Eupenifeldin derivatives and methods of making and using thereof

Abstract

Provided herein are eupenifeldin derivatives, compositions comprising these eupenifeldin derivatives, and methods of using thereof for the treatment of cancer, parasitic infections (e.g., malaria), fungal infections, and bacterial infections.

Description

[0001] Eupenifeldin Derivatives and Methods of Making and Using Thereof STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant Nos. CA125066 and AT008938 awarded by the National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of U.S. Provisional Application No. 63 / 508,719, filed June 16, 2023, which is hereby incorporated herein by reference in its entirety. BACKGROUND Over the last century, secondary metabolites of natural origin have played a crucial role in the discovery of new chemotherapeutic agents, including those from plant, marine and microbial origins. During the period between 1981 and 2019, a total of 185 small molecules were approved for cancer management. Of these, 75% were either natural products, derived from natural products, or inspired by natural products. In reality, however, natural products are rarely employed unchanged in clinical applications, with the natural products themselves representing less than 4% of all the approved drugs (and ~7% of cancer drugs). In most cases, therefore, structural modification of the parent structure is an essential step in its development. Semisynthetic modification can improve selectivity, pharmacological activity, physicochemical properties, and / or the pharmacokinetic profile of the parent natural product, while simultaneously creating patentable compounds. As natural products are a rich source of chemical diversity and pharmacological activity, generating semisynthetic derivatives of natural products is a practical approach to study their structure-activity relationship (SAR), explore their application in disease management, and improve their drug-like properties. This strategy has facilitated the introduction of 356 semisynthetic drugs of natural origin into the market, accounting for ~19% of the newly approved drugs between 1981-2019. In cancer chemotherapy, 23% of the approved small molecule anticancer drugs between the same period were semisynthetic derivatives. Accordingly, there is a significant interest in exploring derivatives of natural products in an effort to develop new active agents, including anticancer agents. SUMMARY Provided herein are eupenifeldin derivatives as well as methods of making and using thereof. For example, provided herein are compounds defined by Formula I Formula I or a pharmaceutically acceptable salt, prodrug, and / or tautomer thereof, wherein R1is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R2is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R3is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rais selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rband Rcare independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; and each RAis independently selected from OH, NO2, CN, N3, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1- 4 alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino; with the proviso that at least one of R1, R2, and R3is not hydrogen. In some embodiments, R3is hydrogen. In other embodiments, R3is carbonyl (-C(=O)-Rd). In some of these embodiments, Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some examples, R3is selected from one of the following In certain embodiments, R3is selected from one of the following . In some embodiments, R1and R2are each independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)-NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, R1and R2are identical. In some embodiments, R1, R2, or a combination thereof are selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, and alkyleneoxy, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, R1and R2are each selected from C1-6alkyl, C2-6alkynyl, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following In some embodiments, R1and R2are each sulfonyl (-S(=O)2-Ra). In some embodiments, R1and R2are each selected from C1-6alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, C1-4haloalkylsulfonyl, C3-10cycloalkylsulfonyl, 6-10 membered arylsulfonyl, 5-10 membered heteroarylsulfonyl, 4-10 membered heterocycloalkylsulfonyl, C3-10cycloalkyl-C1-4alkylenesulfonyl, 4-10 membered heterocycloalkyl-C1-4alkylenesulfonyl, 6-10 membered aryl- C1-4alkylenesulfonyl, 5-10 membered heteroaryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylsulfonyl, 6-10 membered arylsulfonyl, and 6-10 membered aryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following In some embodiments, R1and R2are each carbamyl (-C(=O)-NRbRc). In some embodiments, R1and R2are each selected from C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, C1-6alkenylcarbamyl, di(C1-6alkenyl)carbamyl, C1-6alkynylcarbamyl, di(C1-6alkynyl)carbamyl, C1-6haloalkylcarbamyl, di(C1-6haloalkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, di(6-10 membered aryl)carbamyl, 5-10 membered heteroarylcarbamyl, di(5-10 membered heteroaryl)carbamyl, 4-10 membered heterocycloalkylcarbamyl, di(4-10 membered heterocycloalkyl)carbamyl, C3-10cycloalkyl-C1-4alkylenecarbamyl, di(C3-10cycloalkyl-C1-4alkylene)carbamyl, 6-10 membered aryl-C1-4alkylenecarbamyl, di(6-10 membered aryl-C1-4alkylene)carbamyl, 5-10 membered heteroaryl- C1-4alkylenecarbamyl, di(5-10 membered heteroaryl-C1-4alkylene)carbamyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbamyl, di(4-10 membered heterocycloalkyl-C1-4alkylene)carbamyl, alkyleneonycarbamyl, and di(alkyleneoxy)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, and di(6-10 membered aryl)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following In some embodiments, R1and R2are each carbonyl (-C(=O)-Rd). In some embodiments, R1and R2are each selected from C1-6alkylcarbonyl, C2-6alkenylcarbonyl, C2-6alkynylcarbonyl, C1-4haloalkylcarbonyl, C1-6alkoxycarbonyl, C3-10cycloalkylcarbonyl, 6-10 membered arylcarbonyl, 5-10 membered heteroarylcarbonyl, 4-10 membered heterocycloalkylcarbonyl, C3-10cycloalkyl-C1-4alkylenecarbonyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbonyl, 6-10 membered aryl-C1-4alkylenecarbonyl, 5-10 membered heteroaryl-C1-4alkylenecarbonyl, and alkyleneonycarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylcarbonyl, C1-6alkoxycarbonyl, and C3-10cycloalkylcarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from one of the following In some embodiments, R1, R2, R3, or any combination thereof, comprises a click motif (e.g., an ethylenically unsaturated moiety such as an alkyne). The click motif can then serve as a synthetic handle for further derivatization (e.g., via click chemistry). Also provided herein are pharmaceutical compositions comprising a eupenifeldin derivative described herein dissolved or dispersed in a pharmaceutically acceptable carrier. Also provided herein are methods of treating or preventing cancer in a subject in need thereof that comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the cancer. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer is selected from lymphoma, myeloid leukemia, bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung cancer, myeloma, ovarian cancer, cervical cancer, bone cancer, thyroid cancer, adrenal gland cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, skin cancer, liver cancer, testicular cancer, colon cancer, or breast cancer. In certain embodiments, the cancer is selected from melanoma and breast cancer. In some embodiments, the eupenifeldin derivative described herein or the pharmaceutical composition comprising the eupenifeldin derivative described herein is administered by one or more routes selected from the group consisting of buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral, and topical administration. In some embodiments, the eupenifeldin derivative described herein or the pharmaceutical composition comprising the eupenifeldin derivative described herein is administered in combination with an additional treatment for the cancer (e.g, radiotherapy, surgery, administration of one or more additional active agents, or a combination thereof). Also provided herein are methods for treating or preventing a parasitic infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the parasitic infection. In some examples, the parasitic infection is selected from leishmaniasis, malaria, human African trypanomiasis, babesiosis, Chagas disease, microsporidiosis, pneumocystosis, primary ameobic meningoenchephalitis, and toxoplasmosis. In certain examples, the parasitic infection comprises malaria. Also provided herein are methods for treating or preventing a fungal infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the fungal infection. Also provided herein are methods for treating or preventing a bacterial infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the bacterial infection. DESCRIPTION OF DRAWINGS Figure 1. Chemical structure of eupenifeldin (1). Figure 2. Structures of ester (2-6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-24 & 28) analogues of eupenifeldin accessed via semisynthesis. Figure 3. Structures of propargylic ether analogues and triazole products derived through subsequent click reactions (25-27 & 29-30, respectively). Tropolone rings that experienced tautomerism are shown in blue (if it occurred on the right ring) and red (if it occurred on the left ring). DETAILED DESCRIPTION Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. As used in this specification and the following claims, the terms “comprise” (as well as forms, derivatives, or variations thereof, such as “comprising” and “comprises”) and “include” (as well as forms, derivatives, or variations thereof, such as “including” and “includes”) are inclusive (i.e., open-ended) and do not exclude additional elements or steps. For example, the terms "comprise" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. Other than where noted, all numbers expressing quantities of ingredients, reaction conditions, geometries, dimensions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches. Accordingly, these terms are intended to not only cover the recited element(s) or step(s), but may also include other elements or steps not expressly recited. Furthermore, as used herein, the use of the terms “a”, “an”, and “the” when used in conjunction with an element may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. By “about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. 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. A range may be construed to include the start and the end of the range. For example, a range of 10% to 20% (i.e., range of 10%-20%) can includes 10% and also includes 20%, and includes percentages in between 10% and 20%, unless explicitly stated otherwise herein. As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. It is understood that when combinations, subsets, groups, etc. of elements are disclosed (e.g., combinations of components in a composition, or combinations of steps in a method), that while specific reference of each of the various individual and collective combinations and permutations of these elements may not be explicitly disclosed, each is specifically contemplated and described herein. “Administration" to a subject includes any route of introducing or delivering to a subject an agent. Administration can be carried out by any suitable route, including oral, topical, transcutaneous, transdermal, intra-joint, intra-arteriole, intradermal, intraventricular, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. "Concurrent administration", "administration in combination", "simultaneous administration" or "administered simultaneously" as used herein, means that the compounds are administered at the same point in time or essentially immediately following one another. In the latter case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. "Systemic administration" refers to the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject's body (e.g. greater than 50% of the body), for example through entrance into the circulatory or lymph systems. By contrast, "local administration" refers to the introducing or delivery to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject's body. Administration includes self-administration and the administration by another. As used herein, the term “controlled-release” or “controlled-release drug delivery” or “extended release” refers to release or administration of a drug from a given dosage form in a controlled fashion in order to achieve the desired pharmacokinetic profile in vivo. An aspect of “controlled” drug delivery is the ability to manipulate the formulation and / or dosage form in order to establish the desired kinetics of drug release. As used here, the terms “beneficial agent” and “active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like. When the terms “beneficial agent” or “active agent” are used, then, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, etc. “Therapeutic agent” refers to any composition that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “therapeutic agent” is used, or when a particular agent is specifically identified, it is to be understood that the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. "Inhibit," "inhibiting," and "inhibition" mean to decrease an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the complete ablation of the activity, response, condition, or disease. This may also include, for example, a 10% reduction in the activity, response, condition, or disease as compared to the native or control level. Thus, the reduction can be a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to native or control levels. “Inactivate”, “inactivating” and “inactivation” means to decrease or eliminate an activity, response, condition, disease, or other biological parameter due to a chemical (covalent bond formation) between the ligand and a its biological target. By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. As used herein, the terms “treating” or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder. The terms “treating” and “treatment” can also refer to reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying cause, prevention of the occurrence of symptoms and / or their underlying cause, and improvement or remediation of damage. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. For example, the terms “prevent” or “suppress” can refer to a treatment that forestalls or slows the onset of a disease or condition or reduced the severity of the disease or condition. Thus, if a treatment can treat a disease in a subject having symptoms of the disease, it can also prevent or suppress that disease in a subject who has yet to suffer some or all of the symptoms. As used herein, the term “preventing” a disorder or unwanted physiological event in a subject refers specifically to the prevention of the occurrence of symptoms and / or their underlying cause, wherein the subject may or may not exhibit heightened susceptibility to the disorder or event. By the term “effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect. The amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective’ amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an “effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts. An “effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. As used herein, a “therapeutically effective amount” of a therapeutic agent refers to an amount that is effective to achieve a desired therapeutic result, and a “prophylactically effective amount” of a therapeutic agent refers to an amount that is effective to prevent an unwanted physiological condition. Therapeutically effective and prophylactically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject. The term “therapeutically effective amount” can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect. The precise desired therapeutic effect will vary according to the condition to be treated, the tolerance of the subject, the drug and / or drug formulation to be administered (e.g., the potency of the therapeutic agent (drug), the concentration of drug in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art. As used herein, the term “pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term “pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. Also, as used herein, the term “pharmacologically active” (or simply “active”), as in a “pharmacologically active” derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. A “control” is an alternative subject or sample used in an experiment for comparison purposes. A control can be "positive" or "negative." As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, goats, sheep, pigs, dogs, cats, etc.), and birds (e.g., chickens, turkeys, songbirds, etc.). “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. Administration of the therapeutic agents can be carried out at dosages and for periods of time effective for treatment of a subject. In some embodiments, the subject is a human. The term “n-membered” where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-malkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, “Cn-malkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, “Cn-malkynyl” refers to an alkyl group having one or more triple carbon- carbon bonds and having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, the term “Cn-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan- 1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms. As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkoxycarbonyl” refers to a group of formula -C(O)O- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylcarbonyl” refers to a group of formula -C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylcarbonylamino” refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonylamino” refers to a group of formula -NHS(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonyl” refers to a group of formula -S(O)2NH2. As used herein, the term “Cn-malkylaminosulfonyl” refers to a group of formula -S(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminosulfonyl” refers to a group of formula -S(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminosulfonylamino” refers to a group of formula - NHS(O)2NH2. As used herein, the term “Cn-malkylaminosulfonylamino” refers to a group of formula - NHS(O)2NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminosulfonylamino” refers to a group of formula -NHS(O)2N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “aminocarbonylamino”, employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH2. As used herein, the term “Cn-malkylaminocarbonylamino” refers to a group of formula - NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-malkyl)aminocarbonylamino” refers to a group of formula -NHC(O)N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylcarbamyl” refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “thio” refers to a group of formula -SH. As used herein, the term “Cn-malkylsulfinyl” refers to a group of formula -S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-malkylsulfonyl” refers to a group of formula -S(O)2-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “amino” refers to a group of formula –NH2. As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms. In some embodiments, the aryl group is a substituted or unsubstituted phenyl. As used herein, the term “carbamyl” to a group of formula –C(O)NH2. As used herein, the term “carbonyl”, employed alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O). As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “di(Cn-m-alkyl)carbamyl” refers to a group of formula – C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. As used herein, “Cn-mhaloalkoxy” refers to a group of formula –O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)). Cycloalkyl groups also include cycloalkylidenes. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, or adamantyl. In some embodiments, the cycloalkyl has 6-10 ring-forming carbon atoms. In some embodiments, cycloalkyl is adamantyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six- membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six- membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring- forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring- forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3- position. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone – enol pairs, amide - imidic acid pairs, lactam – lactim pairs, enamine – imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In some embodiments, the compounds described herein can contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures (e.g., including (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, (+) (dextrorotatory) forms, (-) (levorotatory) forms, the racemic mixtures thereof, and other mixtures thereof). Additional asymmetric carbon atoms can be present in a substituent, such as an alkyl group. All such isomeric forms, as well as mixtures thereof, of these compounds are expressly included in the present description. The compounds described herein can also or further contain linkages wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds). Accordingly, all cis / trans and E / Z isomers and rotational isomers are expressly included in the present description. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms of that compound. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972), each of which is incorporated herein by reference in their entireties. It is also understood that the compounds described herein include all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography. Unless specifically defined, compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Unless otherwise stated, when an atom is designated as an isotope or radioisotope (e.g., deuterium, [11C], [18F]), the atom is understood to comprise the isotope or radioisotope in an amount at least greater than the natural abundance of the isotope or radioisotope. For example, when an atom is designated as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated. In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some example acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid. Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl and cyclohexyl substituted amides. In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds provided herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art. The expressions, “ambient temperature” and “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 ºC to about 30 ºC. The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002 The phrase “small molecule,” as used herein, refers to molecules, in particular active agents, having a molecular weight of less than 1000 Da (e.g., less than 800 Da, or less than 500 Da). The phrase ‘biologic drug’ includes any therapeutic agent, whether in discovery, formulation, or commercial production, derived from natural biological sources or synthesized to resemble or be equivalent to biological products. Biologic drugs include, but are not limited to, proteins of any sort, including monoclonal antibodies, polyclonal antibodies, polysaccharides, protein-polysaccharide complexes, oligopeptides, vaccines, lipid nanoparticles, viral capsids, nucleic acids, oligonucleotides, and polynucleic acids such as RNA and DNA. Also included are agents, not necessarily biological, which are used to enhance, functionalize, encapsulate, or deliver a biological agent, such as, but not limited to, encapsulation / delivery synthetic polymers, dendrimers, liposomes, vesicles, and micelles. Eupenifeldin Derivatives Described herein are eupenifeldin derivatives. Eupenifeldin derivatives can include compounds which share the same basic ring structure (referred to as a scaffold) as eupenifeldin, but include one or more different substituents on the eupenifeldin scaffold. For example, the eupenifeldin derivatives can comprise eupenifeldin, wherein one, two, or three of the hydroxy groups in the eupenifeldin molecule are chemically modified. For example, provided herein are compounds defined by Formula I Formula I or a pharmaceutically acceptable salt, prodrug, and / or tautomer thereof, wherein R1is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R2is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R3is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rais selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rband Rcare independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rdis selected from C1- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; and each RAis independently selected from OH, NO2, CN, N3, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1- 4 alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino; with the proviso that at least one of R1, R2, and R3is not hydrogen (i.e., the compound is not eupenifeldin, the structure of which is shown below). . In some embodiments, R3is hydrogen. In other embodiments, R3is carbonyl (-C(=O)-Rd). In some of these embodiments, Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some examples, R3is selected from one of the following . In some embodiments, R1and R2are each independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)-NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, R1and R2are identical. In some embodiments, R1, R2, or a combination thereof are selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, and alkyleneoxy, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, R1and R2are each selected from C1-6alkyl, C2-6alkynyl, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following . In some embodiments, R1and R2are each sulfonyl (-S(=O)2-Ra). In some embodiments, R1and R2are each selected from C1-6alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, C1-4haloalkylsulfonyl, C3-10cycloalkylsulfonyl, 6-10 membered arylsulfonyl, 5-10 membered heteroarylsulfonyl, 4-10 membered heterocycloalkylsulfonyl, C3-10cycloalkyl-C1-4alkylenesulfonyl, 4-10 membered heterocycloalkyl-C1-4alkylenesulfonyl, 6-10 membered aryl- C1-4alkylenesulfonyl, 5-10 membered heteroaryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylsulfonyl, 6-10 membered arylsulfonyl, and 6-10 membered aryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following In some embodiments, R1and R2are each carbamyl (-C(=O)-NRbRc). In some embodiments, R1and R2are each selected from C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, C1-6alkenylcarbamyl, di(C1-6alkenyl)carbamyl, C1-6alkynylcarbamyl, di(C1-6alkynyl)carbamyl, C1-6haloalkylcarbamyl, di(C1-6haloalkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, di(6-10 membered aryl)carbamyl, 5-10 membered heteroarylcarbamyl, di(5-10 membered heteroaryl)carbamyl, 4-10 membered heterocycloalkylcarbamyl, di(4-10 membered heterocycloalkyl)carbamyl, C3-10cycloalkyl-C1-4alkylenecarbamyl, di(C3-10cycloalkyl-C1-4alkylene)carbamyl, 6-10 membered aryl-C1-4alkylenecarbamyl, di(6-10 membered aryl-C1-4alkylene)carbamyl, 5-10 membered heteroaryl- C1-4alkylenecarbamyl, di(5-10 membered heteroaryl-C1-4alkylene)carbamyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbamyl, di(4-10 membered heterocycloalkyl-C1-4alkylene)carbamyl, alkyleneonycarbamyl, and di(alkyleneoxy)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, and di(6-10 membered aryl)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2and each selected from one of the following In some embodiments, R1and R2are each carbonyl (-C(=O)-Rd). In some embodiments, R1and R2are each selected from C1-6alkylcarbonyl, C2-6alkenylcarbonyl, C2-6alkynylcarbonyl, C1-4haloalkylcarbonyl, C1-6alkoxycarbonyl, C3-10cycloalkylcarbonyl, 6-10 membered arylcarbonyl, 5-10 membered heteroarylcarbonyl, 4-10 membered heterocycloalkylcarbonyl, C3-10cycloalkyl-C1-4alkylenecarbonyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbonyl, 6-10 membered aryl-C1-4alkylenecarbonyl, 5-10 membered heteroaryl-C1-4alkylenecarbonyl, and alkyleneonycarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from C1-6alkylcarbonyl, C1-6alkoxycarbonyl, and C3-10cycloalkylcarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In some embodiments, Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups. In certain embodiments, R1and R2are each selected from one of the following In some embodiments, R1, R2, R3, or any combination thereof, comprises a click motif (e.g., an ethylenically unsaturated moiety such as an alkyne). Examples of suitable click motifs are described in more detail below. The click motif can then serve as a synthetic handle for further derivatization (e.g., via click chemistry). In some emboduments, the compound can be one of the eupenifeldin derivatives (Compounds 2-24 and and 28) shown below.

[0002] Click Chemistry and Click Motifs The eupenifeldin derivatives described above can include a click motif, allowing them to be further derivatized using click chemistry. Click chemistry refers to a class chemical reaction (referred to as a “click reaction”) between two click groups that exhibit good yields, wide functional group tolerance, and are highly selective even in the presence of a complex mixture of biological molecules. These characteristics allow the click reactions to proceed even in vivo. Example click motif pairs used as the first click motif and the second click motif include, but not limited to, azide with phosphine; azide with cyclooctyne; nitrone with cyclooctyne; nitrile oxide with norbornene; oxanorbornadiene with azide; trans-cyclooctene with s-tetrazine; quadricyclane with bis(dithiobenzil)nickel(II). In some embodiments, the second click motif comprises an alkene, e.g., a cyclooctene, e.g., a transcyclooctene (TCO) or norbornene (NOR), and the first click motif comprises a tetrazine (Tz). In other embodiments, the second click motif comprises an alkyne, e.g., a cyclooctyne such as dibenzocyclooctyne (DBCO), and the first click motif comprises an azide (Az). In some embodiments, the second click motif comprises a Tz, and the first click motif comprises an alkene such as transcyclooctene (TCO) or norbornene (NOR). Alternatively or in addition, the first click motif comprises an Az, and the second click motif comprises a cyclooctyne such as dibenzocyclooctyne (DBCO). TCO reacts specifically in a click chemistry reaction with a tetrazine (Tz) moiety. DBCO reacts specifically in a click chemistry reaction with an azide (Az) moiety. Norbornene reacts specifically in a click chemistry reaction with a tetrazine (Tz) moiety. Exemplary click chemistry reactions (and by extension click motifs) are shown below. For example, copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) comprises using a Copper (Cu) catalyst at room temperature. The Azide-Alkyne Cycloaddition is a 1,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1,2,3-triazole. Another example of click chemistry includes Staudinger ligation, which is a reaction that is based on the classic Staudinger reaction of azides with triarylphosphines. It launched the field of bioorthogonal chemistry as the first reaction with completely abiotic functional. The azide acts as a soft electrophile that prefers soft nucleophiles such as phosphines. This is in contrast to most biological nucleophiles which are typically hard nucleophiles. The reaction proceeds selectively under water-tolerant conditions to produce a stable product. Phosphines are completely absent from living systems and do not reduce disulfide bonds despite mild reduction potential. Azides had been shown to be biocompatible in FDA-approved drugs such as azidothymidine and through other uses as cross linkers. Additionally, their small size allows them to be easily incorporated into biomolecules through cellular metabolic pathways. Copper-free click chemistry is a bioorthogonal reaction first developed by Carolyn Bertozzi as an activated variant of an azide alkyne cycloaddition. Unlike CuAAC, Cu-free click chemistry has been modified to be bioorthogonal by eliminating a cytotoxic copper catalyst, allowing reaction to proceed quickly and without live cell toxicity. Instead of copper, the reaction is a strain-promoted alkyne-azide cycloaddition (SPAAC). It was developed as a faster alternative to the Staudinger ligation, with the first generations reacting over sixty times faster. The incredible bioorthogonality of the reaction has allowed the Cu-free click reaction to be applied within cultured cells, live zebrafish, and mice. Cyclooctynes were selected as the smallest stable alkyne ring which increases reactivity through ring strain which has calculated to be 19.9 kcal / mol. Copper-free click chemistry also includes nitrone dipole cycloaddition. Copper-free click chemistry has been adapted to use nitrones as the 1,3-dipole rather than azides and has been used in the modification of peptides. This cycloaddition between a nitrone and a cyclooctyne forms N-alkylated isoxazolines. The reaction rate is enhanced by water and is extremely fast with second order rate constants ranging from 12 to 32 M-1·s-1, depending on the substitution of the nitrone. Although the reaction is extremely fast, incorporating the nitrone into biomolecules through metabolic labeling has only been achieved through post-translational peptide modification. Another example of click chemistry includes norbornene cycloaddition. 1,3 dipolar cycloadditions have been developed as a bioorthogonal reaction using a nitrile oxide as a 1,3- dipole and a norbornene as a dipolarophile. Its primary use has been in labeling DNA and RNA in automated oligonucleotide synthesizers. Norbornenes were selected as dipolarophiles due to their balance between strain- promoted reactivity and stability. The drawbacks of this reaction include the cross-reactivity of the nitrile oxide due to strong electrophilicity and slow reaction kinetics. Another example of click chemistry includes oxanorbornadiene cycloaddition. The oxanorbornadiene cycloaddition is a 1,3-dipolar cycloaddition followed by a retro-Diels Alder reaction to generate a triazole-linked conjugate with the elimination of a furan molecule. This reaction is useful in peptide labeling experiments, and it has also been used in the generation of SPECT imaging compounds. Ring strain and electron deficiency in the oxanorbornadiene increase reactivity towards the cycloaddition rate-limiting step. The retro-Diels Alder reaction occurs quickly afterwards to form the stable 1,2,3 triazole. Limitations of this reaction include poor tolerance for substituents which may change electronics of the oxanorbornadiene and low rates (second order rate constants on the order of 10-4). Another example of click chemistry includes tetrazine ligation. The tetrazine ligation is the reaction of a trans-cyclooctene and an s-tetrazine in an inverse-demand Diels Alder reaction followed by a retro-Diels Alder reaction to eliminate nitrogen gas. The reaction is extremely rapid with a second order rate constant of 2000 M-1-s-1(in 9:1 methanol / water) allowing modifications of biomolecules at extremely low concentrations. The highly strained trans-cyclooctene is used as a reactive dienophile. The diene is a 3,6- diaryl-s-tetrazine which has been substituted in order to resist immediate reaction with water. The reaction proceeds through an initial cycloaddition followed by a reverse Diels Alder to eliminate N2 and prevent reversibility of the reaction. Not only is the reaction tolerant of water, but it has been found that the rate increases in aqueous media. Reactions have also been performed using norbornenes as dienophiles at second order rates on the order of 1 M-1s-1in aqueous media. The reaction has been applied in labeling live cells and polymer coupling.

[0003] Another example of click chemistry includes is [4+1] cycloaddition. This isocyanide click reaction is a [4+1] cycloaddition followed by a retro-Diels Alder elimination of N2.

[0004] The reaction proceeds with an initial [4+1] cycloaddition followed by a reversion to eliminate a thermodynamic sink and prevent reversibility. This product is stable if a tertiary amine or isocyanopropanoate is used. If a secondary or primary isocyanide is used, the produce will form an imine which is quickly hydrolyzed.

[0005] Isocyanide is a favored chemical reporter due to its small size, stability, non-toxicity, and absence in mammalian systems. However, the reaction is slow, with second order rate constants on the order of

[0006] Another example of click chemistry includes quadricyclane ligation. The quadricyclane ligation utilizes a highly strained quadricyclane to undergo [2+2+2] cycloaddition with TE systems.

[0007] Quadricyclane is abiotic, unreactive with biomolecules (due to complete saturation), relatively small, and highly strained (~80 kcal / mol). However, it is highly stable at room temperature and in aqueous conditions at physiological pH. It is selectively able to react with electron-poor n systems but not simple alkenes, alkynes, or cyclooctynes.

[0008] Bis(dithiobenzil)nickel(II) was chosen as a reaction partner out of a candidate screen based on reactivity. To prevent light-induced reversion to norbomadiene, diethyldithiocarbamate is added to chelate the nickel in the product.

[0009] These reactions are enhanced by aqueous conditions with a second order rate constant of 0.25 M ’ s"1. Of particular interest is that it has been proven to be bioorthogonal to both oxime formation and copper-free click chemistry.

[0010] The exemplary click chemistry reactions have high specificity, efficient kinetics, and occur in vivo under physiological conditions. See, e.g., Baskin et al. Proc. Natl. Acad. Sci. USA 104(2007): 16793; Oneto et al. Acta biomaterilia (2014); Neves et al. Bioconjugate chemistry 24(2013):934; Koo et al. Angewandte Chemie 51(2012): 11836; and Rossin et al. Angewandte Chemie 49(2010)3375. For a review of a wide variety of click chemistry' reactions and their methodologies, see e.g., Nwe K and Brechbiel M W, 2009 Cancer Biotherapy and Radiopharmaceuticals, 24(3): 289-302; Kolb H C et al., 2001 Angew. ( 'hem. Int. Ed. 40: 2004-2021. The entire contents of each of the foregoing references are incorporated herein by reference. Exemplary click motif pairs are shown in the table below. Functional groups formed by reaction of click motif pairs are well known in the art.

[0011] Other suitable include the motifs can be found, for example, in Patterson, D.M., et al. “Finding the Right (Bioorthogonal) Chemistry,” ACS Chem. Biol., 2014, 9(3): 592–605; Akgun, B., et al. “Synergic "Click" Boronate / Thiosemicarbazone System for Fast and Irreversible Bioorthogonal Conjugation in Live Cells,” J. Am. ( 'hem. Soc., 2017, 139(40): 14285-14291; and Akgun, B. and Hall, D.G. “Fast and Tight Boronate Formation for Click Bioorthogonal Conjugation,” Angew. Chem., Int. Ed. 2016, 55(12): 3909-3913, each of which is hereby incorporated by reference in its entirety.

[0012] Synthesis

[0013] The eupenifeldin derivatives described herein can be prepared using synthetic methodologies known in the art. By way of example, certain eupenifeldin derivatives described herein can be prepared by synthetic modifications of eupenifeldin’s bistropolone rings to attach moieties that can affect drug-like properties while retaining potency. Scheme 1 below illustrates strategies that can be used to prepare ether, carbonate, carbamate, sulfonate, and ester derivatives of eupenifeldin from eupenifeldin.

[0014] Scheme 1. Example strategies for preparing eupenifeldin derivatives.

[0015] It will be appreciated by one skilled in the art that the processes described are not the exclusive means by which compounds provided herein may be synthesized and that a broad repertoire of synthetic organic, inorganic, and organometallic reactions is available to be potentially employed in synthesizing compounds provided herein. The person skilled in the art knows how to select and implement appropriate synthetic routes. Suitable synthetic methods of starting materials, intermediates and products may be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vols. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.) Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky, et al. (Ed.) Comprehensive Organic Functional Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2ndEdition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6thEd. (Wiley, 2007); Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991). The reactions for preparing compounds described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, (e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds described herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., Wiley & Sons, Inc., New York (1999). Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV- visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography. Suitable methods for preparing eupenifeldin derivatives are further detailed in the Examples below. Methods of Treatment As described above, eupenifeldin derivatives, including those described herein, can be administered to treat or prevent cancer. As used herein, the term “cancer” refers to a class of diseases of mammals characterized by uncontrolled cellular growth. The term “cancer” is used interchangeably with the terms “malignancy,” “hyperproliferation” and “neoplasm.” Cancer includes all types of hyperproliferative growth, hyperplasic growth, neoplastic growth, cancerous growth or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Illustrative examples include, lung, prostate, head and neck, breast and colorectal cancer, melanomas and gliomas (such as a high grade glioma, including glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors in adult humans). Examples of proliferative disorders (cancers) that can be treated using the methods disclosed herein include: lung cancer (including small cell lung cancer and non small cell lung cancer), other cancers of the pulmonary system, medulloblastoma and other brain cancers, pancreatic cancer, basal cell carcinoma, breast cancer, prostate cancer and other genitourinary cancers, gastrointestinal stromal tumor (GIST) and other cancers of the gastrointestinal tract, colon cancer, colorectal cancer, ovarian cancer, cancers of the hematopoietic system (including multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma, and myelodysplastic syndrome), polycythemia Vera, Waldenstrom's macroglobulinemia, heavy chain disease, soft-tissue sarcomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, melanoma, and other skin cancers, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, stadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, bladder carcinoma, and other genitourinary cances, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, endometrial cancer, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, esophageal cancer, head and neck cancer, small cell cancers, essential thrombocythemia, agnogenic myeloid metaplasia, hypereosinophilic syndrome, systemic mastocytosis, familiar hypereosinophilia, chronic eosinophilic leukemia, thyroid cancer, neuroendocrine cancers, and carcinoid tumors. In some embodiments, the cancer can comprise a solid tumor. As used herein, the phrase “solid tumor” includes, for example, lung cancer, head and neck cancer, brain cancer, oral cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, and liver cancer. Other types of solid tumors are named for the particular cells that form them, for example, sarcomas formed from connective tissue cells (for example, bone cartilage, fat), carcinomas formed from epithelial tissue cells (for example, breast, colon, pancreas) and lymphomas formed from lymphatic tissue cells (for example, lymph nodes, spleen, thymus). Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein. Thus, in some embodiments, the cancer is a metastatic cancer. “Metastatic cancer,” as used herein, refers to a cancer that has spread from its primary site of origin or where it first formed to other areas of a subject's body. Examples of metastatic cancers include metastatic breast cancer, metastatic colon cancer, metastatic lung cancer, metastatic pancreatic cancer, metastatic prostate cancer, metastatic bone cancer, metastatic blood cancer, metastatic brain cancer, and metastatic liver cancer. In the methods described herein, the subject receiving this treatment can be any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. In certain embodiments, the subject can be a human. Eupenifeldin derivatives can be combined with other cancer treatments. For example, they can be combined with surgical treatments; radiation; biotherapeutics (such as interferons, cytokines—e.g., Interferon Į^^Interferon Ȗ^^and tumor necrosis factor, hematopoietic growth factors, monoclonal serotherapy, vaccines and immunostimulants); antibodies (e.g., Avastin, Erbitux, Rituxan, and Bexxar); endocrine therapy (including peptide hormones, corticosteroids, estrogens, androgens and aromatase inhibitors); anti-estrogens (e.g., Tamoxifen, Raloxifene, and Megestrol); LHRH agonists (e.g., goscrclin and Leuprolide acetate); anti-androgens (e.g., flutamide and Bicalutamide); gene therapy; bone marrow transplantation; photodynamic therapies (e.g., vertoporfin (BPD-MA), Phthalocyanine, photosensitizer Pc4, and Demethoxy- hypocrellin A (2BA-2-DMHA)); and chemotherapeutics. Examples of chemotherapeutics include gemcitabine, methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, prednisolone, dexamethasone, cytarbine, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, and vinorelbine. Additional agents include nitrogen mustards (e.g., cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Estramustine, and Melphalan), nitrosoureas (e.g., carmustine (BCNU) and Lomustine (CCNU)), alkylsulphonates (e.g., busulfan and Treosulfan), triazenes (e.g., Dacarbazine and Temozolomide), platinum containing compounds (e.g., Cisplatin, Carboplatin, and oxaliplatin), vinca alkaloids (e.g., vincristine, Vinblastine, Vindesine, and Vinorelbine), taxoids (e.g., paclitaxel and Docetaxol), epipodophyllins (e.g., etoposide, Teniposide, Topotecan, 9-Aminocamptothecin, Camptoirinotecan, Crisnatol, Mytomycin C, and Mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate and Trimetrexate), IMP dehydrogenase Inhibitors (e.g., mycophenolic acid, Tiazofurin, Ribavirin, and EICAR), ribonucleotide reductase Inhibitors (e.g., hydroxyurea and Deferoxamine), uracil analogs (e.g., Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, and Capecitabine), cytosine analogs (e.g., cytarabine (ara C), Cytosine arabinoside, and Fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., Lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycins (e.g., Actinomycin D and Dactinomycin), bleomycins (e.g., bleomycin A2, Bleomycin B2, and Peplomycin), anthracyclines (e.g., daunorubicin, Doxorubicin (adriamycin), Idarubicin, Epirubicin, Pirarubicin, Zorubicin, and Mitoxantrone), MDR inhibitors (e.g., verapamil), Ca2+ATPase inhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide, erlotinib, gefitinib, sorafenib, and sunitinib, and proteasome inhibitors, including bortezomib. When eupenifeldin derivatives are administered in combination with other treatments, such as additional therapeutics or with radiation or surgery, the doses of each agent or therapy will in most instances be lower than the corresponding dose for single-agent therapy. Also, in general, eupenifeldin derivatives and the second therapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, be administered by different routes. For example, one compound can be administered orally, while the second therapeutic is administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician. Eupenifeldin derivatives and the second therapeutic agent and / or radiation may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially (i.e., one followed by the other, with an optional time interval in between), depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of second therapeutic agent and / or radiation to be administered. If eupenifeldin derivatives and the second therapeutic agent and / or radiation are not administered simultaneously or essentially simultaneously, then the optimum order of administration may be different for different conditions. Thus, in certain situations the eupenifeldin derivatives may be administered first followed by the administration of the second therapeutic agent and / or radiation; and in other situations the second therapeutic agent and / or radiation may be administered first followed by the administration of a eupenifeldin derivatives. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the second therapeutic agent and / or radiation may be administered first, especially if it is a cytotoxic agent, and then the treatment continued with the administration of a eupenifeldin derivatives, followed, where determined advantageous, by the administration of the second therapeutic agent and / or radiation, and so on until the treatment protocol is complete. Also provided herein are methods for treating or preventing a parasitic infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the parasitic infection. In some examples, the parasitic infection is selected from leishmaniasis, malaria, human African trypanomiasis, babesiosis, Chagas disease, microsporidiosis, pneumocystosis, primary ameobic meningoenchephalitis, and toxoplasmosis. In certain examples, the parasitic infection comprises malaria. Also provided herein are methods for treating or preventing a fungal infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the fungal infection. Also provided herein are methods for treating or preventing a bacterial infection in a subject in need thereof. These methods can comprise administering to the subject an effective amount of a eupenifeldin derivative described herein or a pharmaceutical composition comprising a eupenifeldin derivative described herein to treat or prevent the bacterial infection. As used herein, the phrase “effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. An effective amount of a compound provided herein can range, for example, from about 0.01 mg / kg to about 1000 mg / kg, (e.g., from about 0.1 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 100 mg / kg). Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. Combination Therapies As discussed above, the methods provided herein further comprise administering one or more additional therapeutic agents to the subject. In some embodiments, each of the one or more additional therapeutic agents is independently selected from the group consisting of a steroid, an anti-allergic agent, an anesthetic (e.g., for use in combination with a surgical procedure), an immunosuppressant, an anti-microbial agent, an anti-inflammatory agent, and a chemotherapeutic agent. Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Example anesthetics include, but are not limited to local anesthetics such as lidocaine, procain, and ropivacaine. Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus. Example anti-microbial agents include, but are not limited to, aminoglycosides (e.g., gentamicin, neomycin, and streptomycin), penicillins (e.g., amoxicillin and ampicillin), and macrolides (e.g., erythromycin). Example anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib. Example chemotherapeutics include, but are not limited to, proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like. For example, one or more of the following agents may be used in combination with the compounds provided herein and are presented as a non-limiting list: a cytostatic agent, cisplatin, taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, temozolomide, cyclophosphamide, gefitinib, erlotinib hydrochloride, imatinib mesylate, gemcitabine, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, folinic acid, pentostatin, vinblastine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, WHQLSRVLGH^^^^Į-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methyltestosterone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, reloxafine, hexamethylmelamine, bevacizumab, bexxar, velcade, zevalin, trisenox, xeloda, porfimer, erbitux, thiotepa, altretamine, trastuzumab, fulvestrant, exemestane, ifosfamide, rituximab, alemtuzumab, clofarabine, cladribine, aphidicolin, sunitinib, dasatinib, tezacitabine, triapine, trimidox, amidox, bendamustine, and ofatumumab. Pharmaceutical Compositions When employed as pharmaceuticals, eupenifeldin derivatives can be administered in the form of pharmaceutical compositions. These compositions can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, (e.g., intrathecal or intraventricular, administration). Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. In some embodiments, the compounds provided herein, or a pharmaceutically acceptable salt thereof, are suitable for parenteral administration. In some embodiments, the compounds provided herein are suitable for intravenous administration. In some embodiments, the compounds provided herein are suitable for oral administration. In some embodiments, the compounds provided herein are suitable for topical administration. Pharmaceutical compositions and formulations for topical administration may include, but are not limited to, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. In some embodiments, the pharmaceutical compositions provided herein are suitable for parenteral administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for intravenous administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for oral administration. In some embodiments, the pharmaceutical compositions provided herein are suitable for topical administration. Also provided are pharmaceutical compositions which contain, as the active ingredient, a compound provided herein in combination with one or more pharmaceutically acceptable carriers (e.g. excipients). In making the pharmaceutical compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be, for example, in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include, without limitation, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; flavoring agents, or combinations thereof. The active compound can be effective over a wide dosage range and is generally administered in an effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like. The compositions provided herein can be administered one from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound described herein can include a single treatment or a series of treatments. Dosage, toxicity and therapeutic efficacy of the compounds provided herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Compounds exhibiting high therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects. EXAMPLES The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. Example 1: Derivatives of the Fungal Metabolite Eupenifeldin via Targeting the Tropolone Hydroxy Groups Summary Eupenifeldin is a fungal secondary metabolite possessing bis-tropolone moieties that demonstrates nanomolar cytotoxic activity against a number of cancer cell types despite its less than ideal drug properties, particularly poor solubility. As a potential anticancer lead, this meroterpenoid was used to access 29 semisynthetic analogues via functionalization of the reactive hydroxy groups of the bis-tropolones. A total of 22 reactions led to a series of ester (2- 6), carbonate (7-8), sulfonate (9-16), carbamate (17-20), and ether (21-30) analogues of eupenifeldin. Most of these compounds were disubstituted, produced via functionalization of both of the tropolonic hydroxy moieties, although three mono-functionalized analogues (6, 8, and 24) and one tri-functionalized analogue (3) were also obtained. The cytotoxic activities of 1- 30 were evaluated against human melanoma and breast cancer cell lines (i.e., MDA-MB-435 and OVCAR3, respectively). Ester and carbonate analogues of eupenifeldin (2-8) maintained potent cytotoxicity at the nanomolar level, and the greatest improvement in aqueous solubility came from the monosuccinate analogue, which was acylated on the secondary hydroxy at the 11 position (6). Materials and Methods General Experimental Procedures Chemical reagents were used as received from chemical vendors. CDCl3 and pyridine-d5 used for NMR data collection were obtained from Cambridge Isotope Laboratories. All solvents used for chromatography were obtained from Fisher Scientific. NMR data were collected in CDCl3 or pyridine-d5 using either a JEOL ECS-400 spectrometer (JEOL USA, Inc.) operating at 400 MHz for1H and 100 MHz for13C, a JEOL ECS-500 spectrometer (JEOL USA, Inc.) operating at 500 MHz for1H and 125 MHz for13C, or an Agilent 700 MHz NMR spectrometer (Agilent Technologies, Inc.) operating at 700 MHz for1H and 175 MHz for13C. Chemical shift values were referenced to the residual solvent signals for CDCl3 ^į+^^^^^^DQG^į&^^^^^^^DQG^ pyridine-d5 ^į+^^^^^^ ^^^^^^DQG^^^^^^DQG^į&^^^^^^^^^^^^^^^^^^^^^^DQG^UHSRUWHG^LQ^į^SSP^^ multiplicity was shown as: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet of doublets of doublets; coupling constants were conveyed in Hz. The solvent peaks have been marked on the spectra, as have signals for residual H2O. A Waters Acquity UPLC system coupled with a Thermo LTQ Orbitrap-XL mass spectrometer (ThermoFisher, San Jose, CA, USA) with a heated electrospray ionization source was used to collect UV and HRESIMS data. UPLC separations were achieved using an Acquity BEH C18 column (50 mm x ^^^^PP^^^^^^^P^^HTXLOLEUDWHG^DW^^^^^&^DQG^D^IORZ^ rate set at 0.3 mL / min. The mobile phase consisted of a linear gradient CH3CN / H2O modified with 0.1% formic acid starting at 15% CH3CN to 100% over 10 min. UV data were collected from 190 to 500 nm. HPLC separations were achieved using a Varian ProStar HPLC system coupled with a ProStar 335 photodiode array (PDA) detector with UV detection set to 254 and 360 nm. Preparative and semi-preparative reverse phase HPLC purifications were performed using a variety of column types, mobile phase conditions, and flow rates (see Table 3). Experimental Procedures for the Semisynthesis of Compounds 2-30 General procedure for synthesis of eupenifeldin ester 2-5. A mixture of eupenifeldin (10 mg, 0.018 mmol) and acyl chloride (0.180 mmol) was dissolved in 1.8 ml of DCM. 7ULHWK\ODPLQH^^^^^^^^O^^^^^^^^PPRO^^ZDV^DGGHG^DQG^WKH^VROXWLRQ^ZDV^OHIW^WR^VWLU overnight at room temperature. Upon completion, the mixture was quenched with distilled water and was extracted with DCM (x3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. Eupenifeldin Succinate 6. A solution of eupenifeldin (25 mg, 0.046 mmol), succinic anhydride (50 equiv., 100 mg), DMAP (60 equiv., 353 mg), and pyridine (2.5 mL) were stirred at room temperature for ~3 days. The reaction was quenched by drying under nitrogen. The remaining solid was washed by successive re-suspension and centrifugation in acidified water (pH ~3). The remaining solid was then evaporated to dryness under nitrogen. The remaining solid was purified by HPLC to afford eupenifeldin succinate (3.86 mg, 0.006 mmol, 13% yield) as a white amorphous powder General procedure for synthesis of eupenifeldin carbonate 7 and 8. A mixture of eupenifeldin (75 mg, 0136 mmol), 2-PHWKR[\HWK\O^FKORURIRUPDWH^^^^^^O^^^^^^^ mmol), 18- crown-^^^^^^^^PJ^^^^^^^^PPRO^^^DQG^^^^^.2+^VROXWLRQ^^^^^^^O^^ZDV^WDNHQ^XS^LQ^^^^PO of toluene. The solution was stirred at room temperature overnight. Upon completion, the solution was quenched with distilled water and extracted with DCM (x3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. General procedure for synthesis of eupenifeldin sulfonate 9-16. A mixture of eupenifeldin (10 mg, 0.018 mmol), sulfonyl chloride (0.09 mmol), and 4- Dimethylaminopyridine (0.61 mg, 0.005 mmol) was dissolved in 1.8 ml of DCM. Triethylamine ^^^^^O^^^^^^^^PPRO^^ZDV^DGGHG^WR^WKH^VROXWLRQ^DQG^ZDV^VWLUUHG^DW^URRP^WHPSHUDWXUH^RYHUQLJKW^^ TLC showed disappearance of starting material and the solution cooled and quenched with distilled water and was extracted with DCM (x3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. General procedure for synthesis of eupenifeldin carbamate: 17, 18, and 20). A mixture of eupenifeldin (10 mg, 0.018 mmol), carbamoyl chloride (0.090 mmol), and potassium carbonate (15 mg, 0.108 mmol) was dissolved in 0.5 ml of acetonitrile. The solution was stirred at 70°C overnight. TLC showed disappearance of eupenifeldin and the reaction was cooled and quenched with distilled water and extracted with EtOAc (3x). The combined organic layers were washed with brine and was dried over Na2SO4and concentrated under reduced pressure. Eupenifeldin carbamate 19. The carbamoyl chloride was first prepared. To a solution of triphosgene (39 mg, 0.13 mmol) in DCM (0.5 ml) cooled to -78°C, 50 mg (0.38 mmol) of tetrahydoisoquinoline was added. The solution was stirred at room temperature for 2hrs before being quenched with 1N HCl (0.25 ml). The product was extracted with DCM, washed with a saturated aqueous solution of sodium bicarbonate, and dried over sodium Na2SO4. The organic solvent was removed under reduced pressure and the crude mixture was taken up in acetonitrile. To the mixture was added eupenifledin (10 mg, 0.018 mmol), and potassium carbonate (15 mg, 0.108 mmol). The mixture was stirred at 70°C overnight. The reaction was cooled and quenched with distilled water and extracted with EtOAc (3x). The combined organic layers were washed with brine and was dried over Na2SO4and concentrated under reduced pressure. General procedure for synthesis of Eupenifeldin ether 21 and 22. A mixture of eupenifeldin (10 mg, 0.018mmol), bromo-alkane (0.054 mmol), and potassium carbonate (10 mg, 0.072 mmol) was dissolved in 1 mL of acetonitrile. The mixture was stirred and heated to 60°C and left to run overnight. Upon completion, the reaction mixture was quenched with distilled water and was extracted with DCM (x3). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. Compounds 23, 25-30. A solution of eupenifeldin (100 mg, 0.182 mmol), potassium carbonate (4 equiv., 100 mg), and DMSO (10 mL) were stirred at room temperature for 30 min. Then propargylbromide (80 wt% in WROXHQH^^^^^HTXLY^^^^^^^^ / ^^ZDV^DGGHG^DQG^WKH^PL[WXUH^ stirred overnight at room temperature. The reaction mixture was transferred to two separate vials (half in each) then quenched by drying under nitrogen. The remaining solid in one vial was purified by HPLC to afford 22 (18 mg, 0.030 mmol, 33% yield) as a yellow amorphous powder, 24 (6.0 mg, 0.010 mmol, 11% yield) as a yellow amorphous powder, 25 (6.2 mg, 0.010 mmol, 11% yield) as a yellow amorphous powder, and 26 (1.2 mg, 0.002 mmol, 2% yield) as a yellow amorphous powder. The remaining solid in the other vial underwent a second reaction step to afford 27-29. Copper (II) sulfate (7 equiv., 100 mg), sodium ascorbate (20 equiv., 400 mg), methyl 2-D]LGRDFHWDWH^^^^^HTXLY^^^^^^^^ / ^^^DQG^^^^^t-BuOH:H2O (10 mL) were added to the vial and stirred overnight at room temperature. The reaction was quenched by drying under nitrogen. The remaining solid was purified by HPLC to afford 27 (18 mg, 0.021 mmol, 23% yield) as a white amorphous powder, 28 (3.3 mg, 0.004 mmol, 4% yield) as a white amorphous powder, and 29 (3.4 mg, 0.004 mmol, 4% yield) as a white amorphous powder. 2-O-Propargyleupenifeldin 24. A solution of eupenifeldin (50 mg, 0.091 mmol), potassium carbonate (2 equiv., 25 mg), and DMSO (5 mL) were stirred at room temperature for 30 min. Then propargylbromide (80 wt% in WROXHQH^^^^HTXLY^^^^^^^ / ^^ZDV^DGGHG^DQG^WKH^ mixture stirred overnight at room temperature. The reaction mixture was then quenched by drying under nitrogen. The remaining solid was purified by HPLC to afford 2-O- propargyleupenifeldin (2.83 mg, 0.004 mmol, 4% yield) as a yellow amorphous powder. Table 3. Reverse-phase HPLC purification methods on compounds 2-30.

[0016] Results and Discussion In our own efforts to develop new anticancer leads from fungal secondary metabolites, we generated ten semisynthetic analogues of verticillins with nanomolar cytotoxic activity, several of which were predicted to improve solubility relative to the parent compound. Seven derivatives were also produced for the TAK1 inhibitor, (5Z)-7-oxozeaenol, where a nonaromatic difluoro-derivative was generated with similar potency to the parent compound, and this was followed up by 35 semisynthetic analogues of the structurally related analogue, hypothemycin, that probe derivatization of the C8-C9 diol. Based on the relatively poor pharmaceutical properties observed for the natural product eupenifeldin, a similar semisynthetic approach was employed with this compound. Eupenifeldin (1) is a fungal meroterpenoid from Eupenicillium brefeldianum that was originally described in 1993. In addition to the unique structural attributes afforded by the bis- tropolone rings, eupenifeldin has displayed potent antimalarial, antifungal, and cytotoxic activities, including nanomolar potency against a variety of cancer cell lines. The promising cytotoxicity profile of eupenifeldin was also evident when evaluated against the NCI 60 cell line panel. Eupenifeldin is a prominent example of a structurally novel, natural product-derived anticancer lead; however, furtherinvestigation of its activity has been limited to a single in vivo study against a murine model of leukemia, which was reported 30 years ago. This might be attributed to the poor physiochemical properties of eupenifeldin represented mainly by its low water solubility (~1.7 µg / mL in phosphate buffer saline), and the observed poor solubility in most organic solvents (e.g. methanol, ethanol, acetonitrile, acetone, and chloroform). One approach to overcome this challenge is utilizing a specialized drug delivery system, such as a chemotherapy-loaded polymer buttress, which afforded prolonged local release of eupenifeldin, significantly decreasing local tumor recurrence and increasing disease- free survival in an in vivo resection model of lung cancer. Another approach, as mentioned above, would be to modify the structure of eupenifeldin through semisynthesis, maintaining the features responsible for its promising biological activity. Structurally, eupenifeldin consists of a humulene-derived eleven-membered ring, which is flanked with pyran rings, each of which are fused with tropolone units (Figure 1). The tropolone hydroxy groups (i.e., at positions C-2 and C-24) were targeted as the primary reactive sites to perform chemical modifications, with the goal of keeping the core scaffold intact. We hypothesized that the higher reactivity of these hydroxy groups, as compared to the secondary alcohol at C-11, would permit selective functionalization, resulting in disubstituted analogues of eupenifeldin. Importantly, more than four grams of eupenifeldin were secured for these semisynthetic reactions by fermentation and isolation from large-scale cultures of the fungus, Neosetophoma sp. Utilizing this strategy, we accessed 29 analogues (2-30) from 22 different reaction partners to investigate the relative reactivity and resulting regioselectivity of transformations with the natural product. Initially, only reactions with acyl and sulfonyl reagents were considered, with the goal of generating prodrugs of eupenifeldin. This led to a series of esters (2- 6), carbonates (7-8), sulfonates (9-16), and carbamates (17-20). Notably, the sulfonates and carbamates showed greater stability than the esters, which could easily be hydrolyzed under acidic conditions. Also, treatment of eupenifeldin with excess acetic anhydride led to the unexpected formation of the triacetylated product (3) as the major product in addition to the anticipated bisacetylated product (2), presumably due to the relatively high reactivity and small size of the acetyl group. In reactions with other acylating agents, no attempt was made to obtain the trifunctionalized or the monofunctionalized products. Interestingly, however, three reactions did result in mono-functionalization of eupenifeldin. For example, the mono-functionalized derivative (8) was isolated, along with the major and expected di-functionalized product (7), from reaction with 2-methoxyethylchloroformate. The substitution pattern of this product was subsequently identified using 2D NMR spectra. In addition, treatment of eupenifeldin with succinic anhydride did not produce the expected disubstituted analogue, but rather resulted exclusively in the formation of the mono-substituted derivative at 11-OH (6). To explore the chemistry of semisynthetic analogues of eupenifeldin in more detail, additional alkylated products were generated via ether linkages (21-30). In our attempt to generate the di-alkyne derivative of eupenifeldin (23), four di-alkyne compounds were isolated from the reaction mixture, and all shared the same molecular formula of C39H45O7 as identified by HRESIMS data. The differences between these structurally similar analogues (23 & 25-27) were then elucidated via analysis of 1D and 2D NMR data. Besides the expected di-alkyne product (23) (Figure 2), keto-enol tautomerism of the tropolone rings led to three additional analogues (25-27) (Figure 3). Analogue 25 resulted from tautomerism at the C-1 and C-2 positions, tautomerism at C-24 and C-25 led to analogue 26, while tautomerism in both tropolone rings was observed in 27. Interestingly, these analogues were obtained in a ratio of 15 (23): 5 (25): 5 (26): 1 (27), and such tautomeric behavior was not observed in any of the other reactions (Table 3). Generation of mono-alkyne products was achieved by the reaction with 50- 90 mol% of reagents, resulting in a mixture of mono- and di-alkylated products, as well as unreacted eupenifeldin. The mono-alkylated product (24) was isolated from the mixture, and the substitution pattern was identified using 2D NMR. Unlike the di-alkyne products, 24 could not be fully characterized in CDCl3, as the quaternary carbon of the alkyne moiety was not visible in this solvent. The use of an aromatic solvent (pyridine-d5) for 1D & 2D NMR analysis mitigated this setback. To generate the triazole analogues (28-30), the di-alkyne reaction was repeated to generate (23, and 25-27) as confirmed by UPLCHRESIMS. The mixture was then reacted via copper (I)-catalyzed azide-alkyne cycloadditions (CuAAC). Successful application of the click reaction on these substrates indicate that late-stage functionalization of the propargyl eupenifeldin compounds can be targeted to introduce additional functionality that may be helpful for the modulation of drug properties or development of probe molecules. For all 22 reactions, generation of the targeted analogue was confirmed via UPLC- HRESIMS data before subjecting the reaction mixture to preparative HPLC (Table 3) to obtain the pure compounds. Compounds 2-30 were characterized via HRESIMS data and 1D and 2D NMR spectra. Afterward, the cytotoxic activity for both the semisynthetic derivatives and the parent compound were evaluated against the human ovarian (OVCAR3) and breast (MDA-MB- 435) cancer cell lines. Ester and carbonate analogues of eupenifeldin (2-8), in addition to the carbamates (18 & 20) and the alkyl analogue (22), retained potent cytotoxicity at the nanomolar level against human ovarian and / or breast cancer cell lines (Table 1). The IC50 values of the other derivatives (9-17, 19, 21, and 23-30) were all greater than 250 nM (i.e., more than three times less potent than 1). We believe that the high potency of the ester and the carbonate analogues is, at least in part, related to their hydrolysis and the release of the parent compound. In comparison, the more stable derivatives (i.e, the sulfonates and the alkylated analogues) are less cytotoxic. Similar phenomena was observed with the semisynthetic derivative of hypothemycin. The physiochemical properties of the semisynthetic derivatives (2-30) were predicted by calculating their logP, logD, and solubility values (Tables 1 & 2). Althought the vast majority of the synthesized analogues do not directly address the limited water solubility, the succinic acid derivative of eupenifeldin (6) is predicted to exhibit forty times higher solubility compared to eupenifeldin. The relative solubility of the other analogues was in the range of 1 x 10-1to 7 x 10-7, with compounds 2, 7, 8, 17, 24, and 28-30 being the closest to the solubility of eupenifeldin (Table 2). Moreover, LogD for compounds 9, 21, and 28-30 were found to be similar to that of eupenifeldin. Importantly, the introduction of the acyl and alkyl substituents did improve the organic solubility of the eupenifeldin analogues, suggesting that additional analogues can be designed to specifically tune the desired properties for this lead compound. In addition to the promising water solubility demonstrated by the succinate 6, compounds 3, 5, and 8 show the most promising cytotoxicity. While these compounds retain similar potencies (or even better in the case of 8) against MDA-MD-435 cells, their activity against OVCAR3 cells is lower than that of eupenifeldin itself, suggesting the possibility of an impact on target selectivity as well. Studies to generate second generation analogues based on each of their frameworks are ongoing. Table 1. IC50values and calculated solubility of eupenifeldin and related analogues. Table 2. Physiochemical properties of eupenifeldin (1) and semisynthetic derivatives 2-30. References (1) Kinghorn, A. D.; Chin, Y.-W.; Swanson, S. M. Discovery of natural product anticancer agents from biodiverse organisms. Curr. Opin. Drug Discov. Devel. 2009, 12 (2), 189-196. From http: / / worldcat.org / z-wcorg / . (2) Aldrich, L. N.; Burdette, J. E.; Carcache de Blanco, E.; Coss, C. C.; Eustaquio, A. S.; Fuchs, J. R.; Kinghorn, A. D.; MacFarlane, A.; Mize, B. K.; Oberlies, N. H.; et al. Discovery of anticancer agents of diverse natural origin. J. Nat. Prod. 2022, 85 (3), 702-719. DOI: 10.1021 / acs.jnatprod.2c00036. (3) Newman, D. J.; Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01 / 1981 to 09 / 2019. J. Nat. Prod. 2020, 83 (3), 770–803. DOI: 10.1021 / acs.jnatprod.9b01285. (4) Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B 2017, 7 (2), 119-136. DOI: 10.1016 / j.apsb.2016.06.003 From NLM. (5) Majhi, S.; Das, D. Chemical derivatization of natural products: semisynthesis and pharmacological aspects- A decade update. Tetrahedron 2021, 78, 131801. DOI: https: / / doi.org / 10.1016 / j.tet.2020.131801. (6) Amrine, C. S. M.; Huntsman, A. C.; Doyle, M. G.; Burdette, J. E.; Pearce, C. J.; Fuchs, J. R.; Oberlies, N. H. Semisynthetic derivatives of the verticillin class of natural products through acylation of the C11 hydroxy group. ACS Med. Chem. Lett. 2021, 12 (4), 625-630. DOI: 10.1021 / acsmedchemlett.1c00024. (7) Fuchs, J. H., A.; Oberlies, N. H.; Amrine, C. S.; Raja, H.; Burdette, J.; Pearce, C. J. Semi-synthetic analogues of epipolythiodioxopiperazine alkaloids for cancer therapy. 2020, App # 62 / 851,939- WO2020-US34268. (8) Fakhouri, L.; El-Elimat, T.; Hurst, D. P.; Reggio, P. H.; Pearce, C. J.; Oberlies, N. H.; Croatt, M. P. Isolation, semisynthesis, covalent docking and transforming growth factor betaactivated kinase 1 (TAK1)-inhibitory activities of (5Z)-7-oxozeaenol analogues. Bioorg. Med. Chem. 2015, 23 (21), 6993-6999. From http: / / worldcat.org / z-wcorg / . (9) Pearce, C. J. C., M. P.; Fakhouri, L.; Oberlies, N. H. Preparation of difluororesorcylic acid lactone derivatives for use as TAK-1 inhibitors. 2016, App # 62 / 170,789- WO2016- US34562. (10) Al Subeh, Z. Y.; Li, T.; Ustoyev, A.; Obike, J. C.; West, P. M.; Khin, M.; Burdette, J. E.; Pearce, C. J.; Oberlies, N. H.; Croatt, M. P. Semisynthesis of hypothemycin analogues targeting the C8–C9 diol. J. Nat. Prod. 2022, 85 (5). DOI: 10.1021 / acs.jnatprod.2c00434. (11) Mayerl, F.; Gao, Q.; Huang, S.; Klohr, S. E.; Matson, J. A.; Gustavson, D. R.; Pirnik, D. M.; Berry, R. L.; Fairchild, C.; Rose, W. C. Eupenifeldin, a novel cytotoxic bistropolone from Eupenicillium brefeldianum. J Antibiot. 1993, 46 (7), 1082-1088. From http: / / worldcat.org / z- wcorg / . (12) Liu, N.; Song, W.; Schienebeck, C. M.; Zhang, M.; Tang, W. Synthesis of naturally occurring tropones and tropolones. Tetrahedron 2014, 70 (49), 9281-9305. DOI: 10.1016 / j.tet.2014.07.065 PubMed. (13) Bunyapaiboonsri, T.; Veeranondha, S.; Boonruangprapa, T.; Somrithipol, S. Ramiferin, a bisphenol-sesquiterpene from the fungus Kionochaeta ramifera BCC 7585. Phytochem. Lett. 2008, 1 (4), 204-206. DOI: https: / / doi.org / 10.1016 / j.phytol.2008.09.008. (14) Zhang, J.; Liu, L.; Wang, B.; Zhang, Y.; Wang, L.; Liu, X.; Che, Y. Phomanolides A and B from the fungus Phoma sp.: meroterpenoids derived from a putative tropolonic sesquiterpene via Hetero-Diels–Alder reactions. J. Nat. Prod.2015, 78 (12), 3058-3066. DOI: 10.1021 / acs.jnatprod.5b00969. (15) El-Elimat, T.; Raja, H. A.; Ayers, S.; Kurina, S. J.; Burdette, J. E.; Mattes, Z.; Sabatelle, R.; Bacon, J. W.; Colby, A. H.; Grinstaff, M. W.; et al. Meroterpenoids from Neosetophoma sp.: a dioxa[4.3.3]propellane ring system, potent cytotoxicity, and prolific expression. Org. Lett. 2019, 21 (2), 529-534. From http: / / worldcat.org / z-wcorg / . (16) Al Subeh, Z. Y.; Chu, N. Q.; Korunes-Miller, J. T.; Tsai, L. L.; Graf, T. N.; Hung, Y. P.; Pearce, C. J.; Grinstaff, M. W.; Colby, A. H.; Colson, Y. L.; et al. Delivery of eupenifeldin via polymer-coated surgical buttresses prevents local lung cancer recurrence. J. Control. Release 2021, 331, 260-269. DOI: 10.1016 / j.jconrel.2021.01.026. (17) Bentley, R. A fresh look at natural tropolonoids. Nat. Prod. Rep. 2008, 25 (1), 118-138. DOI: 10.1039 / b711474e. (18) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc. 2005, 127 (1), 210-216. DOI: 10.1021 / ja0471525. (19) Worrell, B. T.; Malik, J. A.; Fokin, V. V. Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions. Science (New York, N.Y.) 2013, 340 (6131), 457-460. DOI: 10.1126 / science.1229506. (20) The ACD Percepta software. The platform for in silico molecular property calculations. 2020.2.0. (21) Amrine, C. S. M.; Huntsman, A. C.; Doyle, M. G.; Burdette, J. E.; Pearce, C. J.; Fuchs, J. R.; Oberlies, N. H. Semisynthetic Derivatives of the Verticillin Class of Natural Products through Acylation of the C11 Hydroxy Group. ACS Med Chem Lett 2021, 12 (4), 625-630. (2) Lemoucheux, L.; Rouden, J.; Ibazizene, M.; Sobrio, F.; Lasne, M.-C. Debenzylation of Tertiary Amines Using Phosgene or Triphosgene: An Efficient and Rapid Procedure for the Preparation of Carbamoyl Chlorides and Unsymmetrical Ureas. Application in Carbon-11 Chemistry. J. Org. Chem. 2003, 68 (19), 7289–7297. The compounds, compositions, and methods of the appended claims are not limited in scope by the specific compounds, compositions, and methods described herein, which are intended as illustrations of a few aspects of the claims. Any compounds, compositions, and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compounds, compositions, and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compounds, components, compositions, and method steps disclosed herein are specifically described, other combinations of the compounds, components, compositions, and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than where noted, all numbers expressing geometries, dimensions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A compound defined by Formula IFormula I or a pharmaceutically acceptable salt, prodrug, and / or tautomer thereof, wherein R1is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)-NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R2is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)-NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; R3is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra),carbamyl (-C(=O)-NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl- C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rais selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3- 10 cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rband Rcare independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1- 4 alkylene, 6-10 membered aryl-C1-4alkylene, and 5-10 membered heteroaryl-C1-4alkylene, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups; and each RAis independently selected from OH, NO2, CN, N3, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C1-6alkoxy, C1-6haloalkoxy, alkyleneoxy, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, amino, C1-6alkylamino, di(C1-6alkyl)amino, thio, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, carbamyl, C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, carboxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylcarbonylamino, C1-6alkylsulfonylamino, aminosulfonyl, C1-6alkylaminosulfonyl, di(C1-6alkyl)aminosulfonyl,aminosulfonylamino, C1-6alkylaminosulfonylamino, di(C1-6alkyl)aminosulfonylamino, aminocarbonylamino, C1-6alkylaminocarbonylamino, and di(C1-6alkyl)aminocarbonylamino; with the proviso that at least one of R1, R2, and R3is not hydrogen.

2. The compound of claim 1, wherein R3is hydrogen.

3. The compound of claim 1, wherein R3is carbonyl (-C(=O)-Rd).

4. The compound of claim 3, wherein Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

5. The compound of claim 4, wherien Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

6. The compound of any one of claims 3-5, wherein R3is selected from one of the following7. The compound of any one of claims 3-6, wherein R3is selected from one of the following.

8. The compound of any one of claims 1-7, wherein R1and R2are each independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy, sulfonyl (-S(=O)2-Ra), carbamyl (-C(=O)- NRbRc), carboxy, and carbonyl (-C(=O)-Rd), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl,C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

9. The compound of any one of claims 1-8, wherein R1and R2are identical.

10. The compound of any one of claims 1-9, wherein R1, R2, or a combination thereof are selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C3-10cycloalkyl- C1-4alkylene, 4-10 membered heterocycloalkyl-C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, C3-10cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4- 10 membered heterocycloalkyl, C3-10cycloalkyl-C1-4alkylene, 4-10 membered heterocycloalkyl- C1-4alkylene, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, alkyleneoxy are each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

11. The compound of any one of claims 1-10, wherein R1and R2and each selected from C1-6alkyl, C2-6alkynyl, 6-10 membered aryl-C1-4alkylene, 5-10 membered heteroaryl-C1-4alkylene, and alkyleneoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

12. The compound of any one of claims 1-11, wherein R1and R2and each selected from one of the following.

13. The compound of any one of claims 1-10, wherein R1and R2are each sulfonyl (-S(=O)2- Ra).

14. The compound of claim 13, wherein R1and R2are each selected from C1-6alkylsulfonyl, C2-6alkenylsulfonyl, C2-6alkynylsulfonyl, C1-4haloalkylsulfonyl, C3-10cycloalkylsulfonyl, 6-10 membered arylsulfonyl, 5-10 membered heteroarylsulfonyl, 4-10 membered heterocycloalkylsulfonyl, C3-10cycloalkyl-C1-4alkylenesulfonyl, 4-10 membered heterocycloalkyl-C1-4alkylenesulfonyl, 6-10 membered aryl-C1-4alkylenesulfonyl, 5-10membered heteroaryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

15. The compound of any one of claims 13-14, wherein R1and R2are each selected from C1- 6 alkylsulfonyl, 6-10 membered arylsulfonyl, and 6-10 membered aryl-C1-4alkylenesulfonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

16. The compound of any one of claims 13-15, wherein R1and R2and each selected from one of the following17. The compound of any one of claims 1-10, wherein R1and R2are each carbamyl (- C(=O)-NRbRc).

18. The compound of claim 17, wherein R1and R2are each selected from C1-6alkylcarbamyl, di(C1-6alkyl)carbamyl, C1-6alkenylcarbamyl, di(C1-6alkenyl)carbamyl, C1-6alkynylcarbamyl, di(C1-6alkynyl)carbamyl, C1-6haloalkylcarbamyl, di(C1-6haloalkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, di(6-10 membered aryl)carbamyl, 5-10 membered heteroarylcarbamyl, di(5-10 membered heteroaryl)carbamyl, 4-10 membered heterocycloalkylcarbamyl, di(4-10 membered heterocycloalkyl)carbamyl, C3-10cycloalkyl-C1-4alkylenecarbamyl, di(C3-10cycloalkyl-C1-4alkylene)carbamyl, 6-10 membered aryl-C1-4alkylenecarbamyl, di(6-10 membered aryl-C1-4alkylene)carbamyl, 5-10 membered heteroaryl-C1-4alkylenecarbamyl, di(5-10 membered heteroaryl-C1-4alkylene)carbamyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbamyl, di(4-10 membered heterocycloalkyl-C1-4alkylene)carbamyl, alkyleneonycarbamyl, anddi(alkyleneoxy)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

19. The compound of any one of claims 17-18, wherein R1and R2are each selected from C1- 6 alkylcarbamyl, di(C1-6alkyl)carbamyl, C3-10cycloalkylcarbamyl, di(C3-10cycloalkyl)carbamyl, 6-10 membered arylcarbamyl, and di(6-10 membered aryl)carbamyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

20. The compound of any one of claims 17-19, wherein R1and R2and each selected from one of the following21. The compound of any one of claims 1-10, wherein R1and R2are each carbonyl (-C(=O)- Rd).

22. The compound of claim 21, wherein R1and R2are each selected from C1-6alkylcarbonyl, C2-6alkenylcarbonyl, C2-6alkynylcarbonyl, C1-4haloalkylcarbonyl, C1-6alkoxycarbonyl, C3-10cycloalkylcarbonyl, 6-10 membered arylcarbonyl, 5-10 membered heteroarylcarbonyl, 4-10 membered heterocycloalkylcarbonyl, C3-10cycloalkyl-C1-4alkylenecarbonyl, 4-10 membered heterocycloalkyl-C1-4alkylenecarbonyl, 6-10 membered aryl-C1-4alkylenecarbonyl, 5-10 membered heteroaryl-C1-4alkylenecarbonyl, and alkyleneonycarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

23. The compound of claim 22, wherein R1and R2are each selected from C1-6alkylcarbonyl, C1-6alkoxycarbonyl, and C3-10cycloalkylcarbonyl, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

24. The compound of claim 21, wherein Rdis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

25. The compound of claim 24, wherien Rdis selected from C1-6alkyl, C1-4haloalkyl, alkyleneoxy, C1-6alkoxy, and C1-6haloalkoxy, each optionally substituted with 1, 2, 3, or 4 independently selected RAgroups.

26. The compound of any one of claims 21-25, wherein R1and R2are each selected from one of the following27. The compound of any one of claims 1-26, wherein R1, R2, R3, or any combination thereof, comprises a click motif.

28. The compound of claim 27, wherein the click motif comprises an alkyne.

29. The compound of any one of claims 1-28, wherein the compound comprises one of the following30. A pharmaceutical composition comprising a compound of any one of claims 1-29 dissolved or dispersed in a pharmaceutically acceptable carrier.

31. A method for treating or preventing cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 to treat or prevent the cancer.

32. The method of claim 31, wherein the cancer comprises a solid tumor.

33. The method of any one of claims 31-32, wherein the cancer is selected from lymphoma, myeloid leukemia, bladder cancer, brain cancer, head and neck cancer, kidney cancer, lung cancer, myeloma, ovarian cancer, cervical cancer, bone cancer, thyroid cancer, adrenal gland cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, skin cancer, liver cancer, testicular cancer, colon cancer, or breast cancer.

34. The method of any one of claims 31-33, wherein the cancer is selected from melanoma and breast cancer.

35. The method of any one of claims 31-34, wherein the compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 is administered by one or more routes selected from the group consisting of buccal, sublingual, intravenous, subcutaneous, intradermal, transdermal, intraperitoneal, oral, eye drops, parenteral, and topical administration.

36. The method of any one of claims 31-35, wherein the compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 is administered in combination with an additional treatment for the cancer.

37. The method of claim 36, wherein the additional treatment for the cancer comprises radiotherapy, surgery, administration of one or more additional active agents, or a combination thereof.

38. A method for treating or preventing a parasitic infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 to treat or prevent the parasitic infection.

39. The method of claim 38, wherein the parasitic infection is selected from leishmaniasis, malaria, human African trypanomiasis, babesiosis, Chagas disease, microsporidiosis, pneumocystosis, primary ameobic meningoenchephalitis, and toxoplasmosis.

40. The method of claim 39, wherein the parasitic infection comprises malaria.

41. A method for treating or preventing a fungal infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 to treat or prevent the fungal infection.

42. A method for treating or preventing a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound defined by any one of claims 1-29 or the pharmaceutical composition of claim 30 to treat or prevent the bacterial infection.

Images