FBXO21 MEDIATED P85a UBIQUITYLATION AS A THERAPEUTIC TARGET IN CANCER

Abstract

The present disclosure is concerned with compounds and compositions for use in the prevention and treatment of cancer associated with FBOX21 mediated p85a ubiquitination such as, for example, cancer (e.g., 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, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma)). 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

Attorney Docket No.21101.0487P1 FBXO21 MEDIATED P85 UBIQUITYLATION AS A THERAPEUTIC TARGET IN CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 699,520, filed on September 26, 2024, and U.S. Application No.63 / 841,660, filed on July 10, 2025, the contents of which are incorporated herein by reference in their entireties. REFERENCE TO SEQUENCE LISTING

[0002] The Sequence Listing submitted on September 26, 2025 as a xml file named “21101.0487P1.xml,” created on September 25, 2025, and having a size of 45,178 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). BACKGROUND

[0003] The breakdown of regulatory proteins through the ubiquitin-proteasome system plays a crucial role in controlling the activation or deactivation of a cell’s molecular machinery at an appropriate time and within the correct subcellular compartment. The precision of this system is dependent on numerous ubiquitin ligases, with the SKP1-CUL1-FBOX (SCF) family of RING-finger E3 ligases being the largest group. Notably, approximately 70 distinct FBOX proteins have been identified. All FBOX proteins are categorized into three groups based on their substrate binding domain: FBXW (F-box with WD40 domains), FBXL (F-box with leucine-rich repeats), and FBXO (F-box proteins with other domains). One characteristic shared by most FBOX proteins is the need for a phosphodegron. A phosphodegron is a specific amino acid sequence, typically containing a serine, a threonine, or a tyrosine, whose phosphorylation permits recognition by the E3 ligase preceding ubiquitination for proteasomal degradation. These sequences can be unique or have specific commonalities. An example includes the TPxxS degron motif for FBXW7 (LLPTPPLS (SEQ ID NO: 1) is the c- MYC degron motif). FBOX proteins recognize about 20% of proteins degraded by the UPS and have been found to ubiquitinate substrates important for cell survival, cell cycle regulators, transcription factors, and cell-surface receptors. The FBOX substrate interface has recently been the focus of drug discovery efforts. For instance, substituted-aryl-ethane-1,2- diamine analogs (BC1215 and BC1258) inhibit FBXO3-Fbxl2 interaction to either stabilize TRAF or promote Aurora B degradation, indicating tractability of targeting FBOX proteins.Attorney Docket No.21101.0487P1 These studies emphasize the critical role of FBOX E3 ligases as targetable proteins for drug discovery to create more effective and targeted therapies.

[0004] High expression levels of the FBOX ubiquitin E3 ligase, FBXO21, is associated with poor patient survival in acute myeloid leukemia (AML). Silencing FBXO21 in AML leads todifferentiation, and delayed tumor progression. Further, p85 , a regulatory subunit of thephosphoinositide 3-kinase (PI3K) pathway was identified as a novel substrate of FBXO21,marking it for proteasomal degradation. Depletion of FBXO21 stabilizes p85 , leading todimerization of free p85 and decreased activation of the PI3K pathway. Therefore, FBXO21 may serve as a novel regulator of the PI3K signaling pathway, offering an alternative approach to modulating PI3K activity in AML.

[0005] Despite these efforts at targeting the PI3K / AKT signaling pathway in cancer treatment is limited by off-target effects, dose-limiting toxicities, and resistance mechanisms. As such, there remains a need for compounds and compositions with fewer off-target effects and better potency for the treatment of cancers, and methods of 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 for usein the prevention and treatment of cancer associated with FBOX21 mediated p85ubiquitination such as, for example, cancer (e.g., 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, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma)).

[0007] Thus, disclosed are compounds having a structure represented by a formula: ,Attorney Docket No.21101.0487P1 wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, O2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0008] Also disclosed are compounds selected from: ,Attorney Docket No.21101.0487P1

[0009] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier.

[0010] Also disclosed are methods of inhibiting F-box protein 21 (FBOX21) mediated p85ubiquitination in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0011] Also disclosed are methods of inhibiting FBOX21 mediated p85 ubiquitination in asubject, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0012] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R4aand R4bhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen, or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen andAttorney Docket No.21101.0487P1 C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0013] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: , , , or a

[0014] Also disclosed are kits comprising a compound having a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4aand R4bis hydrogen, halogen, NH2, OH,NO2, CN, C1-C4 alkyl, C1- C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen, or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof, and one or more of: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0015] Also disclosed are kits comprising a compound selected from: ,Attorney Docket No.21101.0487P1 , , or a agent; (b)instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0016] 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.Attorney Docket No.21101.0487P1 BRIEF DESCRIPTION OF THE FIGURES

[0017] 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.

[0018] FIG.1A-E show representative data illustrating that FBXO21 specificallyubiquitinates p85 through K48-linked ubiquitination, requiring the YccV domain (SEQ IDNO: 2) and lysine residue K692.

[0019] FIG.2A and FIG.2B show representative data illustrating that FBXO21 binds to andubiquitinates p85 via the iSH2 domain and phosphorylation site Y467.

[0020] FIG.3A-E show representative data illustrating that phosphodegron containing Y467is required for p85 ubiquitination.

[0021] FIG. 4A-F show representative data illustrating the inhibition of FBXO21 / p85interaction by terphenyl analog 57-057.

[0022] FIG.5A-F show representative data illustrating the efficacy and specificity of 57-057 in primary AML and healthy CD34+ cells.

[0023] FIG.6A-F show representative data illustrating that 57-057 targets AML tumors in mouse model of MLL-AF9.

[0024] FIG.7A-F show data illustrating the sensitivity of AML cells to FBXO21 inhibitor 57-057 and its effect on PI3K signaling.

[0025] FIG.8A-E show representative data illustrating the pharmacokinetics and tissue distribution of 57-057.

[0026] 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

[0027] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0028] 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 toAttorney Docket No.21101.0487P1 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.

[0029] 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.

[0030] 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

[0031] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural references 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.Attorney Docket No.21101.0487P1

[0032] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0033] 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.

[0034] 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 is generally 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.

[0035] 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.Attorney Docket No.21101.0487P1

[0036] 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.

[0037] As used herein, “IC50” 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 IC50 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, IC50refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0038] 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, EC50refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.

[0039] 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.

[0040] 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.

[0041] 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,Attorney Docket No.21101.0487P1 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, i.e., arresting its development; or (iii) relieving the disease, i.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.).

[0042] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0043] 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.

[0044] 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.

[0045] 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 undesiredAttorney Docket No.21101.0487P1 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.

[0046] 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 desoxycholate), 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- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g.,Attorney Docket No.21101.0487P1 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.

[0047] 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 be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0048] 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, troubleshooting, 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.

[0049] As used herein, the term “therapeutic agent” includes 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, theAttorney Docket No.21101.0487P1 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, non- nucleoside 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, anti- inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0050] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0051] 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 whoseAttorney Docket No.21101.0487P1 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.

[0052] 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.

[0053] 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 andAttorney Docket No.21101.0487P1 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 (i.e., further substituted or unsubstituted).

[0054] 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.

[0055] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.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.

[0056] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6Attorney Docket No.21101.0487P1 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0057] 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 group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0058] 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.

[0059] 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 orAttorney Docket No.21101.0487P1 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.

[0060] The term “polyalkylene group” as used herein is a group having two or more CH2groups 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.

[0061] 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.

[0062] 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.

[0063] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.Attorney Docket No.21101.0487P1

[0064] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can 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.

[0065] 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.

[0066] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized electrons above and below the plane of the molecule, where the clouds contain (4n+2) 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.

[0067] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fusedAttorney Docket No.21101.0487P1 ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0068] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a shorthand notation for a carbonyl group, i.e., C=O.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0073] 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.

[0074] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is representedAttorney Docket No.21101.0487P1 by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0075] The terms “halo,” “halogen,” and “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0076] The terms “pseudohalide,” “pseudohalogen,” and “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.

[0077] 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.

[0078] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0079] The terms “heterocycle” and “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems inAttorney Docket No.21101.0487P1 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.

[0080] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0081] 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 fourAttorney Docket No.21101.0487P1 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.

[0082] The terms “hydroxyl” and “hydroxyl” as used herein are represented by the formula —OH.

[0083] 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.

[0084] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0085] The term “nitro” as used herein is represented by the formula —NO2.

[0086] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0087] 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.

[0088] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a shorthand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0089] The term “thiol” as used herein is represented by the formula —SH.

[0090] “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 theAttorney Docket No.21101.0487P1 groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.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.

[0091] 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 (i.e., further substituted or unsubstituted).

[0092] 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.

[0093] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R ; –(CH2)0–4OR ; -O(CH2)0-4Ro, –;C(NOR )R ; -(CH2)0–4SSR ; –(CH2)0–4S(O)2R ; –(CH2)0–4S(O)2OR ; –(CH2)0–4OS(O)2R ; –S(O)2NR 2; -(CH2)0–4S(O)R ; -N(R )S(O)2NR 2; –N(R )S(O)2R ; –N(OR )R ; –Attorney Docket No.21101.0487P1 C(NH)NR 2; –P(O)2R ; -P(O)R 2; -OP(O)R 2; –OP(O)(OR )2; SiR 3; –(C1–4 straight orbranched alkylene)O–N(R )2; or –(C1–4 straight or branched alkylene)C(O)O–N(R )2,wherein each R may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -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.

[0094] Suitable monovalent substituents on R (or the ring formed by taking two independentoccurrences of R together with their intervening atoms), are independently halogen, –(CH2)0–2R , –(haloR ), –(CH2)0–2OH, –(CH2)0–2OR , –(CH2)0–2CH(OR )2; -O(haloR ), –CN,–N3, –(CH2)0–2C(O)R , –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR , –(CH2)0–2SR , –(CH2)0–2SH,–(CH2)0–2NH2, –(CH2)0–2NHR , –(CH2)0–2NR 2, –NO2, –SiR 3, –OSiR 3, -C(O)SR , –(C1–4straight or branched alkylene)C(O)OR , or –SSR wherein each R is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, 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 =Oand =S.

[0095] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein eachwhich may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Attorney Docket No.21101.0487P1

[0096] 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 onlywith one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0097] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of 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.

[0098] 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 onlywith one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0099] 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, triflate, mesylate, tosylate, and brosylate.

[0100] 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).

[0101] The term “organic residue” defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain variousAttorney Docket No.21101.0487P1 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.

[0102] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: , regardless of whetherthe compound. In some embodiments the radical (for example an alkyl) can be further modified (i.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.

[0103] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1- 12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide,Attorney Docket No.21101.0487P1 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.

[0104] 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.

[0105] 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.

[0106] 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 l 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 be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it isAttorney Docket No.21101.0487P1 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.

[0107] 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.

[0108] 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, greater than 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 beAttorney Docket No.21101.0487P1 substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0109] 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.

[0110] 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.

[0111] “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.

[0112] 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,17O,35S,18FAttorney Docket No.21101.0487P1 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, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. 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.

[0113] 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.

[0114] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0115] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an -hydrogen can exist in an equilibrium of the keto form and the enol form.Attorney Docket No.21101.0487P1Likewise, form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1- unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below. Unless stated to the tautomers.

[0116] It is known that 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.

[0117] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent to, wherein n is typically an integer.to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance. 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.), StremAttorney Docket No.21101.0487P1 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).

[0119] 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.

[0120] 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 when combinations, 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 theAttorney Docket No.21101.0487P1 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.

[0121] 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. COMPOUNDS

[0122] In one aspect, the invention relates to pyrimidinyl compounds for use in theprevention and treatment of disorders associated with FBOX21 mediated p85 ubiquitinationsuch as, for example, cancer (e.g., 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, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, plasma cell neoplasm (myeloma).

[0123] In one aspect, the compounds of the invention are useful in modifying FBOX21mediated p85 ubiquitination, as further described herein.

[0124] In one aspect, the compounds of the invention are useful in the treatment of cancer, as further described herein.

[0125] In one aspect, the compounds of the invention are useful in the treatment of neurodegenerative diseases, as further described herein.

[0126] 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

[0127] In one aspect, disclosed are compounds having a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R1aand R1bhydrogen, halogen, NH2, OH,O2, CN, C1-C4 alkyl, C1- C4 haloalkoxy, C1-C4 (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0128] In one aspect, disclosed are compounds selected from: , ,Attorney Docket No.21101.0487P1 , or a

[0129] one are a a , wherein each of R4aand R4bhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen; or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen; or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0130] In one aspect, disclosed are compounds selected from:Attorney Docket No.21101.0487P1 , , , or a

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

[0132] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0133] In various aspects, the a by a formula: , wherein each of R1a, R1b, andacceptable salt thereof.

[0134] In various aspects, the compound has a structure represented by a formula: , wherein each of R1a, R1b, R2a,acceptable salt thereof.

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

[0136] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0137] In various aspects, the a by a formula: , wherein each of R1a, R1b, andacceptable salt thereof.

[0138] In various aspects, the compound has a structure represented by a formula: , wherein each of R1a, R1b, R2a,acceptable salt thereof.

[0139] In various aspects, the compound is not: , or a pharmaceutically

[0140] In various aspects, the compound is selected from:Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1 ,Attorney Docket No.21101.0487P1 , , or a

[0141] In various aspects, the compound is: , or a pharmaceuticallyAttorney Docket No.21101.0487P1

[0142] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0143] In various aspects, the a by a formula: , or a pharmaceutically

[0144] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, andacceptable salt thereof.

[0145] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0146] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0147] In various aspects, the a by a formula: , or a pharmaceutically

[0148] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0149] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, R5a,acceptable salt thereof.

[0150] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0151] In various aspects, the a by a formula: , or a pharmaceutically

[0152] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, andacceptable salt thereof.

[0153] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, R5a,acceptable salt thereof.

[0154] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0155] In various aspects, a by a formula: , or a pharmaceutically

[0156] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0157] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0158] In various aspects, the compound is not:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0159] In various ,Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1 , , , ,Attorney Docket No.21101.0487P1 , , or a

[0160] one n a n a further aspect, n is 1.

[0161] In one aspect, m is selected from 0 and 1. In a further aspect, m is 0. In a still further aspect, m is 1.

[0162] In one aspect, q is selected from 0 and 1. In a further aspect, q is 0. In a still further aspect, q is 1.

[0163] In one aspect, r is selected from 0 and 1. In a further aspect, r is 0. In a still further aspect, r is 1.

[0164] a. R1AAND R1BGROUPS

[0165] In one aspect, each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen.

[0166] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a further aspect, each of R1aand R1bis independently selected from hydrogen,Attorney Docket No.21101.0487P1 F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl,–OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, –CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, – CH2OH, –CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –– OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, – CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

[0167] In various aspects, each of R1aand R1bis independently selected from halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a further aspect, each of R1aand R1bis independently selected from F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, – CH=CH2, CH=CHCH3, CH2CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a still further aspect, each of R1aandAttorney Docket No.21101.0487P1 R1bis independently selected from F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, –CH2OH, – CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH3)(CH2CH3), – CH2NH2, –CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a yet OH,– OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, –CH2NH2 (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

[0168] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a further aspect, each of R1aand R1bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, – OCH(CH3)CH2Cl, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a yet further aspect, each of R1aand R1bis independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, – CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

[0169] In various aspects, each of R1aand R1bis independently selected from hydrogen, NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen. In a further aspect, each of R1aand R1bis 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), –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a still furtherAttorney Docket No.21101.0487P1 aspect, each of R1aand R1bis independently selected from hydrogen, NH2, –NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a yet further aspect, each of R1aand R1bis independently selected from hydrogen, NH2, –NHCH3, –N(CH3)2, –CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

[0170] In various aspects, each of R1aand R1bis independently selected from hydrogen, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen.

[0171] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, provided that at least one of R1aand R1bis not hydrogen. In a further aspect, each of R1aand R1bis independently selected from hydrogen, F, Cl, Br, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, F, Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In a yet further aspect, each of R1aand R1bis independently selected from hydrogen, F, –CH2F, –CH2Cl, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0172] In various aspects, each of R1aand R1bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 alkoxy, provided that at least one of R1aand R1bis not hydrogen. In a further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, ethyl, – OCH3, and –OCH2CH3. In a yet further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, and –OCH3.

[0173] In various aspects, each of R1aand R1bis independently selected from hydrogen, and C1-C4 alkyl. In a further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each of R1aand R1bis independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R1aand R1bis independently selected from hydrogen and methyl. b. R2AAND R2BGROUPSAttorney Docket No.21101.0487P1

[0174] In one aspect, each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0175] In various aspects, each of R2aand R2bis independently selected from hydrogen, halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a further aspect, each of R2aand R2bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl,–OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, –CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, – CH2OH, –CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a yet further aspect, each of R2aand R2bis independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, – CN,C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a further aspect, each of R2aand R2bis independently selected from F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, – CH=CH2, CH=CHCH3, CH2CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –Attorney Docket No.21101.0487P1 CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a still further aspect, each of R2aand R2bis independently selected from F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, –CH2OH, – CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH3)(CH2CH3), – In a yet OH,NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, – OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, –CH2NH2, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

[0177] In various aspects, each of R2aand R2bis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a further aspect, each of R2aand R2bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3(CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a yet further aspect, each of R2aand R2bis independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, –Attorney Docket No.21101.0487P1 CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

[0178] In various aspects, each of R2aand R2bis independently selected from hydrogen, NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen. In a further aspect, each of R2aand R2bis 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), –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph. In a still further –NHCH3, –2,2, ,2, (CH2CH3)2, –2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

[0179] In various aspects, R2aand R2bis independently selected from hydrogen, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0180] In various aspects, each of R2aand R2bis independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, provided that at least one of R2aand R2bis not hydrogen. In a further aspect, each of R2aand R2bis independently selected from hydrogen, F, Cl, Br, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R2aand R2bis independently selected from hydrogen, F, Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In a yet further aspect, each of R2aand R2bis independently selected from hydrogen, F, –CH2F, –CH2Cl, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0181] In various aspects, each of R2aand R2bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 alkoxy, provided that at least one of R2aand R2bis not hydrogen. In a further aspect, each of R2aand R2bis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a stillAttorney Docket No.21101.0487P1 further aspect, each of R2aand R2bis independently selected from hydrogen, methyl, ethyl, – OCH3, and –OCH2CH3. In a yet further aspect, each of R2aand R2bis independently selected from hydrogen, methyl, and –OCH3.

[0182] In various aspects, each of R2aand R2bis independently selected from hydrogen, and C1-C4 alkyl. In a further aspect, each of R2aand R2bis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each of R2aand R2bis independently is selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R2aand R2bis independently selected from hydrogen and methyl. c. R3GROUPS

[0183] In various aspects, R3is selected from hydrogen and C1-C4 alkyl. In a further aspect, R3is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R3is selected from hydrogen, methyl, and ethyl. In a still further aspect, R3is selected from hydrogen and ethyl.In yet a further aspect, R3is selected from hydrogen and methyl.

[0184] In various aspects, R3is C1-C4 alkyl. In a further aspect, R3is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R3is selected from methyl and ethyl. In a still further aspect, R3is ethyl. In yet a further aspect, R3is methyl.

[0185] In various aspects, R3is hydrogen. d. R4AAND R4BGROUPS

[0186] In one aspect, each of R4aand R4bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen, or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

[0187] In various aspects, each of R4aand R4bis independently selected from hydrogen, halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a further aspect, each of R4aand R4bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –Attorney Docket No.21101.0487P1 CH(CH3)CH2Cl,–OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a still further aspect, each of R4aand R4bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, –CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, – CH2OH, –CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a yet further aspect, each of R4aand R4bis independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, – CH2NH2, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph.

[0188] In various aspects, each of R4aand R4bis independently selected from halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a further aspect, each of R4aand R4bis independently selected from F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, – CH=CH2, CH=CHCH3, CH2CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –(CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a still further aspect, each of R4aand R4bis independently selected from F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, –CH2OH, –Attorney Docket No.21101.0487P1 CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH3)(CH2CH3), – CH2NH2, –CH2CH2NH2, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a yet OH,– OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph.

[0189] In various aspects, each of R4aand R4bis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a further aspect, each of R4aand R4bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph. In a yet further aspect, each of R4aand R4bis independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, – CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph.

[0190] In various aspects, each of R4aand R4bis independently selected from hydrogen, NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen. In a further aspect, each of R4aand R4bis 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), –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – In a still further–NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –Attorney Docket No.21101.0487P1 N(CH2CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph. In a yet further aspect, each of R4aand R4bis(CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph.

[0191] In various aspects, each of R4aand R4bis independently selected from hydrogen, (CH2)nCO2R14, (CH2)nNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen.

[0192] In various aspects, each of R4aand R4bis independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, provided that at least one of R4aand R4bis not hydrogen. In a further aspect, each of R4aand R4bis independently selected from hydrogen, F, Cl, Br, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R4aand R4bis independently selected from hydrogen, F, Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In a yet further aspect, each of R4aand R4bis independently selected from hydrogen, F, –CH2F, –CH2Cl, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0193] In various aspects, each of R4aand R4bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 alkoxy, provided that at least one of R4aand R4bis not hydrogen. In a further aspect, each of R4aand R4bis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R4aand R4bis independently selected from hydrogen, methyl, ethyl, – OCH3, and –OCH2CH3. In a yet further aspect, each of R4aand R4bis independently selected from hydrogen, methyl, and –OCH3.

[0194] In various aspects, each of R4aand R4bis independently selected from hydrogen, and C1-C4 alkyl. In a further aspect, each of R4aand R4bis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each of R4aand R4bis independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R4aand R4bis independently selected from hydrogen and methyl. e. R5AAND R5BGROUPSAttorney Docket No.21101.0487P1

[0195] In one aspect, each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

[0196] In various aspects, each of R5aand R5bis independently selected from hydrogen, halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl,–OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a still further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, –CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, – CH2OH, –CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – andhydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, – CH2NH2, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0197] In various aspects, each of R5aand R5bis independently selected from halogen, CN, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a further aspect, each of R5aand R5bis independentlyAttorney Docket No.21101.0487P1 selected from F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, – CH=CH2, CH=CHCH3, CH2CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, – 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), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a still further aspect, each of R5aand R5bis independently selected from F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH=CH2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, –CH2CH2CN, –CH2OH, – CH2CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH2CH2Cl, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH3)(CH2CH3), – In a yet OH,NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, – OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, –CH2NH2, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0198] In various aspects, each of R5aand R5bis independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, Br, CN, NH2, OH, NO2, methyl, ethyl, propyl, isopropyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, – OCH(CH3)CH2Cl, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a still further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, CN, NH2, OH, NO2, methyl, ethyl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH3, –OCH2CH3(CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. In a yet further aspect, each of R5aand R5bisAttorney Docket No.21101.0487P1 independently selected from hydrogen, F, CN, NH2, OH, NO2, methyl, –CH2F, – CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0199] In various aspects, each of R5aand R5bis independently selected from hydrogen, NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen. In a further aspect, each of R5aand R5bis 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), –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – rNHC and OCH2Ph. In a still further –NHCH3, –2, 2, , 2, (CH2CH3)2, –2, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph. selected from hydrogen,provided that at least one of R5aand R5bis not hydrogen.

[0201] In various aspects, each of R5aand R5bis independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, provided that at least one of R5aand R5bis not hydrogen. In a further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, Br, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, and – OCH(CH3)CH2Cl. In a still further aspect, each of R5aand R5bis independently selected from hydrogen, F, Cl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, – OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, and –OCH2CH2Cl. In a yet further aspect, each of R5aand R5bis independently selected from hydrogen, F, –CH2F, –CH2Cl, – OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, and –OCCl3.

[0202] In various aspects, each of R5aand R5bis independently selected from hydrogen, C1- C4 alkyl, C1-C4 alkoxy, provided that at least one of R5aand R5bis not hydrogen. In a further aspect, each of R5aand R5bis independently selected from hydrogen, methyl, ethyl,Attorney Docket No.21101.0487P1 propyl, isopropyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R5aand R5bis independently selected from hydrogen, methyl, ethyl, – OCH3, and –OCH2CH3. In a yet further aspect, each of R5aand R5bis independently selected from hydrogen, methyl, and –OCH3.

[0203] In various aspects, each of R5aand R5bis independently selected from hydrogen, and C1-C4 alkyl. In a further aspect, each of R5aand R5bis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each of R5aand R5bis independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R5aand R5bis independently selected from hydrogen and methyl. f. R10AND R11GROUPS

[0204] In one aspect, each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen, methyl, ethyl, and ethenyl. In a still further aspect, each occurrence of R10and R11is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R10and R11is independently selected from hydrogen and methyl.

[0205] In one aspect, each occurrence of R10and R11is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R10and R11is independently selected from hydrogen and ethyl.In yet a further aspect, each occurrence of R10and R11is independently selected from hydrogen and methyl.

[0206] In various aspects, each occurrence of R10and R11is independently selected from hydrogen and C2-C4 alkenyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R10and R11is independently selected from hydrogen and ethenyl.

[0207] In various aspects, each occurrence of R10and R11is C1-C4 alkyl. In a further aspect, each of R21aand R21bis independently selected from methyl, ethyl, propyl, and isopropyl. InAttorney Docket No.21101.0487P1 a further aspect, each occurrence of R10and R11is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R10and R11is methyl.

[0208] In various aspects, each occurrence of R10and R11is C2-C4 alkenyl. In a further aspect, each occurrence of R10and R11is independently selected from ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R10and R11is ethenyl.

[0209] In various aspects, each occurrence of R10and R11is hydrogen. g. R12AND R13GROUPS

[0210] In one aspect, each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen, methyl, ethyl, and ethenyl. In a still further aspect, each occurrence of R12and R13is independently selected from hydrogen and ethyl.In yet a further aspect, each occurrence of R12and R13is independently selected from hydrogen and methyl.

[0211] In one aspect, each occurrence of R12and R13is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R12and R13is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R12and R13is independently selected from hydrogen and methyl.

[0212] In various aspects, each occurrence of R12and R13is independently selected from hydrogen and C2-C4 alkenyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R12and R13is independently selected from hydrogen and ethenyl.

[0213] In various aspects, each occurrence of R12and R13is C1-C4 alkyl. In a further aspect, each of R21aand R21bis independently selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R12and R13is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R12and R13is methyl.Attorney Docket No.21101.0487P1

[0214] In various aspects, each occurrence of R12and R13is C2-C4 alkenyl. In a further aspect, each occurrence of R12and R13is independently selected from ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R12and R13is ethenyl.

[0215] In various aspects, each occurrence of R12and R13is hydrogen. h. R14AND R15GROUPS

[0216] In one aspect, each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen, methyl, ethyl, and ethenyl. In a still further aspect, each occurrence of R14and R15is independently selected from hydrogen and ethyl.In yet a further aspect, each occurrence of R14and R15is independently selected from hydrogen and methyl.

[0217] In one aspect, each occurrence of R14and R15is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R14and R15is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R14and R15is independently selected from hydrogen and methyl.

[0218] In various aspects, each occurrence of R14and R15is independently selected from hydrogen and C2-C4 alkenyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R14and R15is independently selected from hydrogen and ethenyl.

[0219] In various aspects, each occurrence of R14and R15is C1-C4 alkyl. In a further aspect, each of R21aand R21bis independently selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R14and R15is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R14and R15is methyl.

[0220] In various aspects, each occurrence of R14and R15is C2-C4 alkenyl. In a further aspect, each occurrence of R14and R15is independently selected from ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R14and R15is ethenyl.

[0221] In various aspects, each occurrence of R14and R15is hydrogen.Attorney Docket No.21101.0487P1 i. R16AND R17GROUPS

[0222] In one aspect, each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen, methyl, ethyl, and ethenyl. In a still further aspect, each occurrence of R16and R17is independently selected from hydrogen and ethyl.In yet a further aspect, each occurrence of R16and R17is independently selected from hydrogen and methyl.

[0223] In one aspect, each occurrence of R16and R17is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each occurrence of R16and R17is independently selected from hydrogen and ethyl. In yet a further aspect, each occurrence of R16and R17is independently selected from hydrogen and methyl.

[0224] In various aspects, each occurrence of R16and R17is independently selected from hydrogen and C2-C4 alkenyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen, ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R16and R17is independently selected from hydrogen and ethenyl.

[0225] In various aspects, each occurrence of R16and R17is C1-C4 alkyl. In a further aspect, each of R21aand R21bis independently selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, each occurrence of R16and R17is independently selected from methyl and ethyl. In a still further aspect, each occurrence of R16and R17is methyl.

[0226] In various aspects, each occurrence of R16and R17is C2-C4 alkenyl. In a further aspect, each occurrence of R16and R17is independently selected from ethenyl, propenyl, and isopropenyl. In a further aspect, each occurrence of R16and R17is ethenyl.

[0227] In various aspects, each occurrence of R16and R17is hydrogen. 2. EXAMPLE COMPOUNDS

[0228] In one aspect, a compound can be present as one or more of the following structures:Attorney Docket No.21101.0487P1 , or a

[0229] In one aspect, a compound can be present as one or more of the following structures: , ,Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1Attorney Docket No.21101.0487P1 , , ,

[0230] 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. ForAttorney Docket No.21101.0487P1 clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0231] 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 I

[0232] In one aspect, substituted pyrimidinyl analogs can be prepared as shown below. SCHEME 1A.s halogen, R is hydrogen, C1-C4 alkyl, and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.Attorney Docket No.21101.0487P1 SCHEME 1B.

[0234] In one aspect, compounds of type 1.8, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.8 can be prepared by a cross-coupling reaction of an aryl halide, e.g., 1.5 as shown above, using an appropriate boronic acid or ester, e.g., 1.6 and 1.7 as shown above. Appropriate aryl halides and appropriate boronic acids and esters are commercially available or prepared by methods known to one skilled in the art. The cross-coupling reaction is carried out in the presence of an appropriate catalyst, e.g., palladium acetate as shown above, in the presence of an appropriate base, e.g., sodium carbonate as shown above, in an appropriate solvent, e.g., dioxane and water, at an appropriate temperature, e.g., 80°C, for an appropriate amount of time, e.g., 12h. 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, and 1.3), can be substituted in the reaction to provide substituted pyrimidinyl analogs similar to Formula 1.4. D. PHARMACEUTICAL COMPOSITIONS

[0235] 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.Attorney Docket No.21101.0487P1

[0236] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein each of R1aand R1bhydrogen, halogen, NH2, OH,O2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier.

[0237] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound selected from: ,Attorney Docket No.21101.0487P1 , or a

[0238] 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 or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by intravenous, topical, or oral administration.

[0239] 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 suchAttorney Docket No.21101.0487P1 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.

[0240] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. CompressedAttorney Docket No.21101.0487P1 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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 theAttorney Docket No.21101.0487P1 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.

[0250] 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.

[0251] 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 antioxidants) 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 / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0252] 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.

[0253] 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.

[0254] 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.E. METHODS FOR OF INHIBITING F-BOX PROTEIN 21 (FBOX21) MEDIATED P85UBIQUITINATION IN A CELL

[0255] In one aspect, disclosed are methods of inhibiting F-box protein 21 (FBOX21)mediated p85 ubiquitination in a cell, the method comprising contacting the cell with aneffective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0256] Thus, in one aspect, disclosed are methods of inhibiting F-box protein 21 (FBOX21)mediated p85 ubiquitination in a cell, the method comprising contacting the cell with aneffective amount of a compound having a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R1aand R1bhydrogen, halogen, NH2, OH,O2, CN, C1-C4 alkyl, C1- C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0257] In one aspect, disclosed are methods of inhibiting F-box protein 21 (FBOX21)mediated p85 ubiquitination in a cell, the method comprising contacting the cell with aneffective amount of a compound selected from: ,Attorney Docket No.21101.0487P1 , or a

[0258] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0259] In various aspects, the compound is not: , or a pharmaceutically

[0260] In various aspects, the cell is mammalian. In a further aspect, the cell is human.

[0261] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0262] In various aspect, contacting is ex vivo.Attorney Docket No.21101.0487P1

[0263] In various aspect, contacting is in vitro.

[0264] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for inhibition of FBOX21 prior to the administering step.F. METHODS OF INHIBITING FBOX21 MEDIATED P85 UBIQUITINATION IN A SUBJECT

[0265] In one aspect, disclosed are methods of inhibiting FBOX21 mediated p85ubiquitination in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0266] Thus, in one aspect, disclosed are methods of inhibiting FBOX21 mediated p85ubiquitination in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R1aand R1bhydrogen, halogen, NH2, OH, O2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof.Attorney Docket No.21101.0487P1

[0267] In one aspect, disclosed are methods of inhibiting FBOX21 mediated p85ubiquitination in a subject, the method comprising administering to the subject with an effective amount of a compound selected from: , or a

[0268] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0269] In various aspects, the compound is not:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0270] In various aspects, a a aspect, the subject is a human.

[0271] In various aspects, administering is oral administration, intranasal administration, intramuscular administration, or intravenous administration.

[0272] In various aspects, the subject has been diagnosed with a need for inhibition ofFBOX21 mediated p85 ubiquitination prior to the administering step.

[0273] In various aspects, the method further comprising identifying a subject in need ofinhibition of FBOX21 mediated p85 ubiquitination.G. METHODS OF TREATING CANCER IN A SUBJECT

[0274] In one aspect, disclosed are methods of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof.

[0275] Thus, in one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R4aand R4bhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen,Attorney Docket No.21101.0487P1 or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof.

[0276] In one aspect, disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: , ,Attorney Docket No.21101.0487P1 , or a

[0277] halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen; and wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen.

[0278] In various aspects, the compound is not: , or a pharmaceutically

[0279] In various aspects, each of R4aand R4bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1- C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen.Attorney Docket No.21101.0487P1

[0280] In various aspects, each of R4aand R4bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen.

[0281] In various aspects, R4ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0282] In various aspects, R4bis hydrogen.

[0283] In various aspects, R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0284] In various aspects, R4ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0285] In various aspects, R4bis hydrogen.

[0286] In various aspects, R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0287] In various aspects, R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0288] In various aspects, R4ais hydrogen.

[0289] In various aspects, R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

[0290] In various aspects, R4ais hydrogen.

[0291] In various aspects, each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0292] In various aspects, each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0293] In various aspects, R5ais selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0294] In various aspects, R5bis hydrogen.Attorney Docket No.21101.0487P1

[0295] In various aspects, R5bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0296] In various aspects, R5ais selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0297] In various aspects, R5bis hydrogen.

[0298] In various aspects, R5bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0299] In various aspects, R5bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0300] In various aspects, R5ais hydrogen.

[0301] In various aspects, R5bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

[0302] In various aspects, R5ais hydrogen.

[0303] In various aspects, each of R4aand R5ais hydrogen.

[0304] In various aspects, each of R4aand R5bis hydrogen.

[0305] In various aspects, each of R4band R5ais hydrogen.

[0306] In various aspects, each of R4band R5bis hydrogen.

[0307] In various aspects, each of R4aand R5ais not hydrogen.

[0308] In various aspects, each of R4aand R5bis not hydrogen.

[0309] In various aspects, each of R4band R5ais not hydrogen.

[0310] In various aspects, each of R4band R5bis not hydrogen.

[0311] In various aspects, each of R4a, R4b, and R5ais not hydrogen.

[0312] In various aspects, each of R4a, R5a, and R5bis not hydrogen.

[0313] In various aspects, each of R4b, R5a, and R5bis not hydrogen.

[0314] In various aspects, each of R4a, R4b, R5a, and R5ais not hydrogen.

[0315] In various aspects, each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

[0316] In various aspects, each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

[0317] In various aspects, each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring and wherein each of R5aAttorney Docket No.21101.0487P1 and R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

[0318] In various aspects, R3is hydrogen.

[0319] In various aspects, R3is C1-C4 alkyl.

[0320] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0321] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0322] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, andacceptable salt thereof.

[0323] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0324] In various aspects, a by a formula: , or a pharmaceutically

[0325] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0326] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0327] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4a, R4b, R5a,acceptable saltthereof.

[0328] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0329] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0330] In various aspects, the compound has a structure represented by a formula: , wherein each of R4a, R4b, andacceptable salt thereof.

[0331] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4a, R4b, R5a,acceptable saltthereof.

[0332] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0333] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0334] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically

[0335] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically

[0336] In various aspects, the , or a pharmaceutically

[0337] In various aspects, the compound is selected from: ,Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1 , , , ,Attorney Docket No.21101.0487P1 , , , or a

[0338] In various aspects, the subject is a mammal. In a further aspect, the subject is a human.

[0339] In various aspect, the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

[0340] In various aspects, the method further comprising identifying a subject in need for treatment of cancer.

[0341] In various aspects, the effective amount is a therapeutically effective amount.

[0342] In various aspects, the effective amount is a prophylactically effective amount.

[0343] In various aspects, 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, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome,Attorney Docket No.21101.0487P1 myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

[0344] In various aspects, the cancer is a primary or secondary tumor.

[0345] In various aspects, the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

[0346] In various aspects, the cancer is a lymphoma or a leukemia.

[0347] In various aspects, the lymphoma or the leukemia is selected from non-Hodgkin lymphoma (e.g., B-cell lymphomas such as diffuse large B-cell lymphoma, large cell lymphomas such as anaplastic large cell lymphoma), acute lymphoblastic leukemia, chronic myelogenous leukemia, and acute myeloid leukemia.

[0348] In various aspects, the cancer is acute myeloid leukemia.

[0349] In various aspects, administering is oral or parental administration.

[0350] In various aspects, the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection. H. KITS

[0351] In one aspect, disclosed are kits comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0352] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula: , wherein each of R4aand R4bishydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen,Attorney Docket No.21101.0487P1 or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof, and one or more of: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

[0353] In one aspect, disclosed are kits comprising a compound selected from: , , ,Attorney Docket No.21101.0487P1 , or a pharmaceutically of: (a) an anti-cancer agent; (b) instructions for administeringwith treating cancer; and (c) instructions for treating cancer.

[0354] In various aspects, each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

[0355] In various aspects, the compound is not: , or a pharmaceutically

[0356] In various aspects, the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage-inducing agent, and a mTor inhibitor agent.

[0357] In various aspects, 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.

[0358] In various aspects, the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine,Attorney Docket No.21101.0487P1 nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0359] In various aspects, 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.

[0360] In various aspects, 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.

[0361] In various aspects, the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

[0362] In various aspects, the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

[0363] In various aspects, the compound and the anti-cancer agent are co-packaged.

[0364] In various aspects, the compound and the anti-cancer agent are co-formulated.

[0365] 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 the art 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.

[0366] 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.Attorney Docket No.21101.0487P1 I. EXAMPLES

[0367] 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.

[0368] The Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS GENERAL EXPERIMENTAL METHODS

[0369] Unless otherwise stated, all the reactions were performed in oven- or flame-dried glassware under an argon atmosphere. Air and / or moisture-sensitive liquids were transferred via a syringe or stainless-steel cannula. Reactions were examined by thin-layer chromatography (TLC) on glass plates pre-coated with silica gel (0.25 mm, 60 Å pore size, 230–400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 nm), visualized under UV light (254 nm). Organic solutions were concentrated under reduced pressure on a Buchi rotary evaporator. Flash chromatography was performed using Buchi Pure C-850 (230- 400 mesh, 40-63 μm prepacked SiliCycle silica cartridges).

[0370] All commercially available reagents were purchased from Ambeed, Combi-block, Sigma-Aldrich, Strem, Oakwood, or Chem-Impex and used without purification unless otherwise indicated. All organic solvents used in the experiment were anhydrous. Extraction and chromatography solvents were reagent grade and used without purification.

[0371] Proton nuclear magnetic resonance (1HNMR) spectra, proton-decoupled carbon nuclear magnetic resonance (13CNMR) spectra, and proton-decoupled fluorine nuclear magnetic resonance (19FNMR) spectra were recorded on Bruker Advance 400 (400 MHz) and 600 (600 MHz) spectrometers using CDCl3and DMSO-d6as the solvents at 25°C. Allchemical shifts ( ) are reported in parts per million (ppm) downfield from tetramethylsilaneand are referenced to the residual solvent signal of the NMR solvent. Data are represented asAttorney Docket No.21101.0487P1 follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration. High-resolution mass spectra (HRMS) were performed on an Agilent 6230 LC / TOF mass spectrometer (Agilent Technology Co., Ltd, Santa Clara, CA, USA). The purity of all the compounds was confirmed to be >95% by HPLC. SYNTHESIS i. SYNTHESIS OF 2-(4,4''-DIFLUORO-[1,1':4',1''-TERPHENYL]-2'- YL)ACETIC ACID (57-057) F F Br Br a

[0372] To a stirred solution of 1 (500 mg, 1.70 mmol, 1.0 equiv) in anhydrous ethanol (10 mL) in an oven-dried round bottom flask was added a catalytic amount of concentrated H2SO4(0.2 eq.). The round bottom flask was placed in a preheated oil bath and refluxed at 80°C for 5 h. Reaction completion was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was neutralized with aq. NaHCO3 solution. The precipitate was filtered, washed withwater (3 5 mL), and dried under a high vacuum to give 2 (520.0 mg, 95% yield) as a buff-colored solid. The crude was characterized by HRMS, 1HNMR, HPLC and taken for step b without further purification. iii. SYNTHESIS OF ETHYL 2-(4,4''-DIFLUORO-[1,1':4',1''- TERPHENYL]-2'-YL)ACETATE (3)

[0373] An oven-dried sealed tube was charged with the 2 (150.0 mg, 0.465 mmol, 1.0 equiv), 4-fluoro phenylboronic acid (195.5 mg, 1.397 mmol, 3.0 equiv), and Na2CO3 (148.1 mg, 1.397 mmol, 3.0 equiv). The reaction tube was evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous dioxane (4 mL) and H2O (2 mL) were then added via a syringe. The resulting reaction mixture was purged with argon for 10Attorney Docket No.21101.0487P1 minutes. Pd(OAc)2 (10.5 mg, 0.046 mmol, 0.1 equiv) was then added, and the sealed tube was capped and placed in a preheated oil bath and stirred at 80°C for 12 h. Reaction completion was monitored by TLC. Upon completion, the reaction mixture was cooled toroom temperature, poured into cold water, and extracted with EtOAc (3 10 mL). Theresulting organic mixture was washed with brine and dried through a Na2SO4bed. The organic layer was concentrated under reduced pressure. The crude residue was purified by flash chromatography (2-10% EtOAc in Hexane) to yield 3 (108.7 mg, 66% yield) as a white solid. The compound was then characterized by HRMS, 1HNMR, and HPLC. iv. SYNTHESIS OF 2-(4,4''-DIFLUORO-[1,1':4',1''-TERPHENYL]-2'- YL)ACETIC ACID (57-057)

[0374] To a stirred solution of 3 (50.0 mg, 0.142 mmol, 1.0 equiv) in methanol (5 mL) in an oven-dried round bottom flask, a catalytic amount of 1N NaOH (0.1 mL) was added. The resulting reaction mixture was placed in a preheated oil bath and refluxed at 70°C for 2 h. Reaction completion was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was acidified with 1N HCl solution. The precipitate was filtered, washed with water, and dried under a high vacuum to yield 57-057 (44.0 mg, 95% yield).

[0375] White solid, 44.0 mg, yield 95%.1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 7.75 (dd, J = 8.7, 5.5 Hz, 2H), 7.67 – 7.59 (m, 2H), 7.40 – 7.26 (m, 7H), 3.60 (s, 2H).13C NMR (101 MHz, DMSO-d6) 173.17, 163.63, 163.21, 161.21, 160.79, 140.40, 138.68, 137.18, 136.54, 133.76, 131.38, 131.30, 130.94, 129.70, 129.11, 129.03, 125.62, 116.38, 116.16, 115.75, 115.54, 40.62, 40.41, 40.21, 40.00, 39.79, 39.58, 39.37, 39.11.19FNMR (564 MHz, DMSO-d6) -115.31 (s, 1H), -115.38 (s, 1H). HRMS (ESI-TOF) m / z: [M+H]+ Calc’d for C20H14F2O2325.1040; found 325.1044. v. SYNTHESIS OF 2'-ETHYL-4,4''-DIFLUORO-1,1':4',1''-TERPHENYL (57-139)Attorney Docket No.21101.0487P1

[0376] An oven-dried sealed tube was charged with the 4 (400.0 mg, 1.286 mmol, 1.0 equiv), 4-fluoro phenylboronic acid (414.2 mg, 2.958 mmol, 2.3 equiv), and Na2CO3(409.0 mg, 3.858 mmol, 3.0 equiv). The reaction tube was evacuated and backfilled with argon (this process was repeated a total of three times). Anhydrous dioxane (3 mL) and H2O (1 mL) were then added via a syringe. The resulting reaction mixture was purged with argon for 10 minutes. Pd(PPh3)4(74.0 mg,0.064 mmol, 0.05 equiv) was then added, and the sealed tube was capped and placed in a preheated oil bath and stirred at 80°C for 12 h. Reaction completion was monitored by TLC. Upon completion, the reaction mixture was cooled toroom temperature, poured into cold water, and extracted with EtOAc (3 10 mL). Theresulting organic mixture was washed with brine and dried through a Na2SO4bed. The organic layer was concentrated under reduced pressure. The crude residue was purified by flash chromatography (1% EtOAc in Hexane) to yield a colorless oil of 57-139 (206.1 mg, 54% yield).

[0377] Colorless oil, 206.1 mg, yield 54%.1H NMR (400 MHz, CDCl3) 7.65 – 7.59 (m, 2H), 7.50 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 7.9, 2.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.28 (s, 1H), 7.20 – 7.11 (m, 4H), 2.67 (q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).13C NMR (101 MHz, CDCl3) 164.18, 163.70, 161.73, 161.25, 142.68, 140.12, 140.06, 137.88, 137.59, 131.23, 131.15, 131.04, 129.15, 129.07, 127.81, 124.74, 116.20, 115.99, 115.58, 115.37, 77.79, 77.48, 77.16, 26.75, 16.11.19FNMR (564 MHz, CDCl3) -115.71 (s, 1H), -115.89 (s, 1H). HRMS (ESI-TOF) m / z: [M+NH4]+ Calc’d for C20H16F2317.0814; found 317.1083.

[0378] vi. ETHYL 2-(4,4''-DIHYDROXY-[1,1':4',1''-TERPHENYL]-2'- YL)ACETATE (57-048):

[0379] 57-048 was synthesized(3). Violet solid, 55.7 mg, yield 30%. 1H NMR (400 MHz, DMSO-d6) 9.60 (s, 1H), 9.55 (s, 1H), 7.56 – 7.46 (m, 4H), 7.22 (d, J = 7.9 Hz, 1H), 7.13 – 7.06 (m, 2H), 6.84 (dd, J = 20.3, 8.6 Hz, 4H), 3.99 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.10 (t, J = 7.1 Hz, 3H).13C NMR (151 MHz, DMSO-d6) 170.10, 137.48, 136.36, 135.11, 134.64, 132.37, 127.46, 124.13, 120.98, 116.13, 116.05, 114.86, 113.69,Attorney Docket No.21101.0487P1 61.14, 40.99, 14.49. HRMS (ESI-TOF) m / z: [M+H]+Calc’d for C22H20O4349.1440; found 349.1435. vii. 2-(4,4''-DIHYDROXY-[1,1':4',1''-TERPHENYL]-2'-YL)ACETIC ACID (57-112):

[0380] 57-112 was synthesized (57-057). White solid, 24.5 mg, yield88%.1H NMR (400 MHz, , 9.52 (d, J = 17.4 Hz, 2H), 7.50 (dd, J = 13.1, 4.7 Hz, 4H), 7.21 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.84 (dd, J = 17.7, 8.3 Hz, 4H), 3.56 (s, 2H).13C NMR (101 MHz, DMSO-d6) 173.45, 157.56, 156.99, 140.44, 139.03, 133.28, 131.57, 130.95, 130.75, 130.42, 128.82, 128.05, 124.81, 116.21, 115.53, 40.61, 40.40, 40.20, 39.99, 39.78, 39.57, 39.36, 39.12. HRMS (ESI-TOF) m / z: [M+NH4]+ Calc'd for C20H16O4338.1392; found 338.1410. viii. 2-(4,4''-DICYANO-[1,1':4',1''-TERPHENYL]-2'-YL)ACETIC ACID (57-125):

[0381] 57-125 was synthesized(57-057). White solid, 46.7 mg, yield 92%.1H NMR (400 MHz, DMSO-d6) 8.00 – 7.92 (m, 6H), 7.82 (d, J = 1.7 Hz, 1H), 7.77 (dd, J = 8.0, 1.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 3.65 (s, 2H). 13C NMR (101 MHz, DMSO-d6) 172.87, 145.56, 144.30, 141.09, 138.45, 133.95, 133.43, 132.80, 130.94, 130.41, 128.03, 126.25, 119.30, 119.24, 110.76, 40.62, 40.41, 40.20, 39.99, 39.78, 39.57, 39.37, 39.02. HRMS (ESI-TOF) m / z: [M+H]+ Calc’d for C22H14N2O2 339.1133; found 339.1134. 2. BIOLOGICAL EXPERIMENTALSAttorney Docket No.21101.0487P1 IN VITRO UBIQUITINATION

[0382] HEK293T cells were transfected with plasmids encoding HA-FBXO21, HA- FBXO21, or GFP-p85 , with or without lysine(K) to arginine(R), or tyrosine(Y) toalanine(A) mutations. FBXO21 and FBXO21 were a kind gift from Dr. Yukiko Yoshida, Tokyo Metropolitan Institute of Medical Science.48 hrs post transfection, HA-FBXO21, HA- FBXO21, or GFP-p85 were immunopurified from the whole cell extracts using Anti-HA(Sigma) or Anti-GFP (MBL International) beads overnight at 4°C. The immunopurified HA-FBXO21 or HA- FBXO21 (0.5 μg) proteins were incubated with immunopurified GFP-p85(0.5 μg), E1 (500 ng), E2-UbcH5a (500 ng), FLAG-ubiquitin (0.5 μg) (BostonBiochem), and ATP (10mM). Ubiquitylation reactions were performed in 100 mM NaCl, 1 mM DTT, 5 mM MgCl2, 25 mM Tris-Cl (pH 7.5), incubated at 30°C for 2hrs, and stopped with 2× laemmli buffer (10 min at 95°C). CELL CULTURE / FLOW CYTOMETRY ANALYSIS

[0383] HEK293T, HL-60, and MOLM-13 cells were purchased from ATCC and DSMZ, and cultured according to ATCC / DSMZ guidelines. Primary human AML cells (Cureline Translational Cro) and CD34+cells were cultured in StemSpan SFEM II media with CD34+ Expansion Supplement (StemCell Technologies) and UM729 (1 M). Primary (CD34+ and AML) cells, along with the human-derived cell lines, were treated with varying doses of the compound 57-057, ranging from 5 nM to 100 nM, for a duration of 72 hours.

[0384] Mouse MLL-AF9 Lin-, Sca1+, cKit+ (LSK) cells were isolated from bone marrow when mice began to show signs of disease (high WBC by CBC and increased Gr1 / Mac1 expression in peripheral blood) and cultured in media consisting of Opti-MEM Media, 10% FBS, 1% Pen / Strep, 50μM -Mercaptoethanol, 50ng / mL Stem Cell Factor, 50ng / mL FLT3 Ligand (FLT3-L), 10ng / mL Interleukin-6 (IL-6), and 10ng / mL Interleukin-3 (IL-3).

[0385] For apoptosis, staining was performed following BioLegend apoptosis staining protocol. Antibodies listed in Table 1. MOUSE STUDIES

[0386] For spleen tumor transplants, one day prior to irradiation, antibiotics were added to the water. Mice were sub-lethally irradiated with 500 cGy 4 – 12 hours prior to transplantation. Samples were prepared under sterile conditions and suspended in sterile PBS for injection. Tumor cells were transplanted via tail vein or retro-orbital injection. The drug,Attorney Docket No.21101.0487P1 57-057, was resuspended in 5% DMSO and corn oil for oral gavage in dose escalation study and in a 5% DMSO, 35% PEG3000, and 60% water solution for intravenous injection in AML mouse model studies. All pharmacokinetic (PK) testing was conducted using a formulation of 10% DMSO, 2% NMP, 50% PEG400, and 38% water. STATISTICAL ANALYSIS

[0387] All experiments were performed in triplicate unless noted and statistical analyses were performed using unpaired two-tailed Student's t-test assuming samples of equal variance. Error bars depict the standard deviation ±mean. 3. RESULTS FBXO21 MEDIATES K-48 LINKED POLYUBIQUITINATION OF P85 ATK692.

[0388] To determine the specificity of p85 ubiquitination by FBXO21, a panel of F-boxproteins was screened using a cell-free in vitro ubiquitination assay. The screen revealed thatonly FBXO21 was able to facilitate the ubiquitination of p85 (FIG. 1A). To further explorethe characteristics of this ubiquitination and the lysine linkage required for FBXO21ubiquitination of p85 , HA tagged wild-type (WT) ubiquitin or a ubiquitin lysine (K) mutantwas transiently expressed. The K linkage mutants only contained the lysine linkage specified, with all other lysines mutated to arginine (R). The ubiquitin WT or mutants were transfectedin addition to FLAG-tagged FBXO21 and GFP-tagged p85 . GFP or HA wasimmunoprecipitated and found that ubiquitinated p85 protein was only detected in cellsexpressing WT ubiquitin and K48-linked ubiquitin, but not in cells with a K48 to arginine (R) mutation (FIG.1B). Without wishing to be bound by theory, this suggests that FBXO21specifically ubiquitinates p85 through K48-linked ubiquitination. ten lysine residues havepreviously been identified as sites of ubiquitination on p85 . a new lysine residue, K692 wasidentified, from the K- -GG immunoprecipitation followed by mass spectrometry (FIG. 1C)as the target of FBXO21 mediated p85 ubiquitination. Immunopurified p85 -K692R (lane5) led to the loss of ubiquitination, while the other ten previously reported lysine mutationsdid not affect p85 ubiquitination, demonstrating that FBXO21 mediates polyubiquitinationof p85 selectively at K692 (FIG. 1D).

[0389] It was found that interaction and ubiquitination of p85 depends on the YccV domain(residues 503-557) of FBXO21 (SEQ ID NO: 2), which is consistent with previous studiesAttorney Docket No.21101.0487P1 showing FBXO21 interacts with previously identified substrate, EID1, through its YccV domain (SEQ ID NO: 2) (FIG.1E-G). In vitro ubiquitination assay demonstrated immunopurified FBXO21, but not the YccV-deficient FBXO21 mutant, was able toubiquitinate p85 in vitro (FIG. 1F). This suggests that the YccV domain of FBXO21 (SEQID NO: 2) serves as the substrate recognition domain required for binding to p85 . Thesefindings provide important insights into the molecular mechanisms underlying theubiquitination of p85 by FBXO21 and further the understanding of the regulatory role ofFBXO21 in the modulation of the PI3K signaling pathway. ix. P85 PHOSPHODEGRON WITHIN ISH2 DOMAIN REQUIRED FORFBXO21 BINDING.

[0390] Next, the FBXO21-binding motif in p85 was determined by using deletion mutantsto identify the domain of p85 required for binding (FIG. 2A). GFP-tagged domain mutantsof p85 were transiently transfected alongside HA-tagged FBXO21 into HEK293T cells andperformed immunoprecipitation for both FBXO21 and p85 . Interestingly, it was found thatthe interaction between p85 and FBXO21 was lost upon deletion of the iSH2 domain ofp85 (FIG. 2B). The iSH2 (inter-SH2) domain of p85 directly binds to the p110 catalyticsubunit of PI3K functioning as a tether to maintain the structural integrity of the p85 / p110complex, which is essential for the activation and proper functioning of the PI3K pathway.To identify the sequence in p85 that interacts with FBXO21, comparative bioinformaticsanalyses was conducted to predict small peptide sequences that had a high probability of interacting with the YccV domain of FBXO21 (SEQ ID NO: 2). Three potential degron sequences, L466YEEYT471(SEQ ID NO: 3), I493FEEQC498(SEQ ID NO: 4), andR544LEEDL549 (SEQ ID NO: 5) on p85 were identified (FIG. 2C). The top three identifiedsites were all within the iSH2 domain of p85 , further confirming the results of theimmunoprecipitation. Overlay of the identified docked p85 sequences with EID1 sequence(F161IEELF166 (SEQ ID NO: 6)) identified L466YEEYT471 (SEQ ID NO: 3) in p85 showedcomparable docking scores (FIG.2D). It is typical for FBOX ubiquitin E3 ligases to require phosphorylation of their substrates, or phosphorylation of an amino acid within their specific degron, for recognition. Only one of three identified predicted binding sequences (L466YEEYT471(SEQ ID NO: 3)) included a phosphorylatable amino acid (i.e., tyrosine (Y), threonine (T), and serine (S)).Attorney Docket No.21101.0487P1

[0391] Utilizing the predicted computational modeling and previously identified phosphorylation sites, top phosphorylated tyrosine (Y) sites were mutated within the iSH2domain of p85 to alanine (A), rendering these residues incapable of phosphorylation (FIG.2E). It was found that FBXO21 mediated p85 ubiquitination was lost only in the Y467Ap85 mutant, suggesting that phosphorylation of Y467 is required for FBXO21 mediateddegradation of p85 (FIG. 2F-G). Together, the molecular basis for FBXO21 mediated p85ubiquitination was defined, which indicates that a helical mimic of p85 LYEEYT (SEQ IDNO: 3) would bind to the YccV domain of FBXO21 (SEQ ID NO: 2) to disrupt p85ubiquitination. x. SMALL MOLECULE INHIBITS P85 UBIQUITINATION.

[0392] The region of p85 that binds to the YccV domain of FBXO21 (SEQ ID NO: 2)adopts an -helical conformation (FIG.3A). While there are several approaches to design - helical mimics, non-peptide -helix mimetics were focused on. Specifically, the elegant use of substituted terphenyl analogs as -helix mimetics was inspired by work pioneered by the Hamilton group. An iterative design, dock, synthesize and evaluate (DDSE) approach was initiated to identify a substituted terphenyl analog that would disrupt FBXO21 mediatedubiquitination of p85 . The binding mode of the active compound against FBXO21 (57-057)is supported by structure activity relationship of related analogs (FIG.3B). The FBXO21mediated in vitro ubiquitination of p85 was inhibited by the terphenyl analogs 57-057 and57-112. The model indicated that the carboxylic group on the active compounds was within hydrogen bond distance of R561and H511. The complete loss of activity with 57-139 in which the carboxylic acid is replaced with a methyl group and 57-048 in which the carboxylic acid was converted to the ester, suggests that the interaction between the carboxylic acid in the active compounds and R561and H511in FBXO21 is critical. The model also indicates that the fluoro-phenyl ortho to the carboxylic acid occupies a narrow binding pocket, consistently replacing the fluorine atom with two atom nitrile group in 57-125 resulted in complete loss of activity.

[0393] Follow up dose response studies with the active compound 57-057 inhibited FBXO21mediated ubiquitination of p85 at low nanomolar concentrations (lanes 6-8), whereas thecontrol compound 57-139 (lanes 9-11) did not (FIG.3C). This confirms that 57-057effectively disrupts the FBXO21 / p85 interaction. Next, the selectivity of 57-057 wasassessed in three in vitro ubiquitination assay systems viz., FBXO21 mediated p85Attorney Docket No.21101.0487P1 ubiquitination, FBXW7 mediated cMyc ubiquitination, and FBXO9 mediated DPPA5ubiquitination. Remarkably, selective inhibition of FBXO21 mediated p85 ubiquitination by57-057 was observed (lane 5-6, FIG.3D). No such inhibition was observed in either FBXW7 mediated cMyc ubiquitination (lane 8-9, FIG.3D) or FBXO9 mediated ubiquitination of DPPA5 (lane 11-12, FIG.3D). Together the data shows that 57-057 is a selective FBXO21binder that inhibits the in vitro ubiquitination of p85 at low-nM potencies with an IC50 of2.4 nM (FIG.3E).

[0394] The in vitro results were validated in AML models with p85 levels as the read outfor small molecule mediated perturbation of FBXO21. Disruption of p85 binding toFBXO21 should prevent SCF mediated ubiquitination of p85 thus resulting in thestabilization / increase of p85 levels in cells. Consistent with previous FBXO21 knockdownstudies that resulted in increased p85 in AML cells, a dose-dependent increase in p85levels was observed in MOLM-13 cells treated with 57-057. This disruption led to a decrease in AKT activation and a reduction in p85 / p110 dimerization, accompanied by an increase in p85 / p85 dimerization, consistent with the results observed from FBXO21 knockdown experiments (FIG.7B and FIG.7C). xi. 57-057 SHOWS SELECTIVITY TO AML TUMOR CELLS OVER HEALTHY HSPCS.

[0395] Next, the antiproliferative effects of 57-057 was tested on AML cells, specifically MOLM-13 and HL-60. The compound induced a decrease in AML cell viability at low nanomolar concentrations, with IC50 values of 25 nM for MOLM-13 and 32 nM for HL-60 (FIG.7A). A common challenge with PI3K inhibitors is the development of resistance. To test the efficacy of the compound against a PI3K inhibitor-resistant cell line, MOLM-13 Alpelisib-resistant cell lines were created. Alpelisib works by inhibiting the PI3K catalyticsubunit, p110 , which is often mutated and hyperactivated in various cancers. Alpelisibspecifically binds at the ATP-binding pocket of p110 , preventing the phosphorylation ofPIP2 to PIP3, a crucial step in the PI3K / AKT signaling pathway. By blocking this enzyme, Alpelisib reduces the downstream signaling through the AKT / mTOR pathway, thereby inhibiting cancer cell growth and survival. Although PI3K inhibitors are not FDA approved for AML, the PI3K inhibitor Alpelisib is FDA approved for treatment of HR-positive, HER2- negative advanced or metastatic breast cancer. MOLM-13 resistant cell lines were created by gradually exposing the cells to increasing concentrations of Alpelisib over several weeks untilAttorney Docket No.21101.0487P1 resistance was established and confirmed by an increase in IC50 value from 115nM to 455nM (FIG.7D). The increase in IC50suggests that MOLM-13 cells have developed resistance to Alpelisib, which could be due to the activation of alternative survival pathways, such as MAPK or mTOR, which can bypass PI3K inhibition.

[0396] 57-057 was then tested in both normal and Alpelisib-resistant MOLM-13 cells (FIG.7E). Remarkably, even with resistance to the PI3K inhibitor targeting the p110 catalyticsubunit, the small molecule targeting FBXO21 (57-057) remained effective (IC50 = 34nM).The accumulation of p85 and decreased canonical PI3K signaling in both normal andAlpelisib-resistant AML cells demonstrate that targeting FBXO21 leads to cell death through the same mechanism (FIG.7F). This response suggests that targeting FBXO21 can circumvent the resistance mechanisms that often develop against traditional PI3K inhibitors. These findings demonstrate the potent and selective action of 57-057, as it inhibited thegrowth of AML cells by disrupting the FBXO21-p85 interaction and downregulatingcanonical PI3K signaling. The consistent efficacy in both normal and PI3K inhibitor-resistant cells highlights the therapeutic potential of targeting FBXO21 as a novel strategy in AML treatment.

[0397] Previously, it was demonstrated that FBXO21 is dispensable for steady-state hematopoiesis but plays a critical role in the proliferation and survival of AML through itsubiquitination of p85 . Building on these results, the investigation was extended to primaryhealthy CD34+ HSPC and AML patient cells to evaluate the broader applicability and therapeutic potential of the 57-057 compound. It was found that 57-057 exhibited approximately 5-fold selectivity (8 nM vs.39 nM) for killing primary AML cells over CD34+ HSPCs ((FIG.4A). In contrast, Alpelisib did not show such selectivity (47 nM vs.56 nM) ((FIG.4B). In direct comparison with Alpelisib 57-057 inhibited the growth of primary AML cells with approximately 6-fold higher potency (8 nM vs.47 nM) ((FIG.4C).Increased p85 accumulation was also observed in both AML and CD34+ cells treated withthe active compound (57-057), validating that the compound is blocking the ubiquitination ofp85 by FBXO21 (FIG. 4D). There was also a corresponding decrease in AKT activation,which was more apparent in AML cells in comparison to healthy CD34+ cells ((FIG.4D). The greater decrease in AKT activation in AML cells compared to healthy cells upon 57-057 treatment reflects both the higher dependency of cancer cells on the PI3K / AKT pathway for their growth and survival, and the selective cytotoxicity of 57-057 which targets thehyperactive PI3K / AKT pathway by blocking the ubiquitination of p85 , leading to cytotoxiceffects predominantly in cancer cells. Interestingly, it was noted a dose-dependent increase inAttorney Docket No.21101.0487P1p85 / p85 dimerization in both CD34+ and AML samples, and a corresponding loss of p85 / p110 dimerization in AML samples ((FIG.4E). Furthermore, in colony-forming assays with primary AML and healthy CD34+ cells treated with increasing concentrations of 57-057, no significant decrease in colony formation by CD34+ cells treated with 57-057 was found. Importantly, 57-057 treatment in primary AML cells resulted in a dramatic dose-dependent decrease in the number of colonies formed, suggesting a loss of stemness and reduced growth rate (FIG.4F). These findings underscore the potential of 57-057 as a more effective and selective therapeutic option for targeting AML cells, including those resistant to conventional PI3K inhibitors. xii. 57-057 SHOWS PROMISE FOR AML TREATMENT THROUGH EFFECTIVE TARGETING OF FBXO21 AND FAVORABLE PHARMACOKINETICS.

[0398] To advance the compound 57-057 for further study, it was first tested in MLL-AF9 mouse spleen tumors to determine if it would be effective on mouse AML cells as it is on human AML cells. It was confirmed that treating these tumor cells for 72 hours in vitro with increasing doses of 57-057 resulted in increased apoptosis, decreased colonies, and decreased canonical PI3K activity, as evidenced by reduced AKT phosphorylation (FIG.8A-C). Pharmacokinetic (PK) and tissues distribution studies reveal that 57-057 (30 mg / kg) is orally bioavailable, with a half-life of ~6h (FIG.8D) and is primarily cleared by the liver (FIG. 8E).

[0399] Dose escalation studies treating mice IP starting at 2.5mg / kg to 90mg / kg over a 14- week period showed no adverse effects with 57-057 treatment (normal white blood cell counts, no weight loss, and altered metabolic enzymes). Further, no alterations in the percentage of long-term hematopoietic stem cells (LT-HSCs) was observed, short-term hematopoietic stem cells (ST-HSCs), or any multipotent progenitors (MPPs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), or megakaryocyte- erythroid progenitors (MEPs), indicating that the drug does not impair stem or progenitor populations in vivo (FIG.8F). Additionally, there were no differences in bone marrow count or spleen weight across the treatment groups. (FIG.8G and FIG.8H). This is crucial as it suggests that 57-057 does not indiscriminately target healthy cells, preserving normal hematopoiesis and reducing the risk of bone marrow suppression.Attorney Docket No.21101.0487P1

[0400] Next, to evaluate the efficacy of 57-057 in an AML disease model, a transplantation study was conducted where CD45.2 MLL-AF9 AML spleen tumor cells were transplanted into sub-lethally irradiated CD45.1 recipient mice. After confirming tumor engraftment and progression of leukemia, half of these mice were treated with 60 mg / kg of 57-057 by IV injection for five consecutive days and sacrificed for analysis 72 hours post-final treatment. Overall, the treated group showed decreased WBC count and reduced leukemic burden, as evidenced by a decrease in tumor cell engraftment and a reduction in the Gr1 / Mac1 positive tumor population, which represents myeloid leukemia cells critical for disease progression (FIG.4G and FIG.4H). Collectively, the data demonstrates that 57-057 effectively reduces both the overall leukemic burden and specific leukemic cell populations, highlighting its potential as a targeted therapy that can selectively impact AML cells while minimizing harm to normal cells. 4. DISCUSSION

[0401] The findings elucidate the critical role of FBXO21 in the ubiquitination andsubsequent proteasomal degradation of p85 , providing new insights into the regulation ofthe PI3K signaling pathway in AML. The previous studies demonstrated that FBXO21 minimally impacts steady-state hematopoiesis or the maintenance of hematopoietic stem cells, yet its overexpression in AML correlates with poor prognoses. This mechanism ismediated through the ubiquitination of p85 by FBXO21, leading to downstream alterationsin PI3K signaling.

[0402] Among various FBOX proteins, only FBXO21 could facilitate the ubiquitination ofp85 , emphasizing its unique role and specificity in targeting p85 . Further, lysine site K692on p85 was identified as a novel ubiquitination site using a K- -GG immunoprecipitationfollowed by mass spectrometry. Mutation of lysine residue K692R on p85 resulted in theloss of ubiquitination, confirming that FBXO21 specifically mediates ubiquitination at this newly identified site, providing a precise molecular target for potential therapeuticinterventions aimed at modulating p85 stability. This highlights the utility of advancedproteomic approaches like K- -GG IP and mass spectrometry in uncovering critical post-translational modification sites that can be leveraged for targeted cancer therapies.

[0403] The YccV domain of FBXO21 (SEQ ID NO: 2) was found to be the essential substrate binding domain, which is consistent with reported studies. Deletion of this domainabrogated the ability of FBXO21 to ubiquitinate p85 . Computational modeling identifiedAttorney Docket No.21101.0487P1key degron sequence L466YEEYT471 (SEQ ID NO: 3) within p85 ’s iSH2 domain necessaryfor FBXO21 binding. Mutation of these phosphorylation site Y467A suggests that p85could be phosphorylated at this site and FBXO21 binding followed by p85 ubiquitination isphosphorylation dependent. Understanding these precise molecular mechanisms is critical for the development of selective inhibitors that can modulate protein stability and function in cancer cells. The identification of other phospho-degrons has significantly advanced drugdiscovery efforts. For instance, elucidating the phosphodegron of I B for ubiquitination by-TrCP has been pivotal in developing inhibitors that modulate NF- B signaling, and thephosphodegron of I B served as the E3-ligase ligand for the first PROTAC.

[0404] A structure-guided design led to the identification of a terphenyl analog, 57-057,which mimics the helical region of p85 . 57-057 was shown that it effectively disruptedFBXO21 mediated ubiquitination of p85 at low nM concentrations. This compoundexhibited high selectivity for FBXO21 but not other FBOX proteins. In AML cell models 57-057 treatment resulted in stabilization of p85 , reduced AKT activation, and selectivelyinhibited the growth of cancer cells without affecting healthy cells. The studies also suggest that targeting FBXO21 could overcome resistance mechanisms commonly encountered with PI3K inhibitors. In primary AML and CD34+ HSPC, 57-057 displayed selective growth inhibitory effects towards AML cells, with approximately 5-fold selectivity over healthycells, and was ~6-fold more potent than p110 inhibitor Alpelisib.

[0405] Pharmacokinetic studies revealed that 57-057 (30 mg / kg) is orally bioavailable, with a half-life of approximately 6 hours, primarily cleared by the liver. This half-life, while shorter compared to some therapies like Venetoclax, offers advantages in managing the drug's safety profile by potentially reducing prolonged side effects and toxicity, such as cardiotoxicity.

[0406] While these findings provide significant insights, further in vivo studies, specifically within AML diseased mouse models or in patient-derived xenograft (PDX) models, are needed to confirm the therapeutic potential and safety of 57-057 in animal models and ultimately in clinical settings.

[0407] In conclusion, this study highlights the critical role of FBXO21 in the regulation ofp85 and the PI3K signaling pathway within hematopoietic malignancies and validatesFBXO21 as a therapeutic target. The development of the selective compound against FBXO21, 57-057, offers a promising therapeutic strategy for targeting hematopoietic malignancies.Attorney Docket No.21101.0487P1 TABLE 1: WESTERN BLOT ANTIBODIES Antibody Company Ref# Dilution AKT Cell Signaling 9272 1:1000Attorney Docket No.21101.0487P1 TABLE 2: ADDGENE PLASMIDS Plasmid Name Addgene ID PI3KR1 human GFP1 1TABLE 3: CLONING PRIMERS Name Sequence 5’ to 3’ TAttorney Docket No.21101.0487P1 Name Sequence 5’ to 3’ p85_K513,519R_R CCTTCACGTCTAAACTTTTCTATGTATTCTTTGCAttorney Docket No.21101.0487P1 Name Sequence 5’ to 3’ (SEQ ID NO: 35) AAttorney Docket No.21101.0487P1 TABLE 4: FLOW CYTOMETRY ANTIBODIES Antibody Fluorochrome Clone Company Annexin V APC n / a BioLegendJ. REFERENCES

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[0410] Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature reviews. Cancer 6, 369-381 (2006).

[0411] Bai, C. et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell 86, 263-274 (1996).

[0412] Yada, M. et al. Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. Embo J 23, 2116-2125 (2004).

[0413] Hao, B., Oehlmann, S., Sowa, M. E., Harper, J. W. & Pavletich, N. P. Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol Cell 26, 131-143 (2007).

[0414] Jia, L. & Sun, Y. SCF E3 ubiquitin ligases as anticancer targets. Curr Cancer Drug Targets 11, 347-356 (2011).

[0415] Soucy, T. A. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458, 732-736 (2009).

[0416] Liu, Y. & Mallampalli, R. K. Small molecule therapeutics targeting F-box proteins in cancer. Semin Cancer Biol 36, 105-119 (2016).

[0417] Mallampalli, R. K. et al. Targeting F box protein Fbxo3 to control cytokine-driven inflammation. J Immunol 191, 5247-5255 (2013).

[0418] Chen, B. B., Glasser, J. R., Coon, T. A. & Mallampalli, R. K. Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis. Cell Death Dis 4, e759 (2013).Attorney Docket No.21101.0487P1

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[0420] Dobish, K. K. et al. FBXO21 mediated degradation of p85 regulates proliferationand survival of acute myeloid leukemia. Leukemia 37, 2197-2208 (2023).

[0421] Castel, P., Toska, E., Engelman, J. A. & Scaltriti, M. The present and future of PI3K inhibitors for cancer therapy. Nat Cancer 2, 587-597 (2021).

[0422] Wittorf, K. J., Weber, K. K., Swenson, S. A. & Buckley, S. M. Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. Exp Hematol 114, 33-42.e33 (2022).

[0423] Watanabe, K., Yumimoto, K. & Nakayama, K. I. FBXO21 mediates the ubiquitylation and proteasomal degradation of EID1. Genes Cells 20, 667-674 (2015).

[0424] Abe, Y. et al. X-ray crystal structure of Escherichia coli HspQ, a protein involved in the retardation of replication initiation. FEBS letters 591, 3805-3816 (2017).

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[0426] Udeshi, N. D. et al. Refined preparation and use of anti-diglycine remnant (K- -GG)antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments. Mol Cell Proteomics 12, 825-831 (2013).

[0427] Mertins, P. et al. Integrated proteomic analysis of post-translational modifications by serial enrichment. Nat Methods 10, 634-637 (2013).

[0428] Akimov, V. et al. UbiSite approach for comprehensive mapping of lysine and N- terminal ubiquitination sites. Nat Struct Mol Biol 25, 631-640 (2018).

[0429] Fox, M., Mott, H. R. & Owen, D. Class IA PI3K regulatory subunits: p110- independent roles and structures. Biochem Soc Trans 48, 1397-1417 (2020).

[0430] Chapman, R. N., Dimartino, G. & Arora, P. S. A Highly Stable Short -Helix Constrained by a Main-Chain Hydrogen-Bond Surrogate. Journal of the American Chemical Society 126, 12252-12253 (2004).

[0431] Schafmeister, C. E., Po, J. & Verdine, G. L. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. Journal of the American Chemical Society 122, 5891-5892 (2000).

[0432] Lanning, M. E. & Fletcher, S. Multi-Facial, Non-Peptidic alpha-Helix Mimetics. Biology (Basel) 4, 540-555 (2015).Attorney Docket No.21101.0487P1

[0433] Algar, S., Martin-Martinez, M. & Gonzalez-Muniz, R. Evolution in non-peptide alpha-helix mimetics on the road to effective protein-protein interaction modulators. Eur J Med Chem 211, 113015 (2021).

[0434] Whisenant, J. & Burgess, K. Synthetic helical peptide capping strategies. Chem Soc Rev 51, 5795-5804 (2022).

[0435] Sang, P. & Cai, J. Unnatural helical peptidic foldamers as protein segment mimics. Chem Soc Rev 52, 4843-4877 (2023).

[0436] Kutzki, O. et al. Development of a potent Bcl-x(L) antagonist based on alpha-helix mimicry. J Am Chem Soc 124, 11838-11839 (2002).

[0437] Orner, B. P., Ernst, J. T. & Hamilton, A. D. Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an alpha-helix. J Am Chem Soc 123, 5382-5383 (2001). Yin, H. et al. Terphenyl-Based Bak BH3 alpha-helical proteomimetics as low-molecular- weight antagonists of Bcl-xL. J Am Chem Soc 127, 10191-10196 (2005). Reavie, L. et al. Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell 23, 362-375 (2013).

[0438] Swenson, S. A. et al. Ubiquitin E3 Ligase FBXO9 Regulates Pluripotency by Targeting DPPA5 for Ubiquitylation and Degradation. Stem Cells 42, 317-328 (2024).

[0439] Dobish, K. K. et al. FBXO21 mediated degradation of p85alpha regulates proliferation and survival of acute myeloid leukemia. Leukemia 37, 2197-2208 (2023).

[0440] Armaghani, A. J. & Han, H. S. Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data. Breast Cancer (Dove Med Press) 12, 251-258 (2020).

[0441] Cataldo, M. L. et al. The effect of the alpha-specific PI3K inhibitor alpelisib combined with anti-HER2 therapy in HER2+ / PIK3CA mutant breast cancer. Frontiers in Oncology 13 (2023).

[0442] Zhang, M., Jang, H. & Nussinov, R. PI3K inhibitors: review and new strategies. Chemical science 11, 5855-5865 (2020).

[0443] Brandão, M., Caparica, R., Eiger, D. & de Azambuja, E. Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors. Annals of Oncology 30, x27-x42 (2019).

[0444] Wright, S. C. E., Vasilevski, N., Serra, V., Rodon, J. & Eichhorn, P. J. A. Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity. Cancers 13, 1538 (2021).Attorney Docket No.21101.0487P1

[0445] Wittorf, K. J., Weber, K. K., Swenson, S. A. & Buckley, S. M. Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. Exp Hematol 114, 33-42 e33 (2022).

[0446] Kanarek, N., London, N., Schueler-Furman, O. & Ben-Neriah, Y. Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol 2, a000166 (2010).

[0447] Yaron, A. et al. Identification of the receptor component of the IkappaBalpha- ubiquitin ligase. Nature 396, 590-594 (1998).

[0448] Sakamoto, K. M. et al. Protacs: Chimeric molecules that target proteins to the Skp1– Cullin–F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences 98, 8554-8559 (2001).

[0449] Fox, M, et al. Class1A PI3aK regulatory subunits:p110-independent roles and structures. Biochem Soc Trans.48(4):1397-1417 (2020).

[0450] 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 of the 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

1. Attorney Docket No.21101.0487P1 CLAIMS What is claimed is:

1. A compound having a structure represented by a formula: , wherein each of R1aandhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; wherein n is 0 or 1; wherein each occurrence of R10and R11is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen; wherein m is 0 or 1; wherein each occurrence of R12and R13is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R1bis OH, C1-C4 alkoxy, or OCH2Ph, then R1ais not hydrogen and at least one of R2aand R2bis not hydrogen, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)Attorney Docket No.21101.0487P1 dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen.

3. The compound of claim 1 or claim 2, wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen.

4. The compound of claim 1, wherein R1ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

5. The compound of claim 4, wherein R1bis hydrogen.

6. The compound of claim 4, wherein R1bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

7. The compound of claim 1, wherein R1ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

8. The compound of claim 7, wherein R1bis hydrogen.

9. The compound of claim 7, wherein R1bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

10. The compound of claim 1, wherein R1bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.hydrogen.

12. The compound of claim 1, wherein R1bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph.

13. The compound of claim 12, wherein R1ais hydrogen.

14. The compound of claim 1, wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)Attorney Docket No.21101.0487P1 dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R12, (CH2)nNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

15. The compound of claim 1, wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

16. The compound of claim 1, wherein R2ais selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

17. The compound of claim 16, wherein R2bis hydrogen.

18. The compound of claim 16, wherein R2bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

19. The compound of claim 1, wherein R2ais selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

20. The compound of claim 19, wherein R2bis hydrogen.

21. The compound of claim 19, wherein R2bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

22. The compound of claim 1, wherein R2bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.hydrogen.

24. The compound of claim 1, wherein R2bis selected from halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph.

25. The compound of claim 24, wherein R2ais hydrogen.

26. The compound of claim 1, wherein each of R1aand R2ais hydrogen.

27. The compound of claim 1, wherein each of R1aand R2bis hydrogen.Attorney Docket No.21101.0487P1 28. The compound of claim 1, wherein each of R1band R2ais hydrogen.

29. The compound of claim 1, wherein each of R1band R2bis hydrogen.

30. The compound of claim 1, wherein each of R1aand R2ais not hydrogen.

31. The compound of claim 1, wherein each of R1aand R2bis not hydrogen.

32. The compound of claim 1, wherein each of R1band R2ais not hydrogen. The compound of claim 1, wherein each of R1band R2bis not hydrogen.

34. The compound of claim 1, wherein each of R1a, R1b, and R2ais not hydrogen.

35. The compound of claim 1, wherein each of R1a, R2a, and R2bis not hydrogen.

36. The compound of claim 1, wherein each of R1b, R2a, and R2bis not hydrogen.

37. The compound of claim 1, wherein each of R1a, R1b, R2a, and R2ais not hydrogen.

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

39. The compound of claim 1, wherein R3is C1-C4 alkyl.

40. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically41. The compound of claim 1, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically42. The compound of claim 1, wherein the compound has a structure represented by a formula: , wherein each of R1a, R1b,or a pharmaceutically acceptable salt thereof.

43. The compound of claim 1, wherein the compound has a structure represented by a formula: , wherein each of R1a, R1b,or a pharmaceutically acceptable salt thereof.

44. The compound of claim 1, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically45. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically46. The compound of claim 1, wherein the compound has a structure represented by a formula: , wherein each of R1a, R1b,or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R1a, R1b,or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, wherein the compound is not: , or a pharmaceutically49. The compound of claim 1, wherein the compound is selected from: , ,Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1Attorney Docket No.21101.0487P1 , or a50. The compound of claim 1, wherein the compound is: ,or a pharmaceutically 51. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.Attorney Docket No.21101.0487P152. A method of inhibiting F-box protein 21 (FBOX21) mediated p85 ubiquitination in acell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

54. The method of claim 52, wherein the compound is not: , or a pharmaceutically55. The method of claim 52, wherein the cell is mammalian.

56. The method of claim 52, wherein the cell is human.

57. The method of claim 52, wherein the cell has been isolated from a mammal prior to the contacting step.

58. The method of claim 52, wherein contacting is in vitro.

59. The method of claim 52, wherein contacting is ex vivo.

60. The method of claim 52, wherein contacting is via administration to a mammal.Attorney Docket No.21101.0487P1 61. The method of claim 60, wherein the mammal has been diagnosed with a need for inhibition of FBOX21 prior to the administering step.

62. A method of inhibiting FBOX21 mediated p85 ubiquitination in a subject, themethod comprising administering to the subject an effective amount of the compound of any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof.

63. The method of claim 62, wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

64. The method of claim 62, wherein the compound is not: , or a pharmaceutically65. The method of claim 62, wherein the subject is a mammal.

66. The method of claim 63, wherein the mammal is a human.

67. The method of claim 62, wherein administering is oral administration, intranasal administration, intramuscular administration, or intravenous administration.

68. The method of claim 62, wherein the subject has been diagnosed with a need forinhibition of FBOX21 mediated p85 ubiquitination prior to the administering step.Attorney Docket No.21101.0487P1 69. The method of claim 62, further comprising identifying a subject in need of inhibitionof FBOX21 mediated p85 ubiquitination.

70. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein each of R4aandhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen, or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl,Attorney Docket No.21101.0487P1 provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof.

71. The method of claim 70, wherein each of R4aand R4bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen; and wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen.

72. The method of claim 70, wherein the compound is not: , or a pharmaceutically73. The method of claim 70, wherein each of R4aand R4bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen.

74. The method of claim 70, wherein each of R4aand R4bis independently selected from hydrogen, halogen, NH2, CN, C1-C4 alkoxy, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen.

75. The method of claim 70, wherein R4ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.Attorney Docket No.21101.0487P1 76. The method of claim 75, wherein R4bis hydrogen.

77. The method of claim 75, wherein R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

78. The method of claim 70, wherein R4ais selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

79. The method of claim 78, wherein R4bis hydrogen.

80. The method of claim 78, wherein R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

81. The method of claim 70, wherein R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

82. The method of claim 81, wherein R4ais hydrogen.

83. The method of claim 70, wherein R4bis selected from halogen, NH2, CN, C1-C4 alkoxy, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph.

84. The method of claim 83, wherein R4ais hydrogen.

85. The method of claim 70, wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

86. The method of claim 70, wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, CN, C1-C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

87. The method of claim 70, wherein R5ais selected from halogen, NH2, OH, CN, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

88. The method of claim 87, wherein R5bis hydrogen.Attorney Docket No.21101.0487P1 89. The method of claim 87, wherein R5bis selected from halogen, NH2, OH, CN, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

90. The method of claim 70, wherein R5ais selected from halogen, NH2, OH, CN, C1- C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

91. The method of claim 90, wherein R5bis hydrogen.

92. The method of claim 90, wherein R5bis selected from halogen, NH2, OH, CN, C1- C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

93. The method of claim 70, wherein R5bis selected from halogen, NH2, OH, CN, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

94. The method of claim 93, wherein R5ais hydrogen.

95. The method of claim 70, wherein R5bis selected from halogen, NH2, OH, CN, C1- C4 alkoxy, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph.

96. The method of claim 95, wherein R5ais hydrogen.

97. The method of claim 70, wherein each of R4aand R5ais hydrogen.

98. The method of claim 70, wherein each of R4aand R5bis hydrogen.

99. The method of claim 70, wherein each of R4band R5ais hydrogen.

100. The method of claim 70, wherein each of R4band R5bis hydrogen.

101. The method of claim 70, wherein each of R4aand R5ais not hydrogen.

102. The method of claim 70, wherein each of R4aand R5bis not hydrogen.

103. The method of claim 70, wherein each of R4band R5ais not hydrogen.

104. The method of claim 70, wherein each of R4band R5bis not hydrogen.

105. The method of claim 70, wherein each of R4a, R4b, and R5ais not hydrogen.Attorney Docket No.21101.0487P1 106. The method of claim 70, wherein each of R4a, R5a, and R5bis not hydrogen.

107. The method of claim 70, wherein each of R4b, R5a, and R5bis not hydrogen.

108. The method of claim 70, wherein each of R4a, R4b, R5a, and R5ais not hydrogen.

109. The method of claim 70, wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

110. The method of claim 70, wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

111. The method of claim 70, wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring and wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring.

112. The method of claim 70, wherein R3is hydrogen.

113. The method of claim 70, wherein R3is C1-C4 alkyl.

114. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically115. The method of claim 70, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically116. The method of claim 70, wherein the compound has a structure represented by a formula: , wherein each of R4a, R4b,or a pharmaceutically acceptable salt thereof.

117. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically118. The method of claim 70, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically119. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically120. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically121. The method of claim 70, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4a, R4b,or a pharmaceutically acceptable salt thereof.

122. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically123. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically124. The method of claim 70, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4a, R4b,or a pharmaceutically acceptable salt thereof.

125. The method of claim 70, wherein the compound has a structure represented by a formula: , wherein each of R4a, R4b,or a pharmaceutically acceptable salt thereof.

126. The method of claim 70, wherein the compound has a structure represented by a formula: ,or a pharmaceutically 127. The method of claim 70, wherein the compound has a structure represented by a formula:Attorney Docket No.21101.0487P1 , or a pharmaceutically128. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically129. The method of claim 70, wherein the compound has a structure represented by a formula: , or a pharmaceutically130. The method of claim 70, wherein the compound is not:Attorney Docket No.21101.0487P1 , or a pharmaceutically131. The method of claim 70, wherein the compound is selected from: ,Attorney Docket No.21101.0487P1 , ,Attorney Docket No.21101.0487P1 , , ,Attorney Docket No.21101.0487P1 , , , or a132. The method of any one of claims 70 to 131, wherein the effective amount is a therapeutically effective amount.

133. The method of any one of claims 70 to 131, wherein the effective amount is a prophylactically effective amount.

134. The method of any one of claims 70 to 131, wherein the subject is a mammal.

135. The method of claim 134, wherein the mammal is a human.

136. The method of any one of claims 70 to 131, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

137. The method of any one of claims 70 to 131, further comprising identifying a subject in need of treatment of cancer.Attorney Docket No.21101.0487P1 138. The method of any one of claims 70 to 131, 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, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).

139. The method of any one of claims 70 to 131, wherein the cancer is a primary or secondary tumor.

140. The method of claim 139, wherein the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.

141. The method of any one of claims 70 to 131, wherein the cancer is a lymphoma or a leukemia.

142. The method of claim 138, wherein the lymphoma or the leukemia is selected from non-Hodgkin lymphoma (e.g., B-cell lymphomas such as diffuse large B-cell lymphoma, large cell lymphomas such as anaplastic large cell lymphoma), acute lymphoblastic leukemia, chronic myelogenous leukemia, and acute myeloid leukemia.

143. The method of any one of claims 70 to 131, wherein the cancer is acute myeloid leukemia.

144. The method of any one of claims 70 to 131, wherein administering is oral or parental administration.

145. The method of claim 144, wherein the parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.

146. A kit comprising a compound having a structure represented by a formula:Attorney Docket No.21101.0487P1 , wherein each of R4aandhydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)qCO2R14, (CH2)qNHC(O)R15, and OCH2Ph, provided that at least one of R4aand R4bis not hydrogen, or wherein each of R4aand R4bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein q is 0 or 1; wherein each occurrence of R14and R15is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; wherein each of R5aand R5bis independently selected from hydrogen, halogen, NH2, OH, NO2, CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)rCO2R16, (CH2)rNHC(O)R17, and OCH2Ph, provided that at least one of R5aand R5bis not hydrogen, or wherein each of R5aand R5bis covalently bonded, and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl ring; wherein r is 0 or 1; wherein each occurrence of R16and R17is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; and wherein R3is selected from hydrogen and C1-C4 alkyl, provided that when R4bis OH, C1-C4 alkoxy, or OCH2Ph, then R4ais not hydrogen and at least one of R5aand R5bis not hydrogen, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anti-cancer agent;Attorney Docket No.21101.0487P1 (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

147. The kit of claim 146, wherein each of R1aand R1bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)nCO2R10, (CH2)nNHC(O)R11, and OCH2Ph, provided that at least one of R1aand R1bis not hydrogen; and wherein each of R2aand R2bis independently selected from hydrogen, halogen, NH2, OH, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, (CH2)mCO2R12, (CH2)mNHC(O)R13, and OCH2Ph, provided that at least one of R2aand R2bis not hydrogen.

148. The kit of claim 146, wherein the compound is not: , or a pharmaceutically149. The kit of claim 146, wherein the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage-inducing agent, and a mTor inhibitor agent.

150. The kit of claim 147, wherein 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.

151. The kit of claim 147, wherein the antimetabolite agent is selected from gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine,Attorney Docket No.21101.0487P1 nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

152. The kit of claim 147, wherein 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.

153. The kit of claim 147, wherein 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.

154. The kit of claim 147, wherein the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

155. The kit of claim 147, wherein the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.

156. The kit of claim 146, wherein the compound and the anti-cancer agent are co- packaged.

157. The kit of claim 146, wherein the compound and the anti-cancer agent are co- formulated.

158. A compound selected from: ,Attorney Docket No.21101.0487P1 , or a159. A pharmaceutical composition comprising an effective amount of the compound of claim 158 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

160. A method of inhibiting F-box protein 21 (FBOX21) mediated p85 ubiquitination in acell, the method comprising contacting the cell with an effective amount of the compound of claim 158 or a pharmaceutically acceptable salt thereof.

161. A method of inhibiting FBOX21 mediated p85 ubiquitination in a subject, themethod comprising administering to the subject an effective amount of the compound of claim 158 or a pharmaceutically acceptable salt thereof.

162. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from: ,Attorney Docket No.21101.0487P1 , , or a163. A kit comprising a compound selected from: , ,Attorney Docket No.21101.0487P1 , or a(a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.

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