Cleavable linkers with tunable half-lives

Abstract

The present disclosure is concerned with chemical release agents containing a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent such as, for example, a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, containing the compounds, and methods for using the same. Also disclosed are intermediate compounds useful in the preparation of chemical release agents. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

CLEAVABLE LINKERS WITH TUNABLE HALF-LIVESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63 / 639,376, filed on April 26, 2024, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0001] Many drugs and drug candidates are suboptimal or ineffective due to a short duration of action. For example, peptides and proteins with promising therapeutic value often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to polyethylene glycol (PEG), the Fc portion of IgG, serum albumin, and other long-lived macromolecules. These large carriers slow kidney filtration, thereby increasing the plasma half-life of the attached drug. To date, much success has been realized using PEG as the macromolecular carrier. PEG is nontoxic and nonimmunogenic, and the plasma half-life is a function of hydrodynamic size. Conjugation of drugs to PEG with molecular mass ~40 kDa has been successfully used with peptides, nucleic acids, and small molecules and can afford half-lives of up to ~7 d in humans. As of 2011, ten PEGylated peptide-based drugs had been approved by the Food and Drug Administration (FDA) and ~40 were in clinical trials (Alconcel et al. (2011 ) Polym. Chem. 2: 1442-1448; Fishburn, C. S. (2008) J. Pharm. Sci 97: 4167-4183).

[0002] Unfortunately, the currently marketed PEG-protein conjugates are permanently PEGylated. Moreover, attachment of large PEG moi eties often reduces the therapeutic activity of the active agent and higher concentrations of conjugate are necessary to achieve the required biological activity. A further limitation is that permanent PEGylation is generally not applicable to small-molecule drugs because the bulky carrier usually prevents their binding to targets and cell penetration.

[0003] To circumvent these issues, releaseable macromolecule attachment to therapeutic and diagnostic agents has been investigated. See, e.g., Filpula and Zhao (2008) Adv. Drug Deliv. Rev. 60: 29-49. Here, the drug is attached to the macromolecular carrier (e.g., PEG) by a linker that is cleaved to release the native drug. For example, linkers have been developed that can be cleaved under physiological conditions and for which the rate of drug release cancontrolled via an electon-withdrawing modulator (Santi et. al. (2012) PNAS 109(6): 6211- 6216). These types of linkers have been designed for slow release of drugs with a minimum reported half-life of in vitro cleavage of 14 hours (Santi, D.V. et. al. (2012) PNAS 109(6): 6211-6216). Similarly, a fluorenyloxy carbonyl based analog has also been utilized as linker between a PEG polymeric moiety and a drug with a non-enzymatic cleavage half-life of between 8.4 and 13.8 hours (Tsubery et al. (2004) Journal of Biological Chemistry 279(37): 38118-38124). In each case, the applicability remains limited due to the slow release rate.

[0004] Cleavage of linkers via enzymatic hydrolysis and redox mechanisms may provide faster release kinetics; however, these methods have their own limitations. In particular, enzymatic hydrolysis via esterases to separate the polymeric attachment can be difficult to regulate and have greater variance (i.e., non-first order release rates). Further, the rate of enzymatic hydrolysis remains largely unpredictable and is uncontrollable under physiological conditions. Release of macromolecule linked therapeutic agents by redox mechanisms (e.g., disulfide based bonds) is limited by environmental constraints, requiring select environments with high concentrations of disulfide bond cleavage agents such as tumor tissues and cytosol. In addition, cleavage in serum is yet quite slow.

[0005] Thus, despite the advancements made in developing macromolecular conjugates for controlled chemical release, cleavable linkers that are stable during storage but that dissociate in a controlled, rapid manner upon administration have remained elusive. Therefore, there remains a need for linkers with predictable and tunable properties and making and using same.SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds, and compositions comprising the compounds, for use as chemical release agents. As disclosed herein, the chemical release agents contain a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent such as, for example, a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent. Also disclosed are compounds useful in the preparation of the chemical release agents, as further described herein.

[0007] Thus, disclosed are compounds having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then R1is hydrogen, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety, and provided that when n is 2 and R1is the tethering moiety, then the tethering moiety is not -NH2.

[0008] Also disclosed are compounds having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (Cl- C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety.

[0009] Also disclosed are compounds having a structure represented by a formula:wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0010] Also disclosed are compounds having a structure represented by a formula:wherein Z is selected fromand *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0011] Also disclosed are methods of administering a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent to a subject in need thereof, the method comprising administering to the subject a compound having a structure represented by a formula:wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0012] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.BRIEF DESCRIPTION OF THE FIGURES

[0013] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0014] FIG. 1A-D show representative data illustrating the effect of substitution around the benzisooxazolyl ring on the corresponding Kemp elimination rates.

[0015] FIG. 2A-C show representative data depicting the release of a fluorophore from a benzisoxazole derivative and corresponding monitoring of fluorophore release.

[0016] FIG. 3 shows a representative schematic depicting the release of a therapeutic agent.

[0017] FIG. 4 shows a representative schematic depicting the stability of the linker in storage solution and serum and the corresponding proposed cleavage mechanism.

[0018] FIG. 5A and FIG. 5B show a representative approach for utilization of a cleavable linker in targeted therapy.

[0019] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.DETAILED DESCRIPTION

[0020] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0021] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0022] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-expressbasis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0023] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.A. DEFINITIONS

[0024] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referent. s unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0025] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0026] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular 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. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0027] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It isgenerally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0028] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0029] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0030] As used herein, “ICso” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an ICso can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0031] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.

[0032] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0033] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0034] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, z.e., arresting its development; or (iii) relieving the disease, z.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0035] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially byadvance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0036] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0037] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0038] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0039] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxy cholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxy ethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0040] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0041] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0042] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-ALS agents such as entry inhibitors, fusion inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7 inhibitors, protease inhibitors, and integrase inhibitors; analgesics and analgesic combinations, anorexics, antiinflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinicagents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0043] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, z.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0044] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0045] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

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

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

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

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

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

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

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

[0053] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a — , where “a” is an integer of from 2 to 500.

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

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

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

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

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

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

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

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

[0062] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0063] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0064] The term “dialkylamino” as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like.

[0065] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0066] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or — (A1O(O)C-A2-OC(O))a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0067] The term “ether” as used herein is represented by the formula AXOA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A10-A20)a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0068] The terms “halo,” “halogen,” or “halide,” as used herein, can be used interchangeably and refer to F, Cl, Br, or I.

[0069] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as used herein, can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0070] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0071] The term “heteroaryl,” as used herein, refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, A-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodi oxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzoft ] oxazolyl, benzo[ ]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0072] The terms “heterocycle” or “heterocyclyl,” as used herein, can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2, 3 -thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2, 3 -triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0073] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein, refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyri din-3 -yl.

[0074] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0075] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0076] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0077] The term “azide” or “azido” as used herein is represented by the formula — Ns.

[0078] The term “nitro” as used herein is represented by the formula — NO2.

[0079] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0080] The term “silyl” as used herein is represented by the formula — SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0081] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)AX, — S(O)2AX, — OS(O)2A1, or — OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2AX, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0082] The term “thiol” as used herein is represented by the formula — SH.

[0083] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (z.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0084] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z.e., further substituted or unsubstituted).

[0085] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0086] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o4R°; -(CH2)o4OR°; -0(CH2)o-4R°, - 0-(CH2)O4C(O)ORO; -(CH2)O4CH(ORO)2; -(CH2)O4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)o40(CH2)o i Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; - (CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)O4C(O)RO; -C(S)R°; -(CH2)O4C(O)OR°; -(CH2)O4C(O)SRO; -(CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°; -OC(0)(CH2)o4SR-, SC(S)SR°; -(CH2)o4SC(O)R°; -(CH2)o ^C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O4SSRO; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2RO; -S(O)2NR°2; -(CH2)O4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO;-P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°s; -(Ci-4straight or branched alkylene)O-N(R°)2; or — (Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)O iPh, - CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0087] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, - (CH2)O2R*, -(haloR*), -(CH2)O2OH, -(CH2)O2OR*, -(CH2)O2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)O2C(O)R*, -(CH2)O2C(O)OH, -(CH2)O2C(O)OR*, -(CH2)O2SR*, -(CH2)O2SH, -(CH2)O2NH2, -(CH2)O2NHR*, -(CH2)O2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci4straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4aliphatic, -CH2Ph, -0(CH2)O iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0088] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*,wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)23O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may besubstituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0089] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0090] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R\ -NRT, -C(O)Rf, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRf2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R:is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0091] Suitable substituents on the aliphatic group of R:are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, tritiate, mesylate, tosylate, and brosylate.

[0093] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids,and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0094] The term “organic residue” defines a carbon-containing residue, z.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di -substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0095] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:

[0096] regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (z.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0097] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatomsbound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di -substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0098] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0099] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0100] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also bereferred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0101] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0102] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greaterthan 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0103] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S) / (R,R) and (R,S) / (S,R)). The pairs of enantiomers (e.g., (S,S) / (R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0104] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0105] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio-actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[0106] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, z.e.,3H, and carbon-14, z.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, z.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0107] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0108] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., TheRoyal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0109] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.keto form enol form amide form imidic acid form

[0110] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, ^-un substituted, 3-A3and A1-unsubstituted, 5-A3as shown below.

[0111] Unless stated to the contrary, the invention includes all such possible tautomers.

[0112] It is known that chemical substances form solids that are present in different states of order, which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0113] In some aspects, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:wherein n is typically an integer. That is, R" is understood to represent five independent substituents, R"(a), R"(b), R"(c), R"(d), R"(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R"(a)is halogen, then R"(b)is not necessarily halogen in that instance.

[0114] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0115] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0116] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that whencombinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0117] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.B. BENZISOXAZOLE COMPOUNDS

[0118] In one aspect, disclosed are benzisoxazole compounds useful as intermediates for the preparation of chemical release agents containing a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent such as, for example, a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent.

[0119] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by thedisclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.1. STRUCTURE

[0120] In one aspect, disclosed are compounds having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then R1is hydrogen, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety, and provided that when n is 2 and R1is the tethering moiety, then the tethering moiety is not -NH2.

[0121] In one aspect, disclosed are compounds having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (Cl- C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, wherein R3is a residueof a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety.

[0122] In one aspect, disclosed are compounds having a structure represented by a formula:wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0123] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0124] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0125] In various aspects, the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0126] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0127] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0128] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0129] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0130] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0131] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0132] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0133] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0134] In various aspects, the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0135] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0136] In one aspect, n is selected from 0, 1, 2, 3, or 4. In a further aspect, n is selected from from 0, 1, 2, or 3. In a still further aspect, n is selected from from 0, 1, or 2. In a yet further aspect, n is selected from 0 or 1. In an even further aspect, n is 0. In an even still further aspect, n is 1. a. L GROUPS

[0137] In one aspect, L is a linker. As used herein, the term “linker” means an organic group that attachs the tethering moiety, as defined herein, to the polymeric moiety, as defined herein. As would be understood by one of skill in the art, the linker can be formed by a conjugation reaction between, for example, an alkyne and an azide, a carboxylic acid and an amine, or an amide and an alcohol. Examples of linkers include, but are not limited to, triazoles, amides, amines, ethers, thioethers, alkenes, and imines. Additional examples of linkers are described in standard reference textbooks such as “Bioconjugate Techniques” (Greg T. Hermanson, Academic Press Inc., 1996).

[0138] In various aspects, L is a linker having a structure selected from:wherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring.

[0139] In various aspect, L is a linker having a structure selected from:

[0140] In a further aspect, Lisa linker having a structure selected from:

[0141] In a still further aspect, L is a linker having a structure selected from:

[0142] In a yet further aspect, Lisa linker having a structure:

[0143] In an even further aspect, Lisa linker having a structure:

[0144] In an even still further aspect, Lisa linker having a structure:

[0145] In a yet even further aspect, Lisa linker having a structure:

[0146] In various aspects, Lisa linker having a structure selected from

[0147] In a further aspect, Lisa linker having a structure:

[0148] In a still further aspect, Lisa linker having a structure:

[0149] In various aspects, Lisa linker having a structure selected fromwherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring.

[0150] In a further aspect, Lisa linker having a structure:

[0151] In a still further aspect, Lisa linker having a structure:

[0152] In various aspects, L is a linker having a structure selected from:wherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring.

[0153] In a further aspect, L is a linker having a structure:

[0154] In a still further aspect, L is a linker having a structure:

[0155] In various aspects, the L is a linker having a structure:wherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring.

[0156] In a further aspect, L is a linker having a structure:

[0157] In a still further aspect, L is a linker having a structure:

[0158] In various aspects, L is a linker having a structure:wherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring.

[0159] In various aspects, L is a linker and does not have a structure:wherein * denotes a bond connected to P and ** denotes a bond connected to benzisoxazole ring. b. P GROUPS

[0160] In one aspect, P is a polymeric moiety. As used herein, the term “polymeric moiety” means a single polymeric chain (branched or unbranched) that is derived from a biopolymer with biodegradable and biocompatible, which is useful in in vitro and in vivo applications. The polymeric moiety can be a synthetic polymer moiety (e.g., a residue of polyethylene glycol (PEG), polyethylenimine (PEI), polyacrylic acid (PAA), or polyvinyl alcohol (PVA)) or a natural polymer moiety (e.g., a residue of alginate, chitosan, hyaluronic acid, or dextran). As detailed herein, the properties of a compound (e.g., a benzisoxazole compound as described herein) can be modified via covalent attachment to a polymeric moiety. For example, the biocompatibility and / or in vivo stability of a compound can be improved via conjugation to a polymeric moiety. Additional exemplary polymeric moieties include, but are not limited to, polysaccharides, poly ethers, polyamino acids (e.g., polylysine), polyvinyl alcohols, polyvinylpyrrolidinones, poly(meth)acrylic acid and derivatives thereof, polyurethanes, and polyphosphazenes.

[0161] In various aspects, the polymeric moiety is a synthetic polymeric moiety. In various further aspects, the polymeric moiety is a natural polymeric moiety.

[0162] Typically, a polymeric moiety as used herein contains at least 5 monomeric units. Thus, in various aspects, the polymeric moiety contains at least 15 monomeric units, at least 20 monomeric units, at least 25 monomeric units, or at least 30 monomeric units.

[0163] In various aspects, the polymeric moiety has a molecular weight of from about 10,000 and to about 500,000. Thus, in various further aspects, the polymeric moiety has a molecular weight of from about 10,000 to about 450,000, about 10,000 to about 400,000, about 10,000 to about 350,000, about 10,000 to about 300,000, about 10,000 to about 250,000, about 10,000 to about 200,000, about 10,000 to about 150,000, about 10,000 to about 100,000, about 10,000 to about 50,000, about 10,000 to about 25,000, about 10,000 to about 20,000, about 20,000 to about 500,000, about 25,000 to about 500,000, about 50,000 to about 500,000, about 100,000 to about 500,000, about 150,000 to about 500,000, about 200,000 to about 500,000, about 250,000 to about 500,000, about 300,000 to about 500,000, about 350,000 to about 500,000, about 400,000 to about 500,000, about 450,000 to about 500,000, about 20,000 to about 450,000, about 25,000 to about 400,000, about 50,000 to about 350,000, about 100,000 to about 300,000, or about 150,000 to about 250,000.

[0164] In various aspects, the polymeric moiety is a derivatized linear, branched, or dendrimeric PEG, monomethoxy-PEG (mPEG), PEI, or PEG-PEI copolymer. Various sizes of derivatized synthetic polymers like PEG and mPEG are commercially available, having a variety of terminal functional groups resulting in molecules comprising hydroxyl, amine, azide, carboxyl, aldehyde, N-hydroxysuccinimidyl ester, imidazolylcarboxamino, imidazolylcarboxy, nitrophenyl carbonate, isocyanate, maleimide, thiol, or epoxide functional groups. Other synthetic polymer derivatives may be prepared using methods known in the art such as, for example, by derivitization using a bromomethyl-substituted aromatic or heteroaromatic aldehyde or an allyl or propargyl halide.

[0165] In a various aspect, the polymeric moiety is a residue of a polymer selected from PEG, PEI, PAA, and PVA.

[0166] In various aspects, the polymeric moiety is a PEG residue. c. Z GROUPS

[0167] In one aspects, Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**, wherein * denotes a bond connected to R3and ** denotes a bond connected to O. In a further aspect, Z is selected from *-NHC(O)-** and *-OC(O)-**. In yet a further aspect, Z is selected from *-NHC(O)-** and *-C(O)-**. In an even further aspect, Z is selected from *-OC(O)-** and *-C(O)-**. In a still further aspect, Z is *-NHC(O)-**. In yet a further aspect, Z is *-OC(O)-**. In an even further aspect, Z is *-C(O)-**.d. R1GROUPS

[0168] In one aspect, R1is selected from hydrogen and a tethering moiety.

[0169] In various aspects, R1is hydrogen.

[0170] In various aspects, R1is a tethering moiety. As used herein, the term“tethering moiety” means a functional group that is capable of being attached to a polymeric moiety as further described herein. Examples of tethering moieties include, but are not limited to, -CCH, -NH2, -N3, -CO2H, -C(O)NH2, -OH, -SH, -Cl, -Br, -I, -CH=CH2, - C(O)H, and a structure:

[0171] In various aspect, the tethering moiety is selected from -CCH, -NH2, -N3, -CO2H, and -C(O)NH2. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is -NH2. In a yet further aspect, the tethering moiety is -N3. In an even further aspect, the tethering moiety is -CO2H. In an even still further aspect, the tethering moiety is -C(O)NH2.

[0172] In various aspects, the tethering moiety is selected from -CCH and -CO2H. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is -CO2H.

[0173] In various aspects, the tethering moiety is selected from -NH2, -N3, and -C(O)NH2. In a further aspect, the tethering moiety is selected from -NH2and -N3. In a still further aspect, the tethering moiety is selected from -NH2and -C(O)NH2. In a yet further aspect, the tethering moiety is selected from -NH2and -N3. In an even further aspect, the tethering moiety is -NH2. In an even still further aspect, the tethering moiety is -N3. In an even still further aspect, the tethering moiety is -C(O)NH2.

[0174] In various aspects, the tethering moiety is selected from -CCH and -N3. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is — N3.

[0175] In various aspects, the tethering moiety is selected from -NH2and -COzH. In a further aspect, the tethering moiety is -NH2. In a still further aspect, the tethering moiety is -CO2H.

[0176] In various aspects, the tethering moiety is -CCH.

[0177] In various aspects, the tethering moiety is not -NH2. e. R2A, R2B, AND R2CGROUPS

[0178] In one aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, - N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCI3, -OCH3, -NHCH3, - N(CHS)2, -CH2NH2, and a tethering moiety.

[0179] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3,-CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2C1, -CH2CC13, -CH2CHC12, -CH2CH2C1, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHC12, -CH2CH2CC13, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2C1, -CHCh, -CC13, -CH2CH2C1, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, and a tethering moiety.

[0180] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2J-CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, - NHCH2CH3, -N(CH3)2, -CH2NH2, and a tethering moiety.

[0181] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, methyl, ethyl, - OCH3, -OCH2CH3, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, -OH, methyl, -OCH3, and a tethering moiety.

[0182] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and a tethering moiety. In afurther aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, methyl, and a tethering moiety.

[0183] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, C1-C6 alkyl, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, C1-C4 alkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, methyl, ethyl, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, methyl, and a tethering moiety.

[0184] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, and a tethering moiety.

[0185] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and a tethering moiety.

[0186] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CC13, -CH2CH2CI, -0CH3, -OCH2CH3, -NHCH3, - NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCI3, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0187] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and-CH2CH2CI. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CCI3.

[0188] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -NH2, -NHCH3, - NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0189] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, each of R2a, R2b, and R2Cis independently selected from hydrogen, -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and - OCH(CH3)CH3. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -OH, methyl, and -OCH3.

[0190] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, and methyl.

[0191] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen and C1-C6 alkyl. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R2a, R2b, and R2cisindependently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen and methyl.

[0192] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0193] In various aspects, each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0194] In various aspects, one of R2a, R2b, and R2cis hydrogen. In a further aspect, two of R2a, R2b, and R2care hydrogen. In a still further aspect, each of R2a, R2b, and R2cis hydrogen.

[0195] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI,-CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -0CH3, -NHCH3, -N(CH3)2, -CH2NH2, and a tethering moiety.

[0196] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2ais selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2ais selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2ais selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2ais selected from -F, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, and a tethering moiety.

[0197] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, R2ais selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2ais selected from -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, - N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2ais selected from -NH2, -NHCH3, -NHCH2CH , -N(CH3)2, -CH2NH2, and a tethering moiety.

[0198] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from -OH, C1-C6 alkyl, C1-C6 alkoxy, and a tethering moiety. In a further aspect, R2ais selected from -OH, C1-C4 alkyl, C1-C4 alkoxy, and a tethering moiety. In a still further aspect, R2ais selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, and a tethering moiety. In a yet further aspect, R2ais selected from -OH, methyl, ethyl, -OCH3, -OCH2CH3, and a tethering moiety. In an even further aspect, R2ais selected from -OH, methyl, -OCH3, and a tethering moiety.

[0199] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and a tethering moiety. In a further aspect, R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and a tethering moiety. In an even further aspect, R2ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, and a tethering moiety.

[0200] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from C1-C6 alkyl, and a tethering moiety. In a further aspect, R2ais selected from C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2ais selected from methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, R2ais selected from methyl, ethyl, and a tethering moiety. In an even further aspect, R2ais selected from methyl, and a tethering moiety.

[0201] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2ais selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CC13, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCI2, -CH2CH2CC13, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -NO2, methyl,ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2ais selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, and a tethering moiety.

[0202] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from-F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and a tethering moiety.

[0203] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CC13, -CH2CH2CI, -0CH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0204] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2ais selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2ais selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. Ina yet further aspect, R2ais selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R2ais selected from -F, methyl, -CH2F, -CHF2, -CF^-C bCl, -CHCh, and -CCI3.

[0205] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2ais selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2ais selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0206] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R2ais selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R2ais selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R2ais selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R2ais selected from -OH, methyl, and -OCH3.

[0207] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R2ais selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R2ais selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0208] In various aspects, each of R2band R2cis hydrogen, and R2ais C1-C6 alkyl. In a further aspect, R2ais C1-C4 alkyl. In a still further aspect, R2ais selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2ais selected from methyl, and ethyl. In an even further aspect, R2ais methyl.

[0209] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2ais selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2ais selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2,-CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R2ais selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R2ais selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0210] In various aspects, each of R2band R2cis hydrogen, and R2ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0211] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2C1, -CHCh, -CC13, -CH2CH2CI, -0CH3, -OCH2CH3, -NHCH3, - NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, -CH2NH2, and a tethering moiety.

[0212] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2bisselected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2bis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2bis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2bis selected from -F, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, and a tethering moiety.

[0213] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In a further aspect, R2bis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2bis selected from -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, - N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, -CH2NH2, and a tethering moiety.

[0214] In various aspects each of R2aand R2cis hydrogen, and R2bis selected from -OH, C1-C6 alkyl, C1-C6 alkoxy, and a tethering moiety. In a further aspect, R2bis selected from -OH, C1-C4 alkyl, C1-C4 alkoxy, and a tethering moiety. In a still further aspect, R2bis selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, and a tethering moiety. In a yet further aspect, R2bis selected from -OH, methyl, ethyl, -OCH3, -OCH2CH3, and a tethering moiety. In an even further aspect, R2bis selected from -OH, methyl, -OCH3, and a tethering moiety.

[0215] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and a tethering moiety. In a further aspect, R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl,isopropyl, and a tethering moiety. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and a tethering moiety. In an even further aspect, R2bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, and a tethering moiety.

[0216] In various aspects each of R2aand R2cis hydrogen, and R2bis selected from C1-C6 alkyl, and a tethering moiety. In a further aspect, R2bis selected from C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2bis selected from methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, R2bis selected from methyl, ethyl, and a tethering moiety. In an even further aspect, R2bis selected from methyl, and a tethering moiety.

[0217] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2bis selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2bis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCI3, and a tethering moiety.

[0218] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and a tethering moiety.

[0219] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2,-CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCI2, -CH2CH2CC13, -CH2CH(C1)CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2C1, -CHCh, -CC13, -CH2CH2CI, -OCH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0220] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2bis selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2bis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CC13, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCI2, -CH2CH2CC13, and -CH2CH(C1)CH3. In a yet further aspect, R2bis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CC13, and -CH2CH2CI. In an even further aspect, R2bis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CC13.

[0221] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2bis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2bis selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0222] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from-OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R2bis selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R2bis selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R2bis selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R2bis selected from -OH, methyl, and -OCH3.

[0223] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R2bis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R2bis selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0224] In various aspects, each of R2aand R2cis hydrogen, and R2bis C1-C6 alkyl. In a further aspect, R2bis C1-C4 alkyl. In a still further aspect, R2bis selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2bis selected from methyl, and ethyl. In an even further aspect, R2bis methyl.

[0225] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2bis selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2bis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R2bis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R2bis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0226] In various aspects, each of R2aand R2cis hydrogen, and R2bis selected from-F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0227] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety. In afurther aspect, R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2cis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, -CH2NH2, and a tethering moiety.

[0228] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2cis selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2cis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2Cis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2cis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCI3 and a tethering moiety.

[0229] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tetheringmoiety. In a further aspect, R2cis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and a tethering moiety. In a still further aspect, R2cis selected from -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, - N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and a tethering moiety. In a yet further aspect, R2cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and a tethering moiety. In an even further aspect, R2cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, -CH2NH2, and a tethering moiety.

[0230] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -OH, C1-C6 alkyl, C1-C6 alkoxy, and a tethering moiety. In a further aspect, R2cis selected from -OH, C1-C4 alkyl, C1-C4 alkoxy, and a tethering moiety. In a still further aspect, R2cis selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, and a tethering moiety. In a yet further aspect, R2cis selected from -OH, methyl, ethyl, -OCH3, -OCH2CH3, and a tethering moiety. In an even further aspect, R2cis selected from -OH, methyl, -OCH3, and a tethering moiety.

[0231] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and a tethering moiety. In a further aspect, R2Cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and a tethering moiety. In an even further aspect, R2cis selected from -F, -NH2, -OH, -NO2, -CN, methyl, and a tethering moiety.

[0232] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from C1-C6 alkyl, and a tethering moiety. In a further aspect, R2cis selected from C1-C4 alkyl, and a tethering moiety. In a still further aspect, R2cis selected from methyl, ethyl, propyl, isopropyl, and a tethering moiety. In a yet further aspect, R2cis selected from methyl, ethyl, and a tethering moiety. In an even further aspect, R2cis selected from methyl, and a tethering moiety.

[0233] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and a tethering moiety. In a further aspect, R2Cis selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and a tethering moiety. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, -NO2,methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and a tethering moiety. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCh, -CH2CH2CI, and a tethering moiety. In an even further aspect, R2cis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCh, and a tethering moiety.

[0234] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and a tethering moiety.

[0235] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CFh)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCh, -CH2CH2CI, -0CH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2cis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0236] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2cis selected from halogen,C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2cis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R2cis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R2cis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CCI3.

[0237] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R2cis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R2cis selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R2cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R2cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0238] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R2cis selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R2cis selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R2cis selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R2cis selected from -OH, methyl, and -OCH3.

[0239] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R2cis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R2Cis selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0240] In various aspects, each of R2aand R2bis hydrogen, and R2cis C1-C6 alkyl. In a further aspect, R2cis C1-C4 alkyl. In a still further aspect, R2cis selected from methyl,ethyl, propyl, and isopropyl. In a yet further aspect, R2cis selected from methyl, and ethyl. In an even further aspect, R2cis methyl.

[0241] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R2cis selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R2cis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R2cis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R2cis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0242] In various aspects, each of R2aand R2bis hydrogen, and R2cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0243] In various aspects, one of R2a, R2b, and R2cis the tethering moiety. Examples of tethering moieties include, but are not limited to, -CCH, -NH2, -N3, -CO2H, -C(O)NH2, -OH, -SH, -Cl, -Br, -I, -CH=CH2, -C(O)H, and a structure:

[0244] In various aspect, the tethering moiety is selected from -CCH, -NH2, -N3, -CO2H, and -C(O)NH2. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is -NH2. In a yet further aspect, the tethering moiety is -N3. In an even further aspect, the tethering moiety is -CO2H. In an even still further aspect, the tethering moiety is -C(O)NH2.

[0245] In various aspects, the tethering moiety is selected from -CCH and -CO2H. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is -CO2H.

[0246] In various aspects, the tethering moiety is selected from -NH2, -N3, and-C(O)NH2. In a further aspect, the tethering moiety is selected from -NH2 and -N3. In a stillfurther aspect, the tethering moiety is selected from -NH2 and -C(O)NH2. In a yet further aspect, the tethering moiety is selected from -NH2 and -N3. In an even further aspect, the tethering moiety is -NH2. In an even still further aspect, the tethering moiety is -N3. In an even still further aspect, the tethering moiety is -C(0)NH2.

[0247] In various aspects, the tethering moiety is selected from -CCH and -N3. In a further aspect, the tethering moiety is -CCH. In a still further aspect, the tethering moiety is -N3.

[0248] In various aspects, the tethering moiety is selected from -NH2 and -CO2H. In a further aspect, the tethering moiety is -NH2. In a still further aspect, the tethering moiety is -CO2H.

[0249] In various aspects, the tethering moiety is -CCH.

[0250] In various aspects, the tethering moiety is not -NH2. f. R3GROUPS

[0251] In one aspect, R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent. As used herein, the term “residue” means the portion of the molecule (e.g., the peptide, the protein, the oligonucleotide, the small molecule therapeutic agent) that remains after the molecule is covalently attached to, for example, the benzisoxazole core motif. Thus, for example, the residue of a peptide can refer to a peptide minus an atom or group of atoms at the N-terminus of the peptide such as, for example, a proton.

[0252] In various aspects, R3is a residue of a drug such as, for example, a peptide, a protein, a nucleic acid (e.g., aptamers or antisense oligomers), or a small molecule. Examples of suitable drugs include those for human or veterinary use including, but not limited to, antidiabetic drugs (e.g., insulin); growth promoters (e.g., human or bovine growth hormone); antibacterials including aminoglycosides (e.g., gentamicin, neomycin and streptomycin), penicillins, (amoxicillin, ampicillin, piperacillin), cephalosporins, (e.g., cefaclor, cefminox and cephalexin), macrolides (e.g, carbomycin, erythromycin, telithromycin) and peptides (e.g, bacitracin, gramicidins, and polymyxins), trimethoprim, piromidic acid, and sulfamethazine; analgesic and anti-inflammatory drugs (e.g., acetaminophen, aspirin, ibufenac, indomethacin), antiallergic and antiasthmatic drugs (e.g., amlexanox and cromolyn), antihypercholesterolemic drugs (e.g., clofibric acid, oxiniacic acid and triparanol), beta-adrenergic blockers and antihypertensive drugs (e.g., bupranolol, captopril, indenolol,propranolol and 4-aminobutanoic acid), antineoplastic drugs (e.g., daunorubicin, azacytidine, 6-mercaptopurine, interferons, interleukin-2, methotrexate, taxol 5-fluorouridine, 5- fluorouracil, capcitibine, and vinblastine), antiviral drugs e.g., acyclovir, ganciclovir, amantadine, interferons, AZT and ribavirin, etc).

[0253] Additional exemplary drugs include peptides, proteins, and nucleic acid drugs. Examples of peptide drugs include, but are not limited to, glucagon-like peptide 1 (GLP-1), exendin-2, exendin-3, exendin-4, atrial natriuretic factor (ANF), ghrellin, vasopressin, growth hormone, growth hormone-releasing hormone (GHRH), RC-3095, somatostatin, bombesin, PCK-3145, Phe-His-Ser-Cys-Asn (PHSCN), IGF1, B-type natriuretic peptide, peptide YY (PYY), interferons, thrombospondin, angiopoietin, calcitonin, gonadotropin-releasing hormone, hirudin, glucagon, anti-TNF-alpha, fibroblast growth factor, granulocyte colony stimulating factor, obinepitide, pituitary thyroid hormone (PTH), leuprolide, sermorelin, pramorelin, nesiritide, rotigaptide, cilengitide, MBP-8298, AL- 108, enfuvirtide, thymalfasin, daptamycin, HLF1-I1, Lactoferrin, Delmitide, glutathione, T-cell epitope PR1, Protease-3 peptides 1-11, B-cell epitope P3, lutenizing hormone-releasing hormone (LHRH), substance P, neurokinin A, neurokinin B, CCK-8, enkephalins, including leucine enkephalin and methionine enkephalin, dermaseptin, [des-Ala20, Gln34] -dermaseptin, surfactant-associated antimicrobial anionic peptide, Apidaecin IA; Apidaecin IB; OV-2; 1025, Acetyl -Adhesin Peptide (1025-1044) amide; Theromacin (49-63); Pexiganan (MSL78); Indolicidin; Apelin- 15 (63-77); CFP1O (71-85); Lethal Factor (LF) Inhibitor Anthrax related; Bactenecin;Hepatitis Virus C NS3 Protease Inhibitor 2; Hepatitis Virus C NS3 Protease Inhibitor 3; Hepatitis Virus NS3 Protease Inhibitor 4; NS4A-NS4B Hepatitis Virus C(NS3 Protease Inhibitor 1); HIV-I, HIV-2 Protease Substrate; Anti-FM Peptide; Bak-BH3; Bax BH3 peptide (55-74) (wild type); Bid BH3-r8; CTT (Gelatinase Inhibitor); E75 (Her-2 / neu) (369-377); GRP78 Binding Chimeric. Peptide Motif; p53(17-26); EGFR2 / KDR Antagonist; Colivelin AGA-(C8R) HNG1 7 (Humanin derivative); Activity-Dependent Neurotrophic Factor (ADNF); Beta-Secretase Inhibitor 1; Beta-Secretase Inhibitor 2; ch [beta] -Amyloid (30-16); Humanun (HN) sHNG, [Glyl4]-HN, [Glyl 4]-Humanin; Angiotensin Converting Enzyme Inhibitor (BPP); Renin Inhibitor III; Annexin 1 (ANXA-1; Ac2-12); Anti-Inflammatory Peptide 1; Anti-Inflammatory Peptide 2; Anti-Inflammatory Apelin 12; [D-Phel2, Leul4]- Bombesin; Antennapedia Peptide (acid) (penetratin); Antennepedia Leader Peptide (CT); Mastoparan; [Thr28, Nle31]-Cholecystokinin (25-33) sulfated; Nociceptin (1-13) (amide); Fibrinolysis Inhibiting Factor; Gamma-Fibrinogen (377-395); Xenin; Obestatin (human);[Hisl, Lys6]-GHRP (GHRP-6); [Ala5, [beta]-Ala8]-Neurokinin A (4-10); Neuromedin B; Neuromedin C; Neuromedin N; Activity-Dependent Neurotrophic Factor (ADNF-14); Acetalin 1 (Opioid Receptor Antagonist 1); Acetalin 2 (Opioid Receptor Antagonist 2); Acetalin 3 (Opioid Receptor Antagonist 3); ACTH (1-39) (human); ACTH (7-38) (human); Sauvagine; Adipokinetic Hormone (Locusta Migralorici) Myristoylated ADP-Ribosylation Factor 6, myr-ARF6 (2-13); PAMP (1-20) (Proadrenomedullin (1-20) human); AGRP (25- 51); Amylin (8-37) (human); Angiotensin I (human); Angiotensin II (human); Apstatin (Aminopeptidase P Inhibitor); Brevinin-1; Magainin 1; RL-37; LL-37 (Antimicrobial Peptide) (human); Cecropin A; Antioxidant peptide A; Antioxidant peptide B; L-Carnosine; Bel 9-2; NPVF; Neuropeptide AF (hNPAF) (Human); Bax BH3 peptide (55-74); bFGF Inhibitory Peptide; bFGF inhibitory Peptide II; Bradykinin; [Des-Argl O]-HOE 140; Caspase 1 Inhibitor II; Caspase 1 Inhibitor VIII; Smac N7 Protein (MEK1 Derived Peptide Inhibitor 1; hBD-1 ([beta]-Defensin-l) (human); hBD-3 ([beta]-Defensin-3) (human); hBD-4 ([beta]- Defensin-4) (human); HNP-I (Defensin Human Neutrophil Peptide 1); HNP-2 (Defensin Human neutrophil Peptide-2 Dynorphin A (1-17)); Endomorphin- 1; [beta]-Endorphin (human porcine); Endothelin 2 (human); Fibrinogen Binding Inhibitor Peptide; Cyclo(-GRGDSP); TP508 (Thrombin-derived Peptide); Galanin (human); GIP (human); Gastrin Releasing Peptide (human); Gastrin- 1 (human); Ghrelin (human); PDGF-BB peptide; [D-Lys3]-GHRP- 6; HCV Core Protein (1-20); a3Bl Integrin Peptide Fragment (325) (amide); Laminin Pentapeptide (amide) Melanotropin-Potentiating Factor (MPF); VA-[beta]-MSH, Lipotropin- Y (Proopiomelanocortin-derived); Atrial Natriuretic Peptide (1-28) (human); Vasonatrin Peptide (1-27); [Ala5, B-Ala8]-Neurokinin A (4-10); Neuromedin L (NKA); Ac-(Leu28, 31)- Neuropeptide Y (24-26); Alytesin; Brain Neuropeptide II; [D-tyrll]-Neurotensin; IKKy NEMO Binding Domain (NBD) Inhibitory Peptide; PTD-p50 (NLS) Inhibitory Peptide;Orexin A (bovine, human, mouse, rat); Orexin B (human); Aquaporin-2(254-267) (human Pancreastatin)(37-52); Pancreatic Polypeptide (human); Neuropeptide; Peptide YY (3-36) (human); Hydroxymethyl-Phytochelatin 2; PACAP (1-27) (amide, human, bovine, rat); Prolactin Releasing Peptide (1-31) (human); Salusin-alpha; Salusin-beta; Saposin C22; Secretin (human); L-Selectin; Endokinin A / B; Endokinin C (Human); Endokinin D (Human); Thrombin Receptor (42-48) Agonist (human); LSKL (Inhibitor of Thrombospondin); Thyrotropin Releasing Hormone (TRH); P55-TNFR Fragment; Urotensin II (human); VIP (human, porcine, rat); VIP Antagonist; Helodermin; Exenatide; ZP1O (AVEOO1OO); Pramlinitide; AC 162352 (PYY)(3-36); PYY; Obinepitide; Glucagon; GRP; Ghrelin(GHRP6); Leuprolide; Histrelin; Oxytocin; Atosiban (RWJ22164); Sermorelin; Nesiritide; bivalirudin (Hirulog); Icatibant; Aviptadin; Rotigaptide (ZP123, GAP486); Cilengitide (EMD-121924, RGD Peptides); AlbuBNP; BN-054; Angiotensin II; MBP-8298; Peptide Leucine Arginine; Ziconotide; AL-208; AL- 108; Carbeticon; Tripeptide; SAL; Coliven; Humanin; ADNF-14; VIP (Vasoactive Intestinal Peptide); Thymalfasin; Bacitracin; Gramidicin; Pexiganan (MSL78); Pl 13; PAC-113; SCV-07; HLF1-I1 (Lactoferrin); DAPTA; TRL1144; Tritrpticin; Antiflammin 2; Gattex (Teduglutide, ALX-0600); Stimuvax (L-BLP25); Chrysalin (TP508); Melanonan II; Spantide II; Ceruletide; Sincalide;Pentagastin; Secretin; Endostatin peptide; E-selectin; HER2; IL-6; IL-8; IL- 10; PDGF; Thrombospondin; uPA (1); uPA (2); VEGF; VEGF (2); Pentapeptide-3; XXLRR; Beta- Amyloid Fibrillogenesis; Endomorphin-2; TIP 39 (Tuberoinfundibular Neuropeptide); PACAP (1-38) (amide, human, bovine, rat); TGFB activating peptide; Insulin sensitizing factor (ISF402); Transforming Growth Factor Bl Peptide (TGF-B1); Caerulein Releasing Factor; IELLQAR (8-branch MAPS); Tigapotide PK3145; Goserelin; Abarelix; Cetrorelix; Ganirelix; Degarelix (Triptorelin); Barusiban (FE 200440); Pralmorelin; Octreotide; Eptifibatide; Netamiftide (INN-00835); Daptamycin; Spantide II; Delmitide (RDP-58); AL- 209; Enfuvirtide; IDR-I; Hexapeptide-6; Insulin-A chain; Lanreotide; Hexa[rho]eptide-3; Insulin B-chain; Glargine-A chain; Glargine-B chain; Insulin-LisPro B-chain analog; Insulin- Aspart B-chain analog; Insulin-Glulisine B chain analog; Insulin-Determir B chain analog; Somatostatin Tumor Inhibiting Analog; Pancreastatin (37-52); Vasoactive Intestinal Peptide fragment (KKYL-NH2); and Dynorphin A. These and other peptide and protein drugs listed, for example, in PCT publication W02008 / 058016 Al (incorporated herein by reference for identity and sequence) are suitable for use with the present invention. Examples of protein drugs include, but are not limited to, immunotoxin SS1P, adenosine deaminase, argininase, and others. Examples of nucleic acid-based drugs include, but are not limited to, the sense strand and antisense strand of any gene from an animal, and particularly from a mammal. Such genes can be those that are already the subjects of antisense DNAs that have been provided with the purpose of treating various diseases, for example genes for protein kinase C-alpha (Aprinocarsen, non-small cell lung cancer), BCL-2 (Oblimersen, malignant melanoma, lung cancer), ICAM-1 (ISIS-3082, Crohn's disease, HCV-related hepatitis C, ischemic / reperfusion injury in transplant), tumor necrosis factor alpha (rheumatoid arthritis, SARS, and psoriasis), adenosine Al receptor (asthma), c-raf kinase (ovarian cancer), H-ras (pancreatic cancer), c-myc (coronary artery disease), protein kinase A RI alpha (colon cancer,AIDS), DNA methyl-transferase (solid cancers), VEGF receptor (cancer), ribonucleotide reductase (kidney cancer), cytomegalovirus IE2 (CMV retinitis), matrix metalloproteinase-9 (prostate cancer), TGF beta 2 (malignant glioma), CD49d (multiple sclerosis), PTP-1B (diabetes), c-myb (cancer), EGFR (breast cancer), mdrl (cancer), autotaxin (cancer), phosphatidylinositol glycan anchor class F (PIGF, cancer), and GLUT-1 (cancer). The nucleic acid drugs may be DNA, modified DNA such as phosphorothioate-DNA, RNA, modified RNA such as 2'-0Me-RNA, locked nucleic acids, peptide nucleic acids, or hybrids.

[0254] In various aspects, R3is a residue of a radioligand. As used herein, the term “radioligand” means a radioactive biochemical substance composed of a radioisotope and a cell-targeting compound. The cell-targeting compound specifically binds to a receptor (e.g., a receptor that is overexpressed in tumors), thereby delivering the radioisotope, which emits high-energy particles, to the target receptor. Detection of the radioligand can be used for diagnosis and / or for research-oriented study of the receptor systems of the body. In addition, a radioligand can also be used for anti-cancer radioligand therapy as the emitted particles can cause damage leading to cell death. Examples of radioligands include, but are not limited to, Lutetium Lu 177 dotatate, Edotreotide gallium Ga-68, 64Cu-NODAGA-JRl l, and Cu-64- DOTA-TATE.

[0255] In various aspects, R3is a residue of a peptide. As used herein, the term “peptide” means an oligomer or short polymer of amino acids that is used for the treatment of a disease. Examples of peptides include, but are not limited to, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, teduglutide, linaclotide, pramlintide, abarelix, degarelix, carfilzomib, mifamurtide, aviptadi, atosiban, carbetocin, taltirelin, bremelanotide, teriparatide, abaloparatide, plecanatide, nesiritide, angiotensin II, icatibant, enfuvirtide, tesamorelin, ziconotide, romiplostim, peginesatide, lucinactant, etelcalcetide, afamelanotide, pasireotide, and setmelanotide.

[0256] In various aspects, R3is a residue of a protein. As used herein, the term “protein” means a natural or modified protein (z.e., a large, complex molecule made up of one or more long, folded chains of amino acids or polypeptides) that is genetically engineered. The protein can be introduced to replace a naturally occurring protein that is abnormal or deficient in a particular disease or to augment the body’s supply of a beneficial protein to help reduce the impact of a disease or chemotherapy. Examples of proteins include, but are not limited to, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins,engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. In a further aspect, the protein is insulin.

[0257] In various aspects, R3is a residue of an oligonucleotide. As used herein, the term “oligonucleotide” means a class of single- or double-stranded small synthetic nucleic acid polymers (~20-mer) that can be used to modulate gene expression. Examples of oligonucleotides include, but are not limited to, fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran, and pegaptanib.

[0258] In various aspects, R3is a residue of a small molecule therapeutic agent. As used herein, the term “small molecule therapeutic agent” means a low molecular weight organic compound (e.g., about 500 Da or less). Typically, a small molecule therapeutic agent is designed to mimic, enhance, or diminish the behaviour of natural substances or products within the body. Examples of small molecule therapeutic agents include, but are not limited to, analgesics (e.g., paracetamol), anti-inflammatories (e.g., aspirin), antibiotics (e.g., penicillin), antihistamines (e.g, diphenhydramine), and statins (e.g, atorvastatin). In a further aspect, the small molecule therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, and mTor inhibitor agents.

[0259] In various aspects, R3is a residue of an alkylating agent. In a further aspect, the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[0260] In various aspects, R3is a residue of an antimetabolite agent. In a further aspect, the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0261] In a various aspect, R3is a residue of an antineoplastic antibiotic agent. In a further aspect, the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

[0262] In a various aspect, R3is a residue of a mitotic inhibitor agent. In a further aspect, the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan,cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0263] In a various aspect, R3is a residue of an mTor inhibitor agent. In a further aspect, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. g. R4GROUPS

[0264] In one aspect, R4is selected from hydrogen and -L-P, wherein L is a linker, and wherein P is a polymeric moiety.

[0265] In various aspects, R4is hydrogen.

[0266] In various aspects, R4is -L-P.

[0267] In various aspects, R4is a structure selected from:

[0268] In various aspects, R4is a structure selected from:wherein m is a number selected from 5 to 5,000. Thus, in various aspects, m is selected from 5 to 4,000, from 5 to 3,000, from 5 to 2,000, from 5 to 1,000, from 5 to 500, from 5 to 100, from 50 to 5,000, from 100 to 5,000, from 500 to 5,000, from 1,000 to 5,000, from 2,000 to 5,000, from 3,000 to 5,000, from 4,000 to 5,000, from 50 to 4,000, from 100 to 3,000, from 500 to 2,000, or from 1,000 to 2,000.

[0269] In various aspects, R4is a structure selected from:wherein m is a number selected from 5 to 5,000. h. R5A, R5B, AND R5CGROUPS

[0270] In one aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -OH,-NCh, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NCh, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCh, -CH2CH2CI, -0CH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -OH, -NCh, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, -0CH3, -NHCH3, -N(CH3)2, -CH2NH2, and -L-P.

[0271] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, and -L-P.

[0272] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In astill further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, - N(CH3)2, -CH2NH2, and -L-P.

[0273] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, C1-C4 alkyl, C1-C4 alkoxy, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)CH3, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, ethyl, -OCH3, -OCH2CH3, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, -OCH3, and -L-P.

[0274] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, methyl, and -L-P.

[0275] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, C1-C6 alkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, C1-C4 alkyl, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, ethyl, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, and -L-P.

[0276] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, and -L-P. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCh, and -L-P.

[0277] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and -L-P.

[0278] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, each of R5a, R5b, and R5cis independentlyselected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CC13, -CH2CH2CI, -0CH3, -OCH2CH3, -NHCH3, - NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCI3, - OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0279] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CCI3

[0280] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, -NHCH2CH3, -N(CHs)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -NH2, -NHCH3, - N(CH3)2, and -CH2NH2.

[0281] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, each of R5a, R5b, andR5cis independently selected from hydrogen, -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and - OCH(CH3)CH3. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -OH, methyl, and -OCH3.

[0282] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -OH, -NO2, -CN, and methyl.

[0283] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, and C1-C6 alkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, and C1-C4 alkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen and methyl.

[0284] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, and -CH2CH2CI. In an evenfurther aspect, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCh.

[0285] In various aspects, each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0286] In various aspects, one of R5a, R5b, and R5cis hydrogen. In a further aspect, two of R5a, R5b, and R5cis hydrogen. In a still further aspect, each of R5a, R5b, and R5cis hydrogen.

[0287] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, -OCH3, -NHCH3, -N(CH3)2, -CH2NH2, and -L-P.

[0288] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5ais selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5ais selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI,-CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, R5ais selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, -CH2CH2CI, and -L-P. In an even further aspect, R5ais selected from -F, methyl, -CH2F, -CHF2, -CF^-CFLCl, -CHCh, -CCI3, and -L-P.

[0289] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5ais selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5ais selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5ais selected from -NH2, - NHCH3, -NHCH2CH3, -N(CH3)2, -CH2NH2, and -L-P.

[0290] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -OH, C1-C6 alkyl, C1-C6 alkoxy, and -L-P. In a further aspect, R5ais selected from -OH, C1-C4 alkyl, C1-C4 alkoxy, and -L-P. In a still further aspect, R5ais selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and -L-P. In a yet further aspect, R5ais selected from -OH, methyl, ethyl, -OCH3, - OCH2CH3, and -L-P. In an even further aspect, R5ais selected from -OH, methyl, -OCH3, and -L-P.

[0291] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and -L-P. In a further aspect, R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and -L-P. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and -L-P. In an even further aspect, R5ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, and -L-P.

[0292] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from C1-C6 alkyl, and -L-P. In a further aspect, R5ais selected from C1-C4 alkyl, and -L-P. In a still further aspect, R5ais selected from methyl, ethyl, propyl, isopropyl, and -L-P. In a yetfurther aspect, R5ais selected from methyl, ethyl, and -L-P. In an even further aspect, R5ais selected from methyl, and -L-P.

[0293] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5ais selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, and -L-P. In an even further aspect, R5ais selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCh, and -L-P.

[0294] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and -L-P.

[0295] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, -0CH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5ais selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0296] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5ais selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5ais selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R5ais selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R5ais selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CCI3.

[0297] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R5ais selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5ais selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5ais selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2

[0298] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R5ais selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R5ais selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R5ais selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R5ais selected from -OH, methyl, and -OCH3.

[0299] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R5ais selected fromhalogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R5ais selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0300] In various aspects, each of R5band R5cis hydrogen, and R5ais C1-C6 alkyl. In a further aspect, R5ais C1-C4 alkyl. In a still further aspect, R5ais selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5ais selected from methyl, and ethyl. In an even further aspect, R5ais methyl.

[0301] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5ais selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5ais selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R5ais selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspectR5ais selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0302] In various aspects, each of R5band R5cis hydrogen, and R5ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0303] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, -CH2CH2CI, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCI3, -OCH3, -NHCH3, -N(CH3)2, -CH2NH2, and -L-P.

[0304] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5bis selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5bis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, R5bis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, -CH2CH2CI, and -L-P. In an even further aspect, R5bis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, and -L-P.

[0305] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from-NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5bis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5bis selected from -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5bis selected from -NH2, - NHCH3, -NHCH2CH3, -N(CH3)2, -CH2NH2, and -L-P.

[0306] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from-OH, C1-C6 alkyl, C1-C6 alkoxy, and -L-P. In a further aspect, R5bis selected from -OH,C1-C4 alkyl, C1-C4 alkoxy, and -L-P. In a still further aspect, R5bis selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and -L-P. In a yet further aspect, R5bis selected from -OH, methyl, ethyl, -OCH3, - OCH2CH3, and -L-P. In an even further aspect, R5bis selected from -OH, methyl, -OCH3, and -L-P.

[0307] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and -L-P. In a further aspect, R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and -L-P. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and -L-P. In an even further aspect, R5bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, and -L-P.

[0308] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from C1-C6 alkyl, and -L-P. In a further aspect, R5bis selected from C1-C4 alkyl, and -L-P. In a still further aspect, R5bis selected from methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, R5bis selected from methyl, ethyl, and -L-P. In an even further aspect, R5bis selected from methyl, and -L-P.

[0309] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5bis selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CC13, -CH2CH2CI, and -L-P. In an even further aspect, R5bis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCh, and -L-P.

[0310] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and -L-P.

[0311] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CC13, -CH2CH2CI, -0CH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5bis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0312] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5bis selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5bis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCI3, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R5bis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspect, R5bis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CCI3.

[0313] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from-NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In afurther aspect, R5bis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5bis selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5bis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0314] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R5bis selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R5bis selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R5bis selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R5bis selected from -OH, methyl, and -OCH3.

[0315] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R5bis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R5bis selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0316] In various aspects, each of R5aand R5cis hydrogen, and R5bis C1-C6 alkyl. In a further aspect, R5bis C1-C4 alkyl. In a still further aspect, R5bis selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5bis selected from methyl, and ethyl. In an even further aspect, R5bis methyl.

[0317] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5bis selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5bis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R5bis selected from -F, -Cl, -NH2, -NO2, methyl,ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, and -CH2CH2C1. In an even further aspectR5bis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2C1, -CHCh, and -CCh.

[0318] In various aspects, each of R5aand R5cis hydrogen, and R5bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0319] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2C1, -CH2CC13, -CH2CHCh, -CH2CH2C1, -CH(C1)CH3, -CH(CH3)CCh, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCh, -CH2CH2CC13, -CH2CH(C1)CH3, - 0CH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2,-CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2C1, -CHCh, -CCh, -CH2CH2C1, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5cis selected from -F, -NH2, -OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CCh, -OCH3, -NHCH3, -N(CH3)2, -CH2NH2, and -L-P.

[0320] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5cis selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5cis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2C1, -CH2CC13, -CH2CHCh, -CH2CH2C1, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCh, -CH2CH2CC13, -CH2CH(C1)CH3, and-L-P. In a yet further aspect, R5cis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F,-CH2C1, -CHCh, -CCI3, -CH2CH2CI, and -L-P. In an even further aspect, R5cis selected from -F, methyl, -CH2F, -CHF2, -CF^-CFLCl, -CHCh, -CCI3, and -L-P.

[0321] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P. In a further aspect, R5cis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -L-P. In a still further aspect, R5cis selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(CH3)CH2NH2, and -L-P. In a yet further aspect, R5cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, and -L-P. In an even further aspect, R5cis selected from -NH2, - NHCH3, -NHCH2CH3, -N(CH3)2, -CH2NH2, and -L-P.

[0322] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from -OH, C1-C6 alkyl, C1-C6 alkoxy, and -L-P. In a further aspect, R5cis selected from -OH, C1-C4 alkyl, C1-C4 alkoxy, and -L-P. In a still further aspect, R5cis selected from -OH, methyl, ethyl, n-propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, and -L-P. In a yet further aspect, R5cis selected from -OH, methyl, ethyl, -OCH3, - OCH2CH3, and -L-P. In an even further aspect, R5cis selected from -OH, methyl, -OCH3, and -L-P.

[0323] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, and -L-P. In a further aspect, R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, and -L-P. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, R5cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, and -L-P. In an even further aspect, R5cis selected from -F, -NH2, -OH, -NO2, -CN, methyl, and -L-P.

[0324] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from C1-C6 alkyl, and -L-P. In a further aspect, R5cis selected from C1-C4 alkyl, and -L-P. In a still further aspect, R5cis selected from methyl, ethyl, propyl, isopropyl, and -L-P. In a yet further aspect, R5cis selected from methyl, ethyl, and -L-P. In an even further aspect, R5cis selected from methyl, and -L-P.

[0325] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, and -L-P. In a further aspect, R5cis selected from halogen, -NH2, -NO2, C1-C4 alkyl, C1-C4 haloalkyl, and -L-P. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, and -L-P. In a yet further aspect, R5cis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, and -L-P. In an even further aspect, R5cis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, -CCh, and -L-P.

[0326] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from-F, -Cl, -Br, -NH2, -NO2, -CF3, methyl, and -L-P.

[0327] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, -OH, -NO2, -CN, methyl, ethyl, n- propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CCh, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, -CH2CH(C1)CH3, -0CH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, - NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, - N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5cis selected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCh, -CH2CH2CI, -0CH3, - OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5cis selected from -F, -NH2,-OH, -NO2, -CN, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, -CC13, -OCH3, -NHCH3, -N(CH3)2, and -CH2NH2.

[0328] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5cis selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5cis selected from -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CC13, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHCh, -CH(CH3)CH2C1, -CH2CH2CC13, -CH2CH2CHCI2, -CH2CH2CC13, and -CH2CH(C1)CH3. In a yet further aspect, R5cis selected from -F, -Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CC13, and -CH2CH2CI. In an even further aspect, R5cis selected from -F, methyl, -CH2F, -CHF2, -CF3,-CH2C1, -CHCh, and -CC13.

[0329] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from -NH2, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. In a further aspect, R5cis selected from -NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, R5cis selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH(CH3)CH2NH2. In a yet further aspect, R5cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -CH2NH2, and -CH2CH2NH2. In an even further aspect, R5cis selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -CH2NH2.

[0330] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from -OH, C1-C6 alkyl, and C1-C6 alkoxy. In a further aspect, R5cis selected from -OH, C1-C4 alkyl, and C1-C4 alkoxy. In a still further aspect, R5cis selected from -OH, methyl, ethyl, n- propyl, isopropyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3. In a yet further aspect, R5cis selected from -OH, methyl, ethyl, -OCH3, and -OCH2CH3. In an even further aspect, R5cis selected from -OH, methyl, and -OCH3.

[0331] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C6 alkyl. In a further aspect, R5cis selected from halogen, -NH2, -OH, -NO2, -CN, and C1-C4 alkyl. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5cisselected from -F, -Cl, -NH2, -OH, -NO2, -CN, methyl, and ethyl. In an even further aspect, R5cis selected from -F, -NH2, -OH, -NO2, -CN, and methyl.

[0332] In various aspects, each of R5aand R5bis hydrogen, and R5cis C1-C6 alkyl. In a further aspect, R5cis C1-C4 alkyl. In a still further aspect, R5cis selected from methyl, ethyl, propyl, and isopropyl. In a yet further aspect, R5cis selected from methyl, and ethyl. In an even further aspect, R5cis methyl.

[0333] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -NO2, C1-C6 alkyl, and C1-C6 haloalkyl. In a further aspect, R5cis selected from halogen, -NH2, -NO2, C1-C4 alkyl, and C1-C4 haloalkyl. In a still further aspect, R5cis selected from -F, -Cl, -Br, -NH2, -NO2, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH(F)CH3, -CH(CH3)CF3, -CH(CH3)CHF2, -CH(CH3)CH2F, -CH2CH2CF3, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH(F)CH3, -CC13, -CHCh, -CH2CI, -CH2CCI3, -CH2CHCI2, -CH2CH2CI, -CH(C1)CH3, -CH(CH3)CC13, -CH(CH3)CHC12, -CH(CH3)CH2C1, -CH2CH2CCI3, -CH2CH2CHCI2, -CH2CH2CCI3, and -CH2CH(C1)CH3. In a yet further aspect, R5cis selected from -F, -Cl, -NH2, -NO2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCh, -CCI3, and -CH2CH2CI. In an even further aspectR5cis selected from -F, -NH2, -NO2, methyl, -CH2F, -CHF2, -CF3, -CH2CI, -CHCh, and -CCI3.

[0334] In various aspects, each of R5aand R5bis hydrogen, and R5cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

[0335] In various aspects, one of R5a, R5b, and R5cis -L-P.

[0336] In various aspects, one of R5a, R5b, and R5cis a structure selected from:

[0337] In various aspects, one of R5a, R5b, and R5cis a structure selected from:wherein m is a number selected from 5 to 5,000.

[0338] In various aspects, one of R5a, R5b, and R5cis a structure selected from:wherein m is a number selected from 5 to 5,000.2. EXAMPLE COMPOUNDS

[0339] In one aspect, the compound has a structure:or a pharmaceutically acceptable salt thereof.3. PROPHETIC COMPOUND EXAMPLES

[0340] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be useful as intermediates for the preparation of chemical release agents containing a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent such as, for example, a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent and that such activity can be determined using the assay methods described herein below.

[0341] In one aspect, the compound has a structure:or a pharmaceutically acceptable salt thereof.

[0342] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0343] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0344] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.C. METHODS OF MAKING INTERMEDIATE BENZISOXAZOLE COMPOUNDS

[0345] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0346] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-II, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.1. ROUTE I

[0347] In one aspect, substituted benzisoxazole analogs can be prepared as shown below.SCHEME 1A.1.6

[0348] Compounds are represented in generic form, wherein X is a halogen, and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME IB.1.12

[0349] In one aspect, compounds of type 1.12, and similar compounds, can be prepared according to reaction Scheme IB above. Thus, compounds of type 1.8 can be prepared by selective protection of an appropriate 2-hydroxybenzoic acid, e.g., 1.7 as shown above. Appropriate 2-hydroxybenzoic acids are commercially available or prepared bymethods known to one skilled in the art. The selective protection can be carried out in an appropriate solvent, e.g., acetone, in the presence of an appropriate acid, e.g., trifluoroacetic acid, and appropriate activating group, e.g., trifluoroacetic anhydride, at an appropriate temperature, e.g, 70 °C, for an appropriate amount of time, e.g., 4 days. Compounds of type 1.10 can be prepared by nucleophilic addition of an appropriate alkyl halide, e.g., 1.9 shown above, to an appropriate aldehyde, e.g, 1.8 as shown above. Appropriate alkyl halides are commercially available or prepared by methods known to one skilled in the art. The nucleophilic addition can be carried out by reacting an alkyl halide, e.g., 1.9 as shown above, with an appropriate metal, e.g., zinc, in the presence of an appropriate catalyst, e.g., titanium chloride, in an appropriate solvent, e.g., tetrahydrofuran, followed by reaction with an appropriate aldehyde, e.g., 1.8 as shown above, in an appropriate solvent, e.g., tetrahydrofuran. Compounds of type 1.11 can be prepared by reductive deprotection of an appropriate salicyclic ester, e.g., 1.10 as shown above. The reductive deprotection can be carried out via reaction with a reducing agent, e.g. diisobutylaluminium hydride, in an appropriate solvent, e.g., di chloromethane, at an appropriate temperature, e.g., -78 °C, for an appropriate amount of time, e.g., 1 hour. Compounds of type 1.12 can be prepared by cyclization of an appropriate salicylaldehyde, e.g. 1.11 as shown above. The cyclization can be carried out in the presence of hydroxylamine-O-sulfonic acid and an appropriate base, e.g., sodium bicarbonate, in an appropriate solvent mixture, e.g., di chloromethane and water, at an appropriate temperature, e.g., 0 °C to room temperature, for an appropriate amount of time, e.g., 30 minutes. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1, 1.2, 1.3, 1.4, and 1.5), can be substituted in the reaction to provide substituted benzisoxazole analogs similar to Formula 1.62. ROUTE II

[0350] In one aspect, substituted benzisoxazole analogs can be prepared as shown below.SCHEME 2A.2.3

[0351] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 2B.

[0352] In one aspect, compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by reacting an appropriate benzisoxazole substituted alcohol, e.g., 2.4 as shown above, and an appropriate amine, e.g., 2.5 as shown above. Appropriate benzisoxazole substituted alcohols and appropriate amines are commercially available or prepared by methods known to one skilled in the art. The reaction can be carried out by reacting the amine, e.g., 2.5 as shown above, with triphosgene in an appropriate solvent, e.g., dichloromethane, in the presence of an appropriate base, e.g., diisopropylethylamine, thereby providing an intermediateisocyanate. The isocyanate can then be reacted with the benzisoxazole, e.g., 2.4 as shown above. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted benzoisoxazole analogs similar to Formula 2.3.3. ROUTE III

[0353] In one aspect, substituted benzisoxazole analogs can be prepared as shown below.SCHEME 3A.

[0354] Compounds are represented in generic form, wherein Y is a functional group that can be conjugated to a tethering moiety, and with other substituents as noted in compound descriptions elsewhere herein. As would be understood by one of ordinary skill in the art, the selection of the Y functional group will depend on the tethering moiety present. For example, as shown below in Scheme 3B, when the tethering moiety is an alkyne, then the functional group can be an azide, such that a triazole (L) is formed. Alternative examples of functional groups that can be conjugated with a tethering moiety include, but are not limited to, -CCH, -NH2, — N3, -CO2H, -C(O)NH2, -OH, -SH, -Cl, -Br, -I, -CH=CH2, and -C(O)H. A more specific example is set forth below.SCHEME 3B.

[0355] In one aspect, compounds of type 3.6, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus, compounds of type 3.6 can be prepared by reacting an appropriate alkyne, e.g., 3.4 as shown above, and an appropriate azide, e.g., 3.5 as shown above. Appropriate alkynes and appropriate azides are commercially available or prepared by methods known to one skilled in the art. The reaction can be carried out by reacting an alkyne, e.g., 3.4 as shown above, with an azide, e.g., 3.5 as shown above, in the presence of an appropriate catalyst, e.g., copper sulfate and an appropriate ligand, e.g., tris((l-benzyl-4-triazolyl)methyl)amine (TBTA) in an appropriate solvent, e.g., tetrahydrofuran. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2), can be substituted in the reaction to provide substituted benzoisoxazole analogs similar to Formula 3.3.D. CHEMICAL RELEASE AGENTS

[0356] In one aspect, disclosed are benzisoxazole compounds and compositions useful as chemical release agents. As detailed herein, the disclosed benzisoxazole compounds contain a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent such as, for example, a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent.

[0357] In one aspect, the benzisoxazole compounds are stable during storage but dissociate at a desired delivery rate to provide an active agent when administered. Thus, in various aspects, the disclosed benzisoxazole compounds exihibit a dissociation half-life in serum at physiological conditions of less than about 24 h. In various further aspects, thedisclosed benzisoxazole compounds exihibit a dissociation half-life in serum at physiological conditions of less than about 22 h, less than about 20 h, less than about 18 h, less than about 16 h, less than about 14 h, less than about 12 h, less than about 10 h, less than about 8 h, less than about 6 h, less than about 4 h, less than about 2 h, less than about 1 h, less than about 30 min, less than about 20 min, less than about 10 min, or less than about 5 min.

[0358] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.1. STRUCTURE

[0359] In one aspect, disclosed are compounds having a structure represented by a formula:wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0360] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0361] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0362] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0363] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0364] In various aspects, the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0365] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0366] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0367] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0368] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0369] In various aspects, the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0370] In various aspects, the compound has a structure:or a pharmaceutically acceptable salt thereof.

[0371] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0372] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0373] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0374] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0375] In various aspects, the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.E. METHODS OF MAKING BENZISOXAZOLE COMPOUNDS

[0376] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0377] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Route I, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.1. ROUTE IV

[0378] In one aspect, chemical release agent analogs can be prepared as shown below.SCHEME 4A.

[0379] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 4B.

[0380] In one aspect, compounds of type 4.6, and similar compounds, can be prepared according to reaction Scheme 4B above. Thus, compounds of type 4.6 can be prepared by reacting an appropriate benzisoxazole substituted alcohol, e.g., 4.4 as shown above, and an appropriate amine, e.g., 4.5 as shown above. Appropriate benzisoxazole substituted alcohols and appropriate amines are commercially available or prepared by methods known to one skilled in the art. The reaction can be carried out by reacting the amine, e.g., 4.5 as shown above, with triphosgene in an appropriate solvent, e.g., dichloromethane, in the presence ofan appropriate base, e.g., diisopropylethylamine, thereby providing an intermediate isocyanate. The isocyanate can then be reacted with the benzisoxazole, e.g., 4.4 as shown above. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1 and 4.2), can be substituted in the reaction to provide substituted benzoisoxazole analogs similar to Formula 4.3.F. PHARMACEUTICAL COMPOSITIONS

[0381] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0382] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound, having a structure represented by a formula:wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0383] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers orexcipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by intravenous, topical, or oral administration.

[0384] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0385] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0386] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0387] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0388] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0389] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0390] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0391] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0392] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0393] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwashes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0394] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0395] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / orpharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0396] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0397] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0398] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.G. METHODS OF ADMINISTERING A RADIOLIGAND, PEPTIDE, PROTEIN, OLIGONUCLEOTIDE, OR SMALL MOLECULE THERAPEUTIC AGENT TO A SUBJECT

[0399] In one aspect, disclosed are methods of administering a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent to a subject in need thereof, the method comprising administering to the subject a disclosed compound.

[0400] Thus, in one aspect, disclosed are methods of administering a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent to a subject in need thereof, the method comprising administering to the subject a compound, having a structure represented by a formula:wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of asmall molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

[0401] As detailed herein, the disclosed compounds contain a release trigger (e.g., a benzisoxazole), a polymeric element, and an active agent. The polymeric element stabilizes the active agent such that decomposition during storage is minimized. Upon administration, however, the benzisoxazole undergoes tandem Kemp elimination and P-elimination reactions to release the active agent. The benzisoxazole can be modified at various position, including at the benzylic position, in order to control the rate with which the drug is released. Further, cleavage is independent of enzymatic activity. In this way, the rapid yet tunable nature of the dissociation of the drug from the polymeric moiety allows for precise control of drug distribution and PK profile to maximize therapeutic efficacy.

[0402] In various aspects, the subject is a mammal. In a still further aspect, the mammal is a human.

[0403] In various aspects, the subject has been diagnosed with a disorder prior to the administering step, wherein the disorder is selected from diabetes and cancer. In a further aspect, the disorder is diabetes. In a still further aspect, the disorder is cancer. In yet a further aspect, the cancer is a primary tumor or a mestastes. Examples of cancer include, but are not limited to, a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma). In an even further aspect, the cancer is selected from colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, head and neck cancer, prostate cancer, and lung cancer.

[0404] In various aspects, the method further comprising the step of identifying a subject in need of treatment of a disorder selected from diabetes and cancer.

[0405] In various aspects, R3is a residue of a radioligand. Examples of radioligands include, but are not limited to, Lutetium Lu 177 dotatate, Edotreotide gallium Ga-68, or Cu 64 NOTA.

[0406] In various aspects, R3is a residue of a peptide. Examples of peptides include, but are not limited to, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, teduglutide, linaclotide, pramlintide, abarelix, degarelix, carfilzomib,mifamurtide, aviptadi, atosiban, carbetocin, taltirelin, bremelanotide, teriparatide, abaloparatide, plecanatide, nesiritide, angiotensin II, icatibant, enfuvirtide, tesamorelin, ziconotide, romiplostim, peginesatide, lucinactant, etelcalcetide, afamel anotide, pasireotide, and setmelanotide.

[0407] In various aspects, R3is a residue of a protein. Examples of a residue of a protein include, but is not limited to, insulin.

[0408] In various aspects, R3is a residue of an oligonucleotide. Examples of a residue of an oligonucleotide include, but is not limited to, fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran, and pegaptanib

[0409] In various aspects, R3is a residue of a small molecule therapeutic agent. Example of a residue of a small molecule therapeutic agent include, but is not limited to, a chemotherapeutic agent.H. METHODS OF USING THE COMPOUNDS

[0410] The benzoisoxazole compounds and compositions disclosed herein are useful in providing a compound that is stable during storage but will dissociate upon administration and release a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent. Thus, in one aspect, disclosed are methods of administering a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent to a subject, the method comprising administering to the subject a disclosed compound or a pharmaceutically acceptable salt thereof.

[0411] The therapeutically effective amount or dosage of the bensoixazole compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications.Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.1. USE OF COMPOUNDS AND COMPOSITIONS

[0412] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for administering a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent.

[0413] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0414] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0415] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0416] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorders associated with diabetes and cancer in a mammal.2. MANUFACTURE OF A MEDICAMENT

[0417] In one aspect, the invention relates to a method for the manufacture of a medicament for administering a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent in a subject in need thereof, the method comprising combining a therapeutically effective amount of adisclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0418] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable period. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[0419] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg / kg and about 1000 mg / kg of body weight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0420] The size of the dose can also be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0421] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

[0422] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in theart to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0423] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.I. EXAMPLES

[0424] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0425] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.1. CHEMISTRY EXAMPLESO O2. RESULTS a. EVALUATION OF THE EFFECT OF SUBSTITUENTS ON KEMP ELIMINATION

[0426] Benzisoxazoles were prepared as detailed herein or purchased with various substitutions around the aromatic ring (FIG. 1A). Compounds were dissolved and half-life of Kemp elimination was obtained. The half-life of the of the Kemp elimination was plotted against the meta substituent Hammett constant (om) and demonstrated a tunable relationship in both the presense and absence of human serum albumin (HSA) as shown in FIG. IB. The Kemp elimination also showed pH dependence in the absence of HSA (FIG. 1C). b. EVALUATION OF RING OPENING HALF-LIFE VALUES

[0427] The ring opening half-life values of four exemplary benzisoxaozoles is shown in Table 1. Half-life values were obtained by varying the pH in the presence and absence of Human Serum Albumin (HSA).TABLE 1.c. 1 ,6-ELIMINATION TO RELEASE FLUOROPHORE

[0428] A fluorescent probe, benzisoxazole-naphthylimide carbamate (BI-NA), was utilized to monitor the Kemp elimination (FIG. 2A). The release of the fluorescent probe in the presence of HSA at pH 7.4 was monitored over time (FIG. 2B). The release kinetics of BI-NA at different pH values was then plotted by monitoring the appearance of N-(methyl- PEG4)-4-amino-l,8-naphthalimide (NA).3. DISCUSSION

[0429] Herein, chemical release agents containing a benzisoxazole release trigger have been developed. Briefly, the chemical release agent undergoes a Kemp elimination to open the benzisoxazole ring, followed by a 1,6-elimination to release the active agent from the rest of the complex (FIG. 2A-C). See also FIG. 3. Because the opening of the benzisoxazole ring triggers the release of the active agent, the rate of this step can be used to control the delivery. In particular, the benzisoxazole ring is stable in acidic media (e.g., pH of 4 to 6) but is labile at physiological pH (e.g., pH of about 7.4). Moreover, release is significantly accelerated in the presence of HSA (e.g., concentration > 35 g / L). See, e.g., FIG. 4. It has also been found that the substitution pattern on the benzoisoxazole ring can be used to tune the release rate. Thus, the disclosed chemical release agents allow for predictable and tunable release of active agents.

[0430] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit ofthe invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then R1is hydrogen, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety, and provided that when n is 2 and R1is the tethering moiety, then the tethering moiety is not -NH2.

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

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

4. The compound of any one of claims 1 to 3, wherein R1is hydrogen.

5. The compound of any one of claims 1 to 3, wherein R1is the tethering moiety.

6. The compound of claim 5, wherein the tethering moiety is selected from -CCH, -NH2, -N3, -CO2H, and -C(O)NH2.

7. The compound of claim 5, wherein the tethering moiety is -CCH.

8. The compound of any one of claims 1 to 7, wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

9. The compound of any one of claims 1 to 7, wherein each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

10. The compound of any one of claims 1 to 7, wherein one of R2a, R2b, and R2cis hydrogen.

11. The compound of any one of claims 1 to 7, wherein two of R2a, R2b, and R2care hydrogen.

12. The compound of any one of claims 1 to 7, wherein each of R2a, R2b, and R2cis hydrogen.

13. The compound of any one of claims 1 to 7, wherein each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

14. The compound of any one of claims 1 to 7, wherein each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

15. The compound of any one of claims 1 to 7, wherein each of R2band R2cis hydrogen, and R2ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

16. The compound of any one of claims 1 to 7, wherein each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

17. The compound of any one of claims 1 to 7, wherein each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

18. The compound of any one of claims 1 to 7, wherein each of R2aand R2cis hydrogen, and R2bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

19. The compound of any one of claims 1 to 7, wherein each of R2aand R2bis hydrogen, and R2Cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

20. The compound of any one of claims 1 to 7, wherein each of R2aand R2bis hydrogen, and R2Cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

21. The compound of any one of claims 1 to 7, wherein each of R2aand R2bis hydrogen, and R2Cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

22. The compound of any one of claims 1 to 7, wherein one of R2a, R2b, and R2cis the tethering moiety.

23. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.The compound of claim 1, wherein the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound has a structure:or a pharmaceutically acceptable salt thereof.

27. A compound having a structure represented by a formula:wherein n is selected from 0, 1, 2, 3, or 4; wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**;wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R1is selected from hydrogen and a tethering moiety; and wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R1, R2a, R2b, and R2cis the tethering moiety.

28. The compound of claim 27, wherein n is 0.

29. The compound of claim 27, wherein n is 1.

30. The compound of any one of claims 27 to 29, wherein R1is hydrogen.

31. The compound of any one of claims 27 to 29, wherein R1is the tethering moiety.

32. The compound of claim 31, wherein the tethering moiety is selected from -CCH, -NH2, -N3, -CO2H, and -C(O)NH2.

33. The compound of claim 31, wherein the tethering moiety is -CCH.

34. The compound of any one of claims 27 to 33, wherein each of R2a, R2b, and R2cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

35. The compound of any one of claims 27 to 33, wherein each of R2a, R2b, and R2cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

36. The compound of any one of claims 27 to 33, wherein one of R2a, R2b, and R2cis hydrogen.

37. The compound of any one of claims 27 to 33, wherein two of R2a, R2b, and R2care hydrogen.

38. The compound of any one of claims 27 to 33, wherein each of R2a, R2b, and R2cis hydrogen.

39. The compound of any one of claims 27 to 33, wherein each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

40. The compound of any one of claims 27 to 33, wherein each of R2band R2cis hydrogen, and R2ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

41. The compound of any one of claims 27 to 33, wherein each of R2band R2cis hydrogen, and R2ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

42. The compound of any one of claims 27 to 33, wherein each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

43. The compound of any one of claims 27 to 33, wherein each of R2aand R2cis hydrogen, and R2bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

44. The compound of any one of claims 27 to 33, wherein each of R2aand R2cis hydrogen, and R2bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

45. The compound of any one of claims 27 to 33, wherein each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and a tethering moiety.

46. The compound of any one of claims 27 to 33, wherein each of R2aand R2bis hydrogen, and R2cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

47. The compound of any one of claims 27 to 33, wherein each of R2aand R2bis hydrogen, and R2cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

48. The compound of any one of claims 27 to 33, wherein one of R2a, R2b, and R2cis the tethering moiety.

49. The compound of any one of claims 27 to 48, wherein R3is the residue of a radioligand.

50. The compound of claim 49, wherein the radioligand is Lutetium Lu 177 dotatate, Edotreotide gallium Ga-68, or Cu 64 NOTA.

51. The compound of any one of claims 27 to 48, wherein R3is the residue of a peptide.

52. The compound of claim 51, wherein the peptide is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, teduglutide, linaclotide, pramlintide, abarelix, degarelix, carfilzomib, mifamurtide, aviptadi, atosiban, carbetocin, taltirelin, bremelanotide, teriparatide, abaloparatide, plecanatide, nesiritide, angiotensin II, icatibant, enfuvirtide, tesamorelin, ziconotide, romiplostim, peginesatide, lucinactant, etelcalcetide, afamelanotide, pasireotide, and setmelanotide.

53. The compound of any one of claims 27 to 48, wherein R3is the residue of a protein.

54. The compound of claim 53, wherein the protein is insulin.

55. The compound of any one of claims 27 to 48, wherein R3is the residue of an oligonucleotide.

56. The compound of claim 55, wherein the oligonucleotide is selected from fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran, and pegaptanib.

57. The compound of any one of claims 27 to 48, wherein R3is the residue of a small molecule therapeutic agent.

58. The compound of claim 57, wherein the small molecule therapeutic agent is a chemotherapeutic agent.

59. The compound of claim 27, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

60. The compound of claim 27, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

61. The compound of claim 27, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

62. The compound of claim 27, wherein the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

63. The compound of claim 27, wherein the compound has structure represented by a formula:or a pharmaceutically acceptable salt thereof.

64. The compound of claim 27, wherein the compound has structure represented by a formula:or a pharmaceutically acceptable salt thereof.

65. The compound of claim 27, wherein the compound has structure represented by a formula:or a pharmaceutically acceptable salt thereof.The compound of claim 27, wherein the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

67. The compound of claim 27, wherein the compound has a structure:or a pharmaceutically acceptable salt thereof.

68. A compound having a structure represented by a formula:wherein R4is selected from hydrogen and -L-P; wherein L is a linker; wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

69. The compound of claim 68, wherein R4is hydrogen.

70. The compound of claim 68, wherein R4is -L-P.

71. The compound of claim 70, wherein the linker is selected from a triazole, an amide, an amine, an ether, a thioether, an alkene, and an imine.

72. The compound of claim 70 or claim 71, wherein the polymeric moiety is selected from a synthetic polymer having a molecular weight of between 10,000 and 100,000.

73. The compound of any one of claims 68 to 72, wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

74. The compound of any one of claims 68 to 72, wherein each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

75. The compound of any one of claims 68 to 72, wherein one of R5a, R5b, and R5cis hydrogen.

76. The compound of any one of claims 68 to 72, wherein two of R5a, R5b, and R5cis hydrogen.

77. The compound of any one of claims 68 to 72, wherein each of R5a, R5b, and R5cis hydrogen.

78. The compound of any one of claims 68 to 72, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

79. The compound of any one of claims 68 to 72, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

80. The compound of any one of claims 68 to 72, wherein each of R5band R5cis hydrogen, and R5ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

81. The compound of any one of claims 68 to 72, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

82. The compound of any one of claims 68 to 72, wherein each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

83. The compound of any one of claims 68 to 72, wherein each of R5aand R5cis hydrogen, and R5bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

84. The compound of any one of claims 68 to 72, wherein each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

85. The compound of any one of claims 68 to 72, wherein each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

86. The compound of any one of claims 68 to 72, wherein each of R5aand R5bis hydrogen, and R5cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

87. The compound of any one of claims 68 to 72, wherein one of R5a, R5b, and R5cis -L-P.

88. A compound having a structure represented by a formula:wherein Z is selected from *-NHC(O)-**, *-OC(O)-**, and *-C(O)-**; wherein * denotes a bond connected to R3and ** denotes a bond connected to O; wherein R4is selected from hydrogen and -L-P; wherein L is a linker;wherein P is a polymeric moiety; and wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P, wherein R3is a residue of a radioligand, a residue of a peptide, a residue of a protein, a residue of an oligonucleotide, or a residue of a small molecule therapeutic agent, or a pharmaceutically acceptable salt thereof, provided that exactly one of R4, R5a, R5b, and R5cis -L-P.

89. The compound of claim 88, wherein n is 0.

90. The compound of claim 88, wherein n is 1.

91. The compound of any one of claims 88 to 90, wherein R3is the residue of a radioligand.

92. The compound of claim 91, wherein the radioligand is Lutetium Lu 177 dotatate, Edotreotide gallium Ga-68, or Cu 64 NOTA.

93. The compound of any one of claims 88 to 90, wherein R3is the residue of a peptide.

94. The compound of claim 93, wherein the peptide is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, teduglutide, linaclotide, pramlintide, abarelix, degarelix, carfilzomib, mifamurtide, aviptadi, atosiban, carbetocin, taltirelin, bremelanotide, teriparatide, abaloparatide, plecanatide, nesiritide, angiotensin II, icatibant, enfuvirtide, tesamorelin, ziconotide, romiplostim, peginesatide, lucinactant, etelcalcetide, afamelanotide, pasireotide, and setmelanotide95. The compound of any one of claims 88 to 90, wherein R3is the residue of a protein.

96. The compound of claim 95, wherein the protein is insulin.

97. The compound of any one of claims 88 to 90, wherein R3is the residue of an oligonucleotide.

98. The compound of claim 97, wherein the oligonucleotide is selected from fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran, and pegaptanib.

99. The compound of any one of claims 88 to 90, wherein R3is the residue of a small molecule therapeutic agent.

100. The compound of claim 99, wherein the small molecule therapeutic agent is a chemotherapeutic agent.

101. The compound of any one of claims 88 to 90, wherein R4is hydrogen.

102. The compound of any one of claims 88 to 90, wherein R4is -L-P.

103. The compound of claim 102, wherein the linker is selected from a triazole, an amide, an amine, an ether, a thioether, an alkene, and an imine.

104. The compound of claim 102 or claim 103, wherein the polymeric moiety is selected from is selected from a synthetic polymer having a molecular weight of between 10,000 and 100,000.

105. The compound of any one of claims 88 to 104, wherein each of R5a, R5b, and R5cis independently selected from hydrogen, halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, Cl- C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

106. The compound of any one of claims 88 to 104, wherein each of R5a, R5b, and R5cis independently selected from hydrogen, -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

107. The compound of any one of claims 88 to 104, wherein one of R5a, R5b, and R5cis hydrogen.

108. The compound of any one of claims 88 to 104, wherein two of R5a, R5b, and R5cis hydrogen.

109. The compound of any one of claims 88 to 104, wherein each of R5a, R5b, and R5cis hydrogen.

110. The compound of any one of claims 88 to 104, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

111. The compound of any one of claims 88 to 104, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

112. The compound of any one of claims 88 to 104, wherein each of R5band R5cis hydrogen, and R5ais selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

113. The compound of any one of claims 88 to 104, wherein each of R5band R5cis hydrogen, and R5ais selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

114. The compound of any one of claims 88 to 104, wherein each of R5aand R5cis hydrogen, and R5bis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

115. The compound of any one of claims 88 to 104, wherein each of R5aand R5cis hydrogen, and R5bis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

116. The compound of any one of claims 88 to 104, wherein each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, C1-C6 aminoalkyl, and -L-P.

117. The compound of any one of claims 88 to 104, wherein each of R5aand R5bis hydrogen, and R5cis selected from halogen, -NH2, -OH, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.

118. The compound of any one of claims 88 to 104, wherein each of R5aand R5bis hydrogen, and R5cis selected from -F, -Cl, -Br, -NH2, -NO2, -CF3, and methyl.

119. The compound of any one of claims 88 to 104, wherein one of R5a, R5b, and R5cis -L-P.

120. A method of administering a radioligand, a peptide, a protein, an oligonucleotide, or a small molecule therapeutic agent to a subject in need thereof, the method comprising administering to the subject the compound of claim 88 or a pharmaceutically acceptable salt thereof.

121. The method of claim 120, wherein the subject is a mammal.

122. The method of claim 120 or claim 121, wherein the subject has been diagnosed with a disorder prior to the administering step, wherein the disorder is selected from diabetes and cancer.

123. The method of claim 122, wherein the disorder is diabetes.

124. The method of claim 122, wherein the disorder is cancer.

125. The method of claim 124, wherein the cancer is a primary tumor or a mestastes.

126. The method of claim 124, wherein the cancer is selected from a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).

127. The method of claim 124, wherein the cancer is selected from colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, head and neck cancer, prostate cancer, and lung cancer.

128. The method of any one of claims 120 to 127, further comprising the step of identifying a subject in need of treatment of a disorder selected from diabetes and cancer.

129. The method of any one of claims 120 to 128, wherein R3is the residue of a peptide.

130. The method of claim 129, wherein the peptide is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, teduglutide, linaclotide, pramlintide, abarelix, degarelix, carfilzomib, mifamurtide, aviptadi, atosiban, carbetocin, taltirelin, bremelanotide, teriparatide, abaloparatide, plecanatide, nesiritide, angiotensin II, icatibant, enfuvirtide, tesamorelin, ziconotide, romiplostim, peginesatide, lucinactant, etelcalcetide, afamelanotide, pasireotide, and setmelanotide.

131. The method of any one of claims 120 to 128, wherein R3is the residue of a protein.

132. The method of claim 131, wherein the protein is insulin.

133. The method of any one of claims 120 to 128, wherein R3is the residue of an oligonucleotide.

134. The method of claim 133, wherein the oligonucleotide is selected from fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran, and pegaptanib.

135. The method of any one of claims 120 to 128, wherein R3is the residue of a small molecule therapeutic agent.

136. The method of claim 135, wherein the small molecule therapeutic agent is a chemotherapeutic agent.

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