiv) were added directly as solids. The reaction mixture was sonicated until homogenous. The reaction was stirred at rt for 2 hours. TLC analysis indicated consumption of SI-24 and formation of SI-29. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-29 was transferred to a new vial with DCM and concentrated. Crude SI-29 was used directly in the next step.

[0298] To a vial containing crude SI-29 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4(2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-29 and formation of SUW439. The reaction was quenched with sat. NH4CI (20 mL). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex,1.5x16 cm) affording SUW439 as a colorless solid (20.5 mg, 98% yield). Compound purity was established by TLC (one spot) analysis.

[0299] 1H NMR (400 MHz, CDCh) 6 7.63 (dd, J = 2.4, 1.4 Hz, 1 H), 5.68 (app d, J = 5.6 Hz, 1 H), 5.48 (s, 1 H), 4.06 (d, J = 13.0 Hz, 1 H), 4.01 (d, J = 13.1 Hz, 1 H), 3.94 (d, J = 9.4 Hz, 1 H), 3.26- 3.20 (m, 2H), 2.55 (d, J = 19.1 Hz, 1 H), 2.48 (d, J = 19.0 Hz, 1 H), 2.15 (s, 3H), 2.13 (s, 1 H), 2.00- 1.91 (m, 1 H), 1.80 (dd, J = 2.9, 1.4 Hz, 3H), 1.37-1.30 (m, 4H), 1.23 (s, 3H), 1.22 (s, 3H), 1.03 (d,

[0300] To a flame dried vial equipped with a stir bar was added SI-24 (20.0 mg, 0.0408 mmol, 1 equiv) and DMF (1.0 ml_). t-hexyldimethylsilyl chloride (71.5 mg, 0.40 mmol, 9.8 equiv) and N- methylimidazole (32.8 mg, 0.40 mmol, 9.8 equiv) were added directly. The reaction mixture was sonicated until homogenous. The reaction was stirred at 80 °C for 24 hours. TLC analysis indicated consumption of SI-24 and formation of SI-30. The reaction was quenched with sat. NH4CI (20 ml_). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. The resulting intermediate SI-30 was transferred to a new vial with DCM and concentrated. Crude SI- 30 was used directly in the next step.

[0301] To a vial containing crude SI-30 equipped with a stir bar was added THF (1.0 mL). Pd(PPh3)4(2.3 mg, 2.0 pmol, 5 mol%) and diethylamine (14.6 mg, 0.20 mmol, 4.9 equiv) were added directly as single portions. The reaction was stirred at rt for 12 hours. TLC analysis indicated consumption of SI-30 and formation of SUW441. The reaction was quenched with sat.NH4CI (20 ml_). The aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x30 mL), dried over Na2SO4, filtered, and concentrated. Purification was accomplished by silica gel flash column chromatography (10-40% EtOAc / Hex, 1.5x16 cm) affording SUW441 as a colorless solid (14.5 mg, 66% yield). Compound purity was established by TLC (one spot) analysis.

[0302] HRMS calculated for C3oH52N07Si+[M+NH4]+: 566.3513; found 566.3509.

[0303] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the abovedescribed embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.REFERENCES1. Abdelnabi, R. et al. Comparative analysis of the anti-chikungunya virus activity of novel bryostatin analogs confirms the existence of a PKC-independent mechanism. (2016) doi:10.1016 / j.bcp.2016.09.020.2. Abrial, E. et al. A role for the PKC signaling system in the pathophysiology and treatment of mood disorders: involvement of a functional imbalance? Molecular Neurobiology 44:407-419 (2011).3. 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Claims

CLAIMSWhat is claimed is:

1. A compound having Formula I or a pharmaceutically acceptable salt thereof:Formula I; wherein Ri is hydrogen, a linear or branched C1-C10 alkoxy group, linear or branched C1-C10 alkyl or alkenyl ester optionally substituted with C3-C6 cycloalkyl or heterocycloalkyl group, or a linear or branched siloxy group; wherein R2is a C1-C10 alkyl group, a C6-C12 alkylaryl or arylalkyl group, or a C3-C6 cycloalkyl or heterocycloalkyl group optionally substituted with a C1-C4 alkyl group; wherein R3and R4together form an epoxide, or are both H, or wherein a bond marked by * is a double bond, R4is absent, and R3is H; wherein R5is hydrogen, a linear or branched C1-C10 alkyl or alkenyl group, or is a substituted or unsubstituted benzyloxycarbonyl group; wherein R6is OH or H; wherein R7is a ketone, a C1-C10 linear or branched alkyl or alkenyl ester, linear or branched siloxy group, a C1-C10 carbamate, or a C6-C10 aryl ester; and wherein the bond marked by * is a double bond or a single bond.

2. The compound of claim 1, wherein Ri is a linear or branched siloxy group comprising one or more alkyl groups bonded to a silicon molecule in the siloxy group.

3. The compound of claim 2, wherein the one or more alkyl groups comprise methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or any combination thereof.

6. The compound or salt of claim 1, wherein R3and R4together form7. The compound or salt of claim 1, wherein R4 is absent and R3 is H.

8. The compound or salt of claim 1, wherein R5 is hydrogen, methyl, or9. The compound or salt of claim 1, wherein Re is OH.10 The compound or salt of claim 1 , wherein R6is hydrogen.

11. The compound or salt of claim 1 , wherein R7is selected from12. The compound or salt of claim 1 , wherein the bond marked by * is a double bond.

13. The compound or salt of claim 1 , wherein the bond marked by * is a single bond.

14. The compound of claim 1 , wherein the compound is selected from15. A pharmaceutical composition comprising a therapeutically effective amount of the compound or salt of any one of claims 1-14.

16. The pharmaceutical composition of claim 15, further comprising at least one pharmaceutically acceptable excipient, diluent, or carrier.

17. A method for treating a disease or disorder in a subject, the method comprising administering the pharmaceutical composition of claim 13 to the subject.

18. The method of claim 17, wherein the subject is a human.

19. The method of claim 17, wherein the disease or disorder comprises a neurological disorder, cancer, a cardiovascular disease or disorder, a viral disease, a metabolic disease or disorder, rejection of a transplanted organ, or any combination thereof.

20. The method of claim 19, wherein the neurological disorder comprises a mood disorder, bipolar disorder, Parkinson’s disease, or any combination thereof.

21. The method of claim 19, wherein the cancer comprises colorectal cancer, melanoma, squamous cell carcinoma, a head and neck solid tumor, or any combination thereof.

22. The method of claim 19, wherein the cardiovascular disease or disorder comprisesstroke.

23. The method of claim 19, wherein the viral disease comprises HIV.

24. The method of claim 19, wherein the metabolic disease or disorder comprises diabetes.

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