Compounds for PPIL4 degradation and compositions and methods thereof

Abstract

In one aspect, the disclosure relates to compounds that behave as molecular glue degraders (MGDs) and methods of making and using same. In various aspects, the disclosed compounds are useful for modulating PPIL4 activity through targeted degradation. In various aspects, the compounds are useful for treating medulloblastoma and / or acute lymphoblastic leukemia (ALL). In further aspects, the present disclosure relates to methods of making the disclosed compounds, pharmaceutical compositions comprising the disclosed compounds, and methods of treating various clinical conditions and disorders using the same, such as T-cell acute lymphoblastic leukemia. 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. 19116.0070P1COMPOUNDS FOR PPIL4 DEGRADATION AND COMPOSITIONS AND METHODS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U. S. Application No. 63 / 734,594, filed on December 16, 2024, the contents of which are incorporated herein by reference in their entireties.BACKGROUND

[0002] Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). A tremendous demand exists for new methods, treatments, and compositions that can be used to treat patients with cancer. Protein degradation plays a role in various cellular functions, i.e., the concentrations of regulatory proteins are adjusted through degradation into small peptides to maintain health and productivity of the cells. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Specifically targeting protein degradation offers a tantalizing prospect of targeting currently undruggable oncoproteins such as transcription factors and chimeric fusion oncoproteins.

[0003] Despite advances in research directed to clinical amelioration of cancer, there is still a scarcity of compounds that are both potent, efficacious, and selective modulators of protein degradation. These needs and other needs are satisfied by the present disclosure.SUMMARY

[0001] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to substituted compounds that modulate PPIL4 activity through targeted degradation, pharmaceutical compositions containing the compounds, and methods of using the compounds in, for example, the prevention and treatment of disordersAttorney Docket No. 19116.0070P1of uncontrolled cellular proliferation such as, for example, cancer (e.g, medulloblastoma and / or acute lymphoblastic leukemia (ALL).

[0004] Thus, in one aspect, disclosed are compounds having a structure represented by the formula below or a pharmaceutically acceptable salt thereof:wherein X1can be selected from — (C-CH3) —, — (CH) —, and — (N) —; wherein R1can be an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, O, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof.

[0005] Also disclosed are compounds having a structure represented by the formula below or a pharmaceutically acceptable salt thereof:Attorney Docket No. 19116.0070P1wherein R1can be selected from a moiety having a structure represented by any one of the following formulas:wherein X1can be — (C-CH3) —, — (CH) —, or — (N) —; any — C(R2)(R2a) —, when present, can be substituted for an — N(R3) — or — O —; any — C(R2) —, when present, can be substituted for an — N —; each R2and R2a, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, — SF5, — CN, — N3, — NH2, —OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — O — (C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, sulfonamide, methylsulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3 alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3 alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl; any two occurrences of R2can be optionally covalently bonded and, together with the intermediate atoms, comprise a 4- to 7-membered cycle; each R3, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0006] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] Also disclosed are methods for treating a disorder of uncontrolled cellular proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceuticallyAttorney Docket No. 19116.0070P1acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition.

[0008] Also disclosed are methods for treating a disorder associated with a PPIL4 dysfunction in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition.

[0009] Also disclosed are methods for treating T cell acute lymphoblastic leukemia in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition.

[0010] Also disclosed are methods for treatment, wherein the at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or disclosed pharmaceutical composition, is administered to the subject or mammal orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially, or intratumorally.

[0011] Also disclosed are methods for treatment, wherein the at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or disclosed pharmaceutical composition, is administered to the subject or mammal orally.

[0012] Also disclosed are methods for modulating cereblon activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition.

[0013] Also disclosed are methods for modulating PPIL4 activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition.

[0014] Also disclosed are methods for modulating cereblon activity in at least one cell, the method comprising contacting the at least one cell with an effective amount of at least oneAttorney Docket No. 19116.0070P1disclosed compound, or a pharmaceutically acceptable salt thereof, or contacting the at least one cell with an effective amount of at least one disclosed pharmaceutical composition.

[0015] Also disclosed are methods for modulating PPIL4 activity in at least one cell, the method comprising contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or contacting the at least one cell with an effective amount of at least one disclosed pharmaceutical composition.

[0016] Also disclosed are kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) at least one agent known to increase cereblon activity; (b) at least one agent known to decrease cereblon activity; (c) at least one agent known to increase PPIL4 activity; (d) at least one agent known to decrease PPIL4 activity; (e) at least one agent known to increase cellular proliferation; (f) at least one agent known to decrease cellular proliferation; (g) at least one agent known to treat a disorder associated with cereblon activity; (h) at least one agent known to treat a disorder associated with PPIL4 activity; (i) at least one agent known to treat a disorder of uncontrolled cellular proliferation; and (j) instructions for treating a disorder of uncontrolled cellular proliferation.

[0017] Also disclosed are uses of at least one disclosed compound or a pharmaceutically acceptable salt thereof or a disclosed pharmaceutical composition or a combination thereof in the manufacture of a medicament for the treatment of a disorder associated with cereblon dysfunction in a mammal.

[0018] Also disclosed are uses of at least one disclosed compound or a pharmaceutically acceptable salt thereof or a disclosed pharmaceutical composition or a combination thereof in the manufacture of a medicament for the treatment of a disorder associated with PPIL4 dysfunction in a mammal.

[0019] Also disclosed are uses of at least one disclosed compound or a pharmaceutically acceptable salt thereof or a disclosed pharmaceutical composition or a combination thereof in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

[0020] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, andAttorney Docket No. 19116.0070P1be protected by the accompanying claims. Tn addition, all optional and preferred features and modifications of the described aspects are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described aspects are combinable and interchangeable with one another.BRIEF DESCRIPTION OF THE FIGURES

[0021] 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.

[0022] FIG. 1A-D show representative data illustrating that SJ42872 degraded PPIL4 in both leukemia and Group 3 Medulloblastoma cells and showed cytotoxicity in those cells.

[0023] FIG. 2A-H show representative data illustrating that SJ42872 reduced tumor burden in mice engrafted with patient derived xenograft (PDX) cells of B-ALL (E-27009, CRLF2-r, KRAS-G12D).

[0024] 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.DETAILED DESCRIPTION

[0025] Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4) is a protein that plays a significant role in protein folding and cellular regulation processes. As a member of the cyclophilin family, PPIL4 is involved in catalyzing the cis-trans isomerization of proline residues in polypeptides and has a role in proper protein folding and stability. Its isomerase activity has been linked to various cellular functions, including RNA splicing and immune response modulation, suggesting potential implications in cell cycle regulation and signaling pathways. Research onPPIL4 also explores its involvement in certain diseases, as disruptions in protein folding mechanisms are often associated with pathologies such as cancer and neurodegenerative disorders.Attorney Docket No. 19116.0070P1Given its multifaceted roles, PPIL4 continues to be a focus in studies aiming to understand the complexities of protein dynamics within the cell and the broader implications for therapeutic interventions.

[0026] PPIL4’s role in cancer has gained attention, as its involvement in protein folding and cell cycle regulation appears to contribute to tumorigenesis in specific cancer types.Overexpression or aberrant expression of PPIL4 has been implicated in cancers such as breast, lung, and colorectal cancer, where it may support cancer cell survival and proliferation by enhancing protein homeostasis and aiding in the maintenance of oncogenic signaling pathways. In breast cancer, PPIL4’s isomerase activity has been observed to influence the splicing of mRNA transcripts involved in cell growth, while in colorectal cancer, PPIL4 has been linked to alterations in apoptosis and DNA repair pathways, possibly promoting cancer cell resilience. Its activity in modulating immune responses is also under investigation, as cancer cells may exploit PPIL4’s regulatory effects to evade immune detection. As such, PPIL4 represents a potential target for cancer therapeutics, and ongoing studies are assessing inhibitors that might disrupt its role in these pathways, aiming to hinder tumor growth and progression.

[0027] The regulatory mechanisms surrounding PPIL4 and its isomerase activity in cancer contexts have encountered several challenges. One primary issue is the lack of selective inhibitors specific to PPIL4’s enzymatic action poses a significant challenge, as most broadspectrum cyclophilin inhibitors inadvertently disrupt the activity of other vital cyclophilins involved in immune response and cell growth regulation. This and other challenges with targeting PPIL4 are addressed with the instant disclosure.

[0028] In various aspects, the instant disclosure provides compounds that target the selective degradation of PPIL4. Also disclosed are pharmaceutical compositions containing a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0029] Aspects described herein provide compounds having a structure represented by a formula:Attorney Docket No. 19116.0070P1wherein X1is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. Aspects described herein provide a pharmaceutically acceptable salt of any one of the foregoing compounds.

[0030] In various aspects, this disclosure provides pharmaceutical compositions containing a therapeutically effective amount of a compound that promotes degradation of PPIL4. In various aspects, this disclosure provides pharmaceutical compositions containing a therapeutically effective amount a pharmaceutically acceptable salt, solvate, or polymorph of a compound that promotes degradation of PPIL4. The compound that promotes degradation of PPIL4 can include the aforementioned compounds or a compound described elsewhere herein. For example, the compounds can include a compound disclosed in Table 1.

[0031] Aspects described herein provide methods for the treatment of a disorder of uncontrolled cellular proliferation in a mammal including the step of administering to the mammal a therapeutically effective amount of at least one compound described herein. Aspects described herein provide methods for the treatment of a disorder of uncontrolled cellular proliferation in a mammal including the step of administering to the mammal a therapeutically effective amount of at least one pharmaceutically acceptable salt, solvate, or polymorph of a compound described herein. In various aspects, the compound promoted degradation of PPIL4.

[0032] Aspects described herein provide methods for the treatment of a disorder of uncontrolled cellular proliferation in a mammal including the step of administering to the mammal a therapeutically effective amount of a pharmaceutical composition described herein. In various aspects, the pharmaceutical composition containing a compound described herein or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

[0033] Aspects described herein provide methods for modulating cereblon activity in a mammal comprising the step of administering to the mammal a therapeutically effective amountAttorney Docket No. 19116.0070P1of at least one compound described herein. Aspects described herein provide methods for modulating cereblon activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one pharmaceutically acceptable salt, solvate, or polymorph of a compound described herein. Aspects described herein provide methods for modulating cereblon activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a pharmaceutical composition described herein. In various aspects, the modulating of cereblon activity includes modulating the degradation of PPIL4.

[0034] In various aspects, methods of modulating PPIL4 activity in a mammal in need thereof are provided. The methods can include administering an effective amount of a compound, salt, solvate, polymorph, or pharmaceutical composition described herein.Modulating PPIL4 activity can include promoting degradation of PPIL4.

[0035] Methods provided herein can include modulating cereblon activity in a cell by contacting the cell with a compound, salt, solvate, polymorph, or pharmaceutical composition described herein. Modulating cereblon activity can include promoting the degradation of PPIL4.

[0036] Methods provided herein can include modulating PPIL4 activity in a cell by contacting the cell with a compound, salt, solvate, polymorph, or pharmaceutical composition described herein. Modulating PPIL4 activity can include promoting the degradation of PPIL4.

[0037] Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0038] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0039] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure.Attorney Docket No. 19116.0070P1

[0040] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0041] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0042] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0043] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0044] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Attorney Docket No. 19116.0070P1A. DEFINITIONS

[0045] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0046] As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound,” “a kinase,” or “a patient,” includes, but is not limited to, two or more such compounds, kinases, or patients, and the like.

[0047] Reference to “a / an” chemical compound, protein, and antibody each refers to one or more molecules of the chemical compound, protein, and antibody rather than being limited to a single molecule of the chemical compound, protein, and antibody. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound, protein, and antibody. Thus, for example, “an” antibody is interpreted to include one or more antibody molecules of the antibody, where the antibody molecules may or may not be identical (e.g., different isotypes and / or different antigen binding sites as may be found in a polyclonal antibody).

[0048] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are several values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0049] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g, the phrase “x to y” includes the range from “x” to “y” as well as the range greater than “x” and less than “y ” The range can also be expressed as an upper limit, e.g., “aboutAttorney Docket No. 19116.0070P1x, y, z, or less,” and should be interpreted to include the specific ranges of “about x,” “about y,” and “about z,” as well as the ranges of “less than x,” “less than y,” and “less than z.” Likewise, the phrase “about x, y, z, or greater” should be interpreted to include the specific ranges of “about x,” “about y,” and “about z,” as well as the ranges of “greater than x,” “greater than y,” and “greater than z.” In addition, the phrase “about ‘x’ to ‘y,’” where “x” and “y” are numerical values, includes “about ‘x’ to about ‘y.’”

[0050] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0051] As used herein, “about,” “approximately,” “substantially,” and the like, when used in connection with a numerical variable, can generally refers to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within + / - 10% of the indicated value, whichever is greater. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” can mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.Attorney Docket No. 19116.0070P1

[0052] 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.

[0053] ‘Effective amount” means an amount of compound of the present disclosure effective in degrading PPIL4 and / or inhibiting PPIL4 activity, and thus producing the desired therapeutic effect.

[0054] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavemous, intrathecal, intravitreal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0055] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such asAttorney Docket No. 19116.0070P1proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians’ Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, antiinflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and 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., 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 proAttorney Docket No. 19116.0070P1drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0056] 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.

[0057] 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.

[0058] As used herein, “attached” can refer to covalent or non-covalent interaction between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Walls forces, dipole-dipole interactions, dipole-induced-dipole interactions, London dispersion forces, hydrogen bonding, halogen bonding, electromagnetic interactions, TT-TT interactions, cation-TT interactions, anion-TT interactions, polar TT-interactions, and hydrophobic effects.

[0059] 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 juvenile subjects, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers toAttorney Docket No. 19116.0070P1a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0060] As used herein, the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom, or condition thereof, such as a disorder of uncontrolled cellular proliferation, a disorder associated with a PPIL4 dysfunction, and / or an immunologic disease or pathological condition involving an immunologic component. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder of uncontrolled cellular proliferation, a disorder associated with a PPIL4 dysfunction, and / or an immunologic disease or pathological condition involving an immunologic component in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term “treatment” as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term “treating”, can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0061] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.Attorney Docket No. 19116.0070P1

[0062] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0063] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0064] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0065] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generallyAttorney Docket No. 19116.0070P1preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0066] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0067] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0068] 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.

[0069] 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.

[0070] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base,Attorney Docket No. 19116.0070P1either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0071] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the present disclosure include Cl-to-C6 alkyl esters and C5-to-C7 cycloalkyl esters, although Cl-to-C4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0072] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary Cl-to-C6 alkyl amines and secondary Cl-to-C6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- orAttorney Docket No. 19116.0070P16-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Cl-to-C3 alkyl primary amides and Cl-to-C2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0073] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0074] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimedAttorney Docket No. 19116.0070P1compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0075] The term “contacting” as used herein refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.

[0076] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0077] 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,Attorney Docket No. 19116.0070P1sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a Cl alkyl, Cl-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, Cl-C9 alkyl, Cl -CIO alkyl, and the like up to and including a C1-C24 alkyl.

[0078] 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.

[0079] 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.

[0080] 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 termAttorney Docket No. 19116.0070P1“heterocycloal kyl” is a type of cycloalkyl group as defined above and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or un substituted. 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.

[0081] The term “alkanediyl” as used herein, refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, — CH2 — (methylene), — CH2CH2 —, — CH2C(CH3)2CH2 —, and — CH2CH2CH2 — are non-limiting examples of alkanediyl groups.

[0082] 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.

[0083] 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)OC(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.

[0084] 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 isAttorney Docket No. 19116.0070P1included 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.

[0085] 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.

[0086] 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.

[0087] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized n electrons above and below the plane of the molecule, where the n clouds contain (4n+2) n 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.Attorney Docket No. 19116.0070P1

[0088] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0089] 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.

[0090] 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 — NHz.

[0091] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) and — N(-alkyl)z, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0092] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0093] 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 theAttorney Docket No. 19116.0070P1formula — (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.

[0094] The term “ether” as used herein is represented by the formula ArOA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0095] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0096] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanate, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0097] 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 quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0098] 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,Attorney Docket No. 19116.0070P1triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodi oxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0099] The term “heterocycle” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2, 3 -oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2, 3 -thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0100] The term “bicyclic heterocycle” 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 aromaticAttorney Docket No. 19116.0070P1ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1,2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and lH-pyrazolo[3,2-b]pyridin-3-yl.

[0101] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi-and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized, and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0102] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula — OH.

[0103] 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.

[0104] The term “azide” or “azido” as used herein is represented by the formula — Ns.

[0105] The term “nitro” as used herein is represented by the formula — NO2.

[0106] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0107] The term “silyl” as used herein is represented by the formula — SiAJA2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0108] “R1,” “R2,” “R3,”... “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the firstAttorney Docket No. 19116.0070P1group can be pendant (z.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0109] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.Combinations of substituents envisioned by this disclosure 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).

[0110] 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.

[0111] 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.

[0112] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e., 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).

[0113] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety isAttorney Docket No. 19116.0070P1actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)sCO- moi eties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0114] The term “organic residue” defines a carbon containing residue, z.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0115] 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:Oregardless of whether thiazolidinedione is used to prepare the compound. In various aspects 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 disclosure unless it is indicated to the contrary elsewhere herein.

[0116] “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,Attorney Docket No. 19116.0070P1an 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 various aspects, 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 alkyl carb oxami de, 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.

[0117] 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 disclosure includes all such possible isomers, as well as mixtures of such isomers.

[0118] 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 disclosure 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.

[0119] 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 andAttorney Docket No. 19116.0070P1L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0120] In various aspects, it is contemplated herein that the disclosed compounds further comprise their bioisosteric equivalents. The term “bioisosteric equivalent” refers to compounds or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical and biological properties. Examples of such equivalents are: (i) fluorine vs. hydrogen, (ii) oxo vs. thio, (iii) hydroxyl vs. amide, (iv) carbonyl vs. oxime, (v) carboxylate vs. tetrazole. Examples of such bioisosteric replacements can be found in the literature and examples of such are: (i) Burger A, Relation of chemical structure and biological activity; in Medicinal Chemistry Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970, 64-80; (ii) Burger, A.; “Isosterism and bioisosterism in drug design”; Prog. Drug Res. 1991, 37, 287-371; (iii) Burger A, “Isosterism and bioanalogy in drug design,” Med. Chem. Res. 1994, 4, 89-92; (iv) Clark R D, Ferguson A M, Cramer R D, “Bioisosterism and molecular diversity,” Perspect. Drug Discovery Des. 1998, 9 / 10 / 11, 213-224; (v) Koyanagi T, Haga T, “Bioisosterism in agrochemicals,” ACS Symp. Ser. 1995, 584, 15-24; (vi) Kubinyi H, “Molecular similarities. Part 1. Chemical structure and biological activity,” Pharm. Unserer ZeitAttorney Docket No. 19116.0070P11998, 27, 92-106; (vii) Lipinski C A.; “Bioisosterism in drug design”; Annu. Rep. Med. Chem.1986, 21, 283-91; (viii) Patani G A, LaVoie E J, “Bioisosterism: A rational approach in drug design,” Chem. Rev. (Washington, D. C.) 1996, 96, 3147-3176; (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic ligands,” Curr. Med. Chem. 1998, 5, 493-512 (x) Thornber C W, “Isosterism and molecular modification in drug design,” Chem. Soc. Rev. 1979, 8, 563-80.

[0121] In further aspects, bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered substantially identical. The term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere. The bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density. Preferred bioisosteres of esters, amides or carboxylic acids are compounds containing two sites for hydrogen bond acceptance. In one aspect, the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1H-imidazolyl, an optionally substituted oxazolyl, 1H-tetrazolyl, [l,2,4]triazolyl, or an optionally substituted [l,2,4]oxadiazolyl.

[0122] In various aspects, it is contemplated herein that the disclosed compounds further comprise their isotopically labeled or isotopically-substituted variants, i.e., 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 disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F, and36C1, 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 disclosure. Certain isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H and 14C 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 resultingAttorney Docket No. 19116.0070P1from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the present disclosure and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0123] In various aspects, the disclosed compounds can be in the form of a co-crystal. 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. Preferred co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0124] The term “pharmaceutically acceptable co-crystal” means one that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0125] In a further aspect, the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, 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 solvate or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates.

[0126] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosed compound with a suitable inorganic or organic base.Attorney Docket No. 19116.0070P1

[0127] Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid. In various aspects, acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. In a further aspect, salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxy ethanesulfonate (isethionate), nicotinate, 2-naphthalenesulfonate, oxalate, pectinate, persulfate, 3 -phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (z.e., 1,1’ -methyl ene-bis-(2 -hydroxy-3 -naphthoate)) salts. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0128] Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethyl ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include di ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may beAttorney Docket No. 19116.0070P1used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0129] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an ot-hydrogen can exist in an equilibrium of the keto form and the enol form.oketo form enol form amide form Imidic acid form

[0130] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the disclosure includes all such possible tautomers.

[0131] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the disclosure can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the disclosure includes all such possible polymorphic forms.

[0132] In various aspects, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:Attorney Docket No. 19116.0070P1Rn(:a>pn(d}wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b)> Rn(c), Rn(d), and 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.

[0133] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N. J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0134] 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 aspects described in the specification.

[0135] Disclosed are the components to be used to prepare the compositions of the disclosure as well as the compositions themselves to be used within the methods disclosed herein. TheseAttorney Docket No. 19116.0070P1and 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 the disclosure. 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 aspect or combination of aspects of the methods of the disclosure.

[0136] 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.

[0137] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E / Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U. S. A.).

[0138] It is understood, that unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (z.e., one atmosphere).Attorney Docket No. 19116.0070P1

[0139] Described herein are compounds that have therapeutic or clinical utility. Also described herein are methods of synthesizing the compounds. Also described herein are methods of administering the disclosed compounds and / or disclosed pharmaceutical compositions to a subject in need thereof. In various aspects, the subject can have disorder of uncontrolled cellular proliferation, a disorder associated with a PPIL4 dysfunction, and / or an immunologic disease or pathological condition involving an immunologic component. Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.B. COMPOUNDS

[0140] Most small-molecule drugs antagonize or aggravate protein function. This narrow focus has limited the development of drugs against some of the most well-validated targets in disease and a myriad of other targets. Thus, alternative pharmacological modulation strategies are desired. One such strategy is targeted protein degradation (TPD) in which small-molecule drugs recruit protein targets to E3 ubiquitin ligases for selective degradation. There are two main classes of TPD drugs: proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs). PROTACs comprise a target-binding warhead and an E3 ligase-binding warhead joined by a flexible linker. See Ng et al. (2023) ACS Chemical Biology 18(12): 2464-2473. Inherently, the degradable proteome explored is constrained to the ligandable proteome. See Hopkins and Groom (2002) Nature Reviews Drug Discovery 1(9): 727-730; Russ etal. (2005) Drug Discovery Today 10(23-24): 1607-1610; and Schneider et al. (2021) Nat. Rev. Drug Discovery 20(10): 789-797.

[0141] In contrast to PROTACs, MGDs have a wider potential target space due to their molecular mechanism. Specifically, MGDs induce cooperative interactions between E3 ligases and a target. The mechanistic elucidation of clinically approved thalidomide analogs as MGDs exemplifies how MGDs can expand the target space. Thalidomide analogs bind and stabilize the CRL4CRBN E3 ligase complex with select zinc finger transcription factors. Consequently, these transcription factors are ubiquitinated and subsequently degraded. See Ito et al. (2010) ScienceAttorney Docket No. 19116.0070P1327(5971): 1345-1350; Lu et al. (2014) 343(6168): 305-309; and Krbnke et al. (2014) 343(6168): 301-305. Other clinically tested compounds, such as indisulam, have also serendipitously been identified as MGDs (recruiting the E3 ligase DCAF15 to degrade the splicing factors RBM23 and RBM39). See Han et al. (2017) Science 356(6336): eaal3755. In both cases, MGDs prompt the degradation of proteins of interest without binding to them in isolation, thus highlighting the potential of MGDs in degrading unliganded proteins. See Kozicka et al. (2021) Cell Chem. Biol. 28(7): 1032-1047; Jan et al. (2021) Nat. Rev. Clin. Oncol. 18(7):401-417.

[0142] PPIL4’s involvement in various cancers remains an area of active research, with some initial studies indicating its potential roles across multiple cancer types. In medulloblastoma, PPIL4 may play a role in tumor progression by supporting protein folding and cellular processes crucial for the rapid growth of cancer cells. Medulloblastoma, a primary childhood brain cancer, often shows complex genetic profiles, and proteins like PPIL4 involved in molecular stability may impact disease development, particularly in cases associated with genetic predispositions.

[0143] Acute lymphoblastic leukemia (ALL) is a common hematological malignancy which can arise in both B cells and T cells. 1 T cell acute lymphoblastic leukemia (T-ALL) accounts for up to 15% of pediatric leukemias, is typically more aggressive, and has worse survival outcome than B cell acute lymphoblastic leukemia (B-ALL).2In ALL and other leukemias, PPIL4 may be implicated due to its influence on cell cycle regulation and apoptosis. For instance, genetic mutations and environmental factors associated with leukemia can lead to alterations in cellular mechanisms where proteins like PPIL4 play a supportive role, although direct links are still under investigation. Hematological cancers often display dysregulation in cell signaling pathways and immune responses, areas where cyclophilin family proteins like PPIL4 are active.

[0144] Lung and colorectal cancers have also been associated with the cyclophilin family, to which PPIL4 belongs, due to these proteins’ impact on cellular stress responses and protein stability. In lung cancer, proteins involved in protein folding and stability can aid in cancer cells’ resistance to apoptosis, allowing for unchecked growth. Similarly, colorectal cancer studies have indicated that PPIL4 might support processes that reduce cellular stress, thus facilitating tumor cell survival and growth.

[0145] Despite PPIL4’s potential implication in numerous cancers, there remains a great medical need for therapeutic approaches for targeting PPIL4 with improved efficacy and safety.Attorney Docket No. 19116.0070P1As the MGD approach has gained considerable attention across industry and academia as a novel therapeutic paradigm offering potential multiple advantages, the application of this approach to PPIL4 is of great interest. Herein, molecular glues that target PPIL4 for degradation are described.1. STRUCTURE

[0146] In the present disclosure, targeting PPIL4 degradation is addressed with a new class of compounds. Thus, disclosed herein are compounds having a structure represented by a formula:wherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. Aspects described herein provide a pharmaceutically acceptable salt of any one of the foregoing compounds.

[0147] In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4Attorney Docket No. 19116.0070P1aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof.

[0148] In various aspects, the compound has a structure represented by a formula:wherein each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, O, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), C(O)CyJ, - OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1, provided that at least two of R10a, R10b, R10c, R10d, and R10eare hydrogen, or a pharmaceutically acceptable salt thereof.

[0149] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof. In a further aspect, R10cis a non-hydrogen group. In a still further aspect, R10cis selected from -C(O)Cy’, -OCy1, -O(C1-C4 alkyl)Cy\ and -(CH2)nCy1.

[0150] In various aspects, n is an integer selected from 0, 1, and 2. In a further aspect, n is an integer selected from 1 and 2. In a still further aspect, n is an integer selected from 0 and 2. In yet a further aspect, n is an integer selected from 0 and 1. In an even further aspect, n is 2. In a still further aspect, n is i. In yet a further aspect, n is 0.Attorney Docket No. 19116.0070P1

[0151] In various aspects, R1is a six-membered ring which can be substituted or unsubstituted and homocyclic or heterocyclic. In various aspects, the six-membered ring is part of a polycyclic ring structure.

[0152] In various aspects, R1is a five-membered ring which can be substituted or unsubstituted and homocyclic or heterocyclic. In various aspects, the five-membered ring is part of a polycyclic ring structure.

[0153] In various aspects, compounds disclosed herein have a structure represented by the formula:

[0154] In various aspects, R1is selected from a moiety having a structure represented by any one of the following formulas:

[0155] In various aspects, X1is — (C-CH3) —, — (CH) —, or — (N) —. In the above structure, any — C(R2)(R2a) —, when present, can be substituted for an — N(R3) — or — O —. In the above structure, any — C(R2) —, when present, can be substituted for an — N —. In the above structure, each R2and R2a, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, — SFs, — CN, — N3, — NH2, — OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — (C1-C3 alkanediyl) — O — (Cl-C3 alkyl), — O — (C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, sulfonamide, methylsulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3 alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3Attorney Docket No. 19116.0070P1alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl. In the above structure, any two occurrences of R2can be covalently bonded and, together with the intermediate atoms, form a 4-to 7-membered cycle. In the above structure, each R3, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In other aspects, a pharmaceutically acceptable salt of any one of the aforementioned compounds is also disclosed.

[0156] In various aspects, X1is — (C-CH3) —. In other aspects, X1is — (N) — ■

[0157] In yet further aspects, compounds are provided having a structure represented by the formula:wherein R1is selected from a moiety having a structure represented by any one of the following formulas:

[0158] In various aspects, X1is — (C-CH3) — or — (N) —. In the above structure, any — C(R2)(R2a) —, when present, can be substituted for an — N(R3) — or — O —. ) —. In the above structure, any — C(R2) —, when present, can be substituted for an — N —. In the above structure, each R2, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, — SFs, — CN, — N3, — NH2, — OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — (C1-C3 alkanediyl) — O — (Cl-C3 alkyl), — O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, sulfonamide,methyl sulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3Attorney Docket No. 19116.0070P1alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3 alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl. In the above structure, any two occurrences of R2can be optionally covalently bonded and, together with the intermediate atoms, form a 4- to 7-membered cycle. In the above structure, each R3, when present, can be independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. Pharmaceutically acceptable salts of a compound having a structure according to the above formula are also provided.

[0159] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula.

[0160] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0161] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0162] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0163] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0164] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0165] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula: / \

[0166] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:>

[0167] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0168] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0169] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:WdH

[0170] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0171] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0172] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0173] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0174] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:........hi - 4 \ - C,)■H ''b <3 'W / YJH

[0175] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0176] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:■bl

[0177] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0178] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0179] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1 Mf /

[0180] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0181] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0182] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0183] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0184] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0185] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0186] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0187] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0188] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0189] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0190] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0191] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0192] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0193] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0194] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0195] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:NH

[0196] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0197] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0198] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0199] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:Attorney Docket No. 19116.0070P1

[0200] In various aspects, a compound or a pharmaceutically acceptable salt of a compound is provided wherein the compound has a structure according to the following formula:

[0201] In various aspects, the compound has a formula selected from:Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1or a pharmaceutically acceptable salt thereof.

[0202] In various aspects, the compound has a formula selected from:or a pharmaceutically acceptable salt thereof.

[0203] In various aspects, the compound has a formula:or a pharmaceutically acceptable salt thereof.

[0204] In various aspects, the compound is:Attorney Docket No. 19116.0070P1or a pharmaceutically acceptable salt thereof.

[0205] In yet further aspects, the disclosure is directed to a compound or pharmaceutically acceptable salt of a compound wherein the compound has a structure according to any one of the compounds in Table 1.a. X1GROUPS

[0206] In one aspect, X1is selected from — (C-CH3) —, — (CH) —, and — (N) —. In a further aspect, X1is selected from — (C-CH3) — and — (CH) —. In a still further aspect, X1is selected from — (C-CH3) — and — (N) —. In yet a further aspect, X1is selected from — (CH) — and — (N) —. In an even further aspect, X1is — (C-CH3) —. In a still further aspect, X1is — (CH) —. In yet a further aspect, X1is — (N) —.

[0207] In one aspect, X1is selected from -N=, -C(H)=, and -C(CH3)=. In a further aspect, X1is selected from -C(H)= and -C(CH3)=. In a still further aspect, X1is selected from -N= and -C(CH3)=. In yet a further aspect, X1is selected from -N= and -C(H)=. In an even further aspect, X1is -N=. In a still further aspect, X1is -C(H)=. In yet a further aspect, X1is -C(CH3)=b. R1GROUPS

[0208] In one aspect, R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms, wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic.

[0209] In one aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4Attorney Docket No. 19116.0070P1alkyl), -C(O)Cy\ -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In a further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)Cy and -(CH2)nCy1. In a still further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alky^Cy1, and -(CH^iCy1. In yet a further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)CyJ, and -(CH^nCy1. In an even further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is unsubstituted.

[0210] In various aspects, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is monosubstituted with a group selected from -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH^Cy1.

[0211] In various aspects, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2CeH5.

[0212] In various aspects, R1is selected from a C6-C 10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0 or 1 methylAttorney Docket No. 19116.0070P1group. In a further aspect, R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is monosubstituted with a methyl group.

[0213] In various aspects, R1is a six-membered ring, which can be substituted or unsubstituted and homocyclic or heterocyclic, optionally, wherein the six-membered ring is part of a polycyclic ring structure. In various further aspects, R1is a five-membered ring, which can be substituted or unsubstituted and homocyclic or heterocyclic, optionally, wherein the five-membered ring is part of a polycyclic ring structure. In various further aspects, the five or sixmembered ring is part of a polycyclic ring structure.

[0214] In various aspects, R1is selected from a moiety having a structure represented by any one of the following formulas:

[0215] In various aspects, R1is a moiety having a structure represented by a formula:

[0216] In various aspects, R1is a moiety having a structure represented by a formula:R2

[0217] In various aspects, R1is selected from a C6-C10 cycloalkyl and a C5-C9 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4Attorney Docket No. 19116.0070P1cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)Cy\ -OCy1, -O(C1-C4 alkyl)Cy\ and -(CH^nCy1. In a further aspect, R1is selected from a C6-C10 cycloalkyl and a C5-C9 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy\ -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In a still further aspect, R1is selected from a C6-C10 cycloalkyl and a C5-C9 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -CfX^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In yet a further aspect, R1is selected from a C6-C10 cycloalkyl and a C5-C9 heterocycloalkyl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -N02, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alky Cy1, and -(CH2)nCy1. In an even further aspect, R1is selected from a C6-C10 cycloalkyl and a C5-C9 heterocycloalkyl, and is unsubstituted.

[0218] In various aspects, R1is a C6-C10 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. Examples of C6-C10 cycloalkyls include, but are not limited to, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, octahydro- IH-indenyl, and decahydronaphthalenyl. In a further aspect, R1is a C6-C10 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)Cy\ -Attorney Docket No. 19116.0070P1OCy1, -O(C1-C4 alkyl)Cy1, and -(CHz)nCy1. Tn a still further aspect, R1is a C6-C10 cycloalkyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CHz^Cy1. In yet a further aspect, R1is a C6-C 10 cycloalkyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, O(C1-C4 alkyl)CyJ, and -(CHz^Cy1. In an even further aspect, R1is an unsubstituted C6-C10 cycloalkyl.

[0219] In various aspects, R1is a C5-C9 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy’, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy’.Examples of C5-C9 heterocycloalkyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzo[d][l,3]dioxolyl, and 2H-benzo[b][l,4]oxazin-3(4H)-onyl. In a further aspect, R1is a C5-C9 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CHz^Cy1. In a still further aspect, R1is a C5-C9 heterocycloalkyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CHz^Cy1. In yet a further aspect, R1is a C5-C9 heterocycloalkyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4Attorney Docket No. 19116.0070P1aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In an even further aspect, R1is an unsubstituted C5-C9 heterocycloalkyl.

[0220] In various aspects, R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy\ -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a further aspect, R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, - NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a still further aspect, R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkypCy1, and -(CH^nCy1. In yet a further aspect, R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH^nCy1. In an even further aspect, R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is unsubstituted.

[0221] In various aspects, R1is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CHOnCy1. Examples of C6-C10 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, R1is a C6-Attorney Docket No. 19116.0070P1CIO aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a still further aspect, R1is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In yet a further aspect, R1is a C6-C10 aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)Cy\ and -(CH2)nCy1. In an even further aspect, R1is an unsubstituted C6-C10 aryl.

[0222] In various aspects, R1is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In a further aspect, R1is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -CfX^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a still further aspect, R1is a C6 aryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)CyJ, and -(CH2)nCy1. In yet a further aspect, R1is a C6 aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4Attorney Docket No. 19116.0070P1haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In an even further aspect, R1is an unsubstituted C6 aryl.

[0223] In various aspects, R1is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. Examples of C2-C9 heteroaryls include, but are not limited to, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, indolyl, and lH-benzo[d]imidazolyl. In a further aspect, R1is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a still further aspect, R1is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In yet a further aspect, R1is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -N02, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In an even further aspect, R1is an unsubstituted C2-C9 heteroaryl.

[0224] In various aspects, R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)Cy and -(CH2)nCy1. In a further aspect, R1is a C2-C9Attorney Docket No. 19116.0070P1heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1. In a still further aspect, R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy\ -OCy1, -O(C1-C4 alkyl)Cy\ and -(CH2)nCy1. In yet a further aspect, R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy’, -OCy1, -O(C1-C4 alkyl)Cy', and -(CH2)nCy1. In an even further aspect, R1is R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is unsubstituted.

[0225] In various aspects, R1is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1. In a further aspect, R1is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)CyJ, and -(CH2)nCy1. In a still further aspect, R1is a pyridinyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, Cl-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -Attorney Docket No. 19116.0070P1CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl )Cy\ and -(CH2)nCy1. In yet a further aspect, R1is a pyridinyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)CyJ, and -(CH2)nCy1. In an even further aspect, R1is an unsubstituted pyridinyl.c. — C(R2)(R2A) — GROUPS

[0226] In one aspect, any one or more occurrence of — C(R2)(R2a) —, when present, can be substituted for a — N(R3) — or a — O — group. In a further aspect, any one or more occurrence of — C(R2)(R2a) —, when present, can be substituted for a — N(R3) — group. In a still further aspect, any one or more occurrence of — C(R2)(R2a) —, when present, can be substituted for a — O — group.

[0227] In various aspects, each occurrence of — C(R2)(R2a) —, when present, is — C(R2)(R2a)—.d. — C(R2) — GROUPS

[0228] In one aspect, any one or more occurrence of — C(R2) —, when present, can be substituted for a — N — group. In a further aspect, one occurrence of — C(R2) —, when present, is substituted for a — N — group. In a still further aspect, two occurrences of — C(R2) —, when present, are substituted for a — N — group. In yet a further aspect, three occurrences of — C(R2) —, when present, are substituted for a — N — group.

[0229] In various aspects, each occurrence of — C(R2) —, when present, is — C(R2) —.e. R2AND R2AGROUPS

[0230] In one aspect, each occurrence of R2and R2a, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Zc / 7-butyl, — SFs, — CN, — N3, — NH2, — OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — Cl-C3 alkanediyl)— O— (Cl -C3 alkyl), — O— (C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl,Attorney Docket No. 19116.0070P1sulfonamide, methylsulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3 alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3 alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl, or wherein any two adjacent occurrences of R2are covalently bonded and, together with the intermediate atoms, comprise a 4- to 7-membered cycle.

[0231] In various aspects, each occurrence of R2is independently selected from hydrogen, — F, —Cl, — Br, — SFs, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2C1, — CHC12, — CC13, — CFhBr, — CHBn, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, — CH2CH2C1, — CH2CHC12, — CH2CC13, — CH2CH2Br, — CH2CHBr2, — CH2CBr3, — OCH2F, — OCHF2, — OCF3, — OCH2Cl, — OCHCl2, — OCCl3, — OCH2Br, — OCHBr2, — OCBr3, OCH2CH2F, OCH2CHF2, — OCH2CF3, — OCH2CH2C1, — OCH2CHC12, — OCH2CC13, — OCH2CH2Br, — OCH2CHBr2, — OCH2CBr3, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3, — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0232] In various aspects, each occurrence of R2is independently selected from hydrogen, — F, — Cl, — OCF3, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy.

[0233] In various aspects, each occurrence of R2is selected from hydrogen, — F, — Cl, and C1-C3 alkyl.

[0234] In various aspects, one occurrence of R2is selected from — F, — Cl, — Br, — SFs, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2C1, — CHCh, — CC13, — CH2Br, — CHBn, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, — CH2CH2C1, — CH2CHC12, — CH2CC13, — CH2CH2Br, — CH2CHBr2, — CH2CBr3, — OCH2F, — OCHF2, — OCF3, — OCH2Cl, — OCHCl2, — OCCl3, — OCH2Br, — OCHBr2, — OCBr3, — OCH2CH2F, — OCH2CHF2, — OCH2CF3, — OCH2CH2C1, — OCH2CHCl2, — OCH2CCl3, — OCH2CH2Br, — OCH2CHBr2, — OCH2CBr3, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3, — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl; and each of the other occurrences of R2are hydrogen.

[0235] In various aspects, two occurrences of R2are each independently selected from — F, —Cl, — Br, — SF5, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2Cl, — CHCl2, — CCl3, — CH2Br, — CHBr2, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, — CH2CH2C1, — CH2CHCh, — CH2CC13, — CH2CH2Br, — CH2CHBn, — CH2CBr3, — OCH2F, — OCHF2, — OCF3, — OCH2Cl, — OCHCl2, — OCCl3, — OCH2Br, — OCHBr2, — OCBr3, — OCH2CH2F, —Attorney Docket No. 19116.0070P1— OCH2CHF2, — OCH2CF3, — OCH2CH2Cl, — OCH2CHCl2, — OCH2CCl3, — OCH2CH2Br, — OCH2CHBr2, — OCH2CBr3, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3, — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and / e / V-butyl; and each of the other occurrences of R2, if present, are hydrogen.

[0236] In various aspects, one occurrence of R2is hydrogen. In a further aspect, two occurrences of R2are hydrogen. In a still further aspect, three occurrences of R2, when present, are hydrogen. In yet a further aspect, four occurrences of R2, when present, are hydrogen. In an even further aspect, each occurrence of R2is hydrogen.

[0237] In various aspects, each occurrence of R2ais hydrogen.f. R3GROUPS

[0238] In one aspect, each occurrence of R3, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and / e / 'Z-butyl.

[0239] In various aspects, each occurrence of R3, when present, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In a further aspect, each occurrence of R3, when present, is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each occurrence of R3, when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each occurrence of R3, when present, is independently selected from hydrogen and ethyl. In an even further aspect, each occurrence of R3, when present, is independently selected from hydrogen and methyl.

[0240] In various aspects, each occurrence of R3, when present, is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and te / 7-butyl. In a further aspect, each occurrence of R3, when present, is independently selected from methyl, ethyl, propyl, and isopropyl. In a still further aspect, each occurrence of R3, when present, is independently selected from methyl and ethyl. In yet a further aspect, each occurrence of R3, when present, is ethyl. In an even further aspect, each occurrence of R3, when present, is methyl.

[0241] In various aspects, each occurrence of R3, when present, is independently selected from hydrogen and halogen. In a further aspect, each occurrence of R3, when present, is independently selected from hydrogen, -Cl, and -F. In a still further aspect, each occurrence ofAttorney Docket No. 19116.0070P1R3, when present, is independently selected from hydrogen and -Cl. In yet a further aspect, each occurrence of R3, when present, is independently selected from hydrogen and -F.

[0242] In various aspects, each occurrence of R3, when present, is independently halogen. In a further aspect, each occurrence of R3, when present, is independently selected from -Br, -Cl, and -F. In a still further aspect, each occurrence of R3, when present, is independently selected from -Br and -Cl. In yet a further aspect, each occurrence of R3, when present, is independently selected from -Cl and -F. In an even further aspect, each occurrence of R3, when present, is -Cl. In a still further aspect, each occurrence of R3, when present, is -F.

[0243] In various aspects, each occurrence of R3is hydrogen.g. R10A, R10B, R10C, R10D, AND R10EGROUPS

[0244] In one aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, Cl-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)Cy1, -OCy1, -O(C1-C4 alkyl)CyJ, and -(CH2)nCy1, provided that at least two of R10a, R10b, R10c, R10d, and R10eare hydrogen.

[0245] In various aspects, at least three of R10a, R10b, R10c, R10d, and R10eare hydrogen. In various further aspect, at least four of R10a, R10b, R10c, R10d, and R10eare hydrogen. In various further aspects, each of R10a, R10b, R10c, R10d, and R10eis hydrogen.

[0246] In various aspects, at least one of R10a, R10b, R10c, R10d, and R10eis a non-hydrogen group. In various further aspects, at least two of R10a, R10b, R10c, R10d, and R10eis a non-hydrogen group. In various further aspects, at least three of R10a, R10b, R10c, R10d, and R10eis a nonhydrogen group. In various further aspects, exactly one of R10a, R10b, R10c, R10d, and R10eis a non-hydrogen group.h. CY1GROUPS

[0247] In one aspect, Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9Attorney Docket No. 19116.0070P1heteroaryl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is unsubstituted.

[0248] In various aspects, Cy1is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is unsubstituted.

[0249] In various aspects, Cy1is a C3-C10 cycloalkyl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. Examples of C3-C10 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, octahydro- IH-indenyl, and decahydronaphthal enyl. In a further aspect, Cy1is a C3-C10 cycloalkyl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is a C3-C10 cycloalkyl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is an unsubstituted C3-C10 cycloalkyl.

[0250] In various aspects, Cy1is a C2-C9 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. Examples of C2-C9 heterocycloalkyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzo[d][l,3]dioxolyl, and 2H-benzo[b][l,4]oxazin-3(4H)-onyl. In a further aspect, Cy1is a C2-C9 heterocycloalkyl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is a C2-C9 heterocycloalkyl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is a C2-C9 heterocycloalkyl unsubstituted.Attorney Docket No. 19116.0070P1

[0251] In various aspects, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted.

[0252] In various aspects, Cy1is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and CH2C6H5. Examples of C6-C10 aryls include, but are not limited to, phenyl and naphthyl. In a further aspect, Cy1is a C6-C10 aryl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is a C6-C10 aryl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is an unsubstituted C6-C10 aryl.

[0253] In various aspects, Cy1is C6 aryl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is C6 aryl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is C6 aryl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is an unsubstituted C6 aryl.

[0254] In various aspects, Cy1is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. Examples of C2-C9 heteroaryls include, but are not limited to, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, indolyl, and lH-benzo[d]imidazolyl. In a further aspect, Cy1is a C2-C9 heteroaryl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is a C2-C9 heteroaryl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is an unsubstituted C2-C9 heteroaryl.

[0255] In various aspects, Cy1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is substituted with 0, 1, or 2 groups independently selectedAttorney Docket No. 19116.0070P1from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, and a pyridinyl, and is unsubstituted.

[0256] In various aspects, Cy1is pyridinyl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a further aspect, Cy1is a pyridinyl substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In a still further aspect, Cy1is pyridinyl monosubstituted with a group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5. In yet a further aspect, Cy1is an unsubstituted C2-C9 heteroaryl.2. EXAMPLE COMPOUNDS

[0257] In one aspect, a compound can be present as one or more of the structures in Table A or a pharmaceutically acceptable salt thereof.

[0258] In one aspect, a compound can be present as one or more of the following structures:Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1Attorney Docket No. 19116.0070P1or a pharmaceutically acceptable salt thereof.Attorney Docket No. 19116.0070P1C. PHARMACEUTICAL COMPOSITIONS

[0259] In one aspect, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. In a further aspect, the disclosed pharmaceutical composition comprises a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

[0260] Thus, in various aspects, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula:wherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic, and a pharmaceutically acceptable carrier. In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4Attorney Docket No. 19116.0070P1alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof.

[0261] As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0262] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant.

[0263] The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral 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.

[0264] In a further aspect, the disclosed pharmaceutical composition is formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratum orally.

[0265] In a further aspect, the disclosed pharmaceutical composition is formulated to allow administration orally.

[0266] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.Attorney Docket No. 19116.0070P1

[0267] In a further aspect, the disclosed pharmaceutical composition further comprises at least one agent known to treat an immunologic disease or pathological condition involving an immunologic component and / or at least one agent known to treat a disorder of uncontrolled cellular proliferation.

[0268] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0269] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.

[0270] In various aspects, a disclosed compound comprising an acidic group or moiety, e.g., a carboxylic acid group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness,Attorney Docket No. 19116.0070P1preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.

[0271] Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, z.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g, lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), lower alkanolammonium and other such bases of organic amines. In a further aspect, derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. In various aspects, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N, N’ -dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, hydrabamine salts, and salts with amino acids such as, for example, histidine, arginine, lysine and the like. The foregoing salt forms can be converted by treatment with acid back into the free acid form.

[0272] In various aspects, a disclosed compound comprising a protonatable group or moiety, e.g., an amino group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with a basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, e.g., by treating theAttorney Docket No. 19116.0070P1corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0273] Acids which can be used to prepare the pharmaceutically acceptable acid-addition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like. Exemplary, but non-limiting, organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like. In a further aspect, the acidaddition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0274] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly andAttorney Docket No. 19116.0070P1intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0275] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0276] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. 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.

[0277] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: ModernAttorney Docket No. 19116.0070P1Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington’s Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds ).

[0278] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0279] Because of the ease in administration, oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. However, other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like. Accordingly, the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. 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, disintegratingAttorney Docket No. 19116.0070P1agents, 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.

[0280] The disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and / or additive. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats, in particular vegetable (for example, peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in each case also optionally hydrated); glycerol esters and polyglycerol esters of saturated fatty acids C12H24O2 to C18H36O2 and their mixtures, it being possible for the glycerol hydroxy groups to be totally or also only partly esterified (for example mono-, di- and triglycerides); pharmaceutically acceptable mono- or multivalent alcohols and polyglycols such as polyethylene glycol and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10-18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentacrythritol, sorbitol, mannitol and the like, which may optionally also be etherified, esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glyceroformals, tetrahydrofurfuryl alcohol, polyglycol ethers with Cl-C12-alcohols, dimethylacetamide, lactamides, lactates, ethylcarbonates, silicones (in particular medium-viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate and the like.

[0281] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone,Attorney Docket No. 19116.0070P1sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose. Conventional coating substances may also be used to produce the oral dosage form. Those that may for example be considered are: polymerizates as well as copolymerizates of acrylic acid and / or methacrylic acid and / or their esters; copolymerizates of acrylic and methacrylic acid esters with a lower ammonium group content (for example EudragitR RS), copolymerizates of acrylic and methacrylic acid esters and trimethyl ammonium methacrylate (for example EudragitR RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methyl cellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate as well as polyvinyl acetate phthalate, carboxy methyl cellulose; methyl cellulose phthalate, methyl cellulose succinate, -phthalate succinate as well as methyl cellulose phthalic acid half ester; zein; ethyl cellulose as well as ethyl cellulose succinate; shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymerizate; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0282] Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropylphthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutyl succinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0283] Moreover, suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia,Attorney Docket No. 19116.0070P1magnesium 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.

[0284] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. In a further aspect, a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0285] In various aspects, an oral dosage form, such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug. Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0286] Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0287] A tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0288] In various aspects, a solid oral dosage form, such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach. In various aspects, enteric coatingAttorney Docket No. 19116.0070P1agents include, but are not limited to, hydroxypropyl methyl cellulose phthalate, methacrylic acidmethacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate. Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull. 33:1615-1619 (1985). Various enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). In a further aspect, the enteric coating may comprise hydroxypropyl-methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.

[0289] In various aspects, an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier. Examples of water soluble or water insoluble carrier include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, or hydroxypropylmethylcellulose, ethyl cellulose, or stearic acid.

[0290] In various aspects, an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle. For example, a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

[0291] For the preparation of solutions or suspensions it is, for example, possible to use water, particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil,Attorney Docket No. 19116.0070P1sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulphoxide, triglycerides and the like.

[0292] In the case of a liquid dosage form such as a drinkable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary Cl-C4-amines or C1-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N, N-diethyl acetamide, N, N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as ethylene diamine, hydroxyethyl theophylline, tromethamine (for example as 0.1 to 20% aqueous solution), aliphatic amino acids.

[0293] In preparing the disclosed liquid dosage form can comprise solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxy ethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this context, polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20. Poly oxy ethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride). Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, com oil. See also Dr. H. P. Fiedler “Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195.

[0294] In various aspects, a liquid dosage form can further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like. Complex formers which may be for example be considered areAttorney Docket No. 19116.0070P1chelate formers such as ethylene diamine tetraacetic acid, nitrilotri acetic acid, diethylene triamine pentaacetic acid and their salts.

[0295] It may optionally be necessary to stabilize a liquid dosage form with physiologically acceptable bases or buffers to a pH range of approximately 6 to 9. Preference may be given to as neutral or weakly basic a pH value as possible (up to pH 8).

[0296] In order to enhance the solubility and / or the stability of a disclosed compound in a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form, it can be advantageous to employ a-, [3- or y-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-0-cyclodextrin or sulfobutyl-0-cyclodextrin. Also, co-solvents such as alcohols may improve the solubility and / or the stability of the compounds according to the present disclosure in pharmaceutical compositions.

[0297] In various aspects, a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0298] Pharmaceutical compositions of the present disclosure suitable injection, such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection 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.

[0299] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, 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 various aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe. The pharmaceutical compositions should 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,Attorney Docket No. 19116.0070P1polyol (e.g, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0300] Injectable solutions, for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In various aspects, a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g., about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.

[0301] In various aspects, a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include but not limited to water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer’s dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like. In a further aspect, a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives. Also contemplated for injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient.

[0302] In addition to the pharmaceutical compositions described herein above, the disclosed compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.Attorney Docket No. 19116.0070P1

[0303] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical administration. As used herein, the phrase “topical application” means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane. By selecting the appropriate carrier and optionally other ingredients that can be included in the composition, as is detailed herein below, the compositions of the present disclosure may be formulated into any form typically employed for topical application. A topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, 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.

[0304] In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and / or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

[0305] Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives. The specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience). As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. EmulsionAttorney Docket No. 19116.0070P1ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.

[0306] Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.

[0307] Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water- washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the “internal” phase, is generally comprised of petrolatum and / or a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.

[0308] Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like. The pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information.

[0309] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred organic macromolecules, / .<?., gelling agents, are crosslinked acrylic acid polymers such as theAttorney Docket No. 19116.0070P1family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark Carbopol™. Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring, or combinations thereof.

[0310] Sprays generally provide the active agent in an aqueous and / or alcoholic solution which can be misted onto the skin for delivery. Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated active agent at the site of administration.

[0311] Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique. Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system. Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.

[0312] Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir. Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protectiveAttorney Docket No. 19116.0070P1permeable layer can be used to protect the adhesive side of the patch prior to its use. Skin patches may further comprise a removable cover, which serves for protecting it upon storage.

[0313] Examples of patch configuration which can be utilized with the present disclosure include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive. In such a transdermal patch design, the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film. In the multi-layer drug-in-adhesive patch a membrane is disposed between two distinct drug-inadhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0314] Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g, emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition. Representative examples of suitable carriers according to the present disclosure therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions. Other suitable carriers according to the present disclosure include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

[0315] Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, comprise a tube. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.Attorney Docket No. 19116.0070P1Such notice, for example, may include labeling approved by the U. S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising the topical composition of the disclosure formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0316] Another patch system configuration which can be used by the present disclosure is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi-permeable membrane and adhesive. The adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane. Yet another patch system configuration which can be utilized by the present disclosure is a matrix system design which is characterized by the inclusion of a semisolid matrix containing a drug solution or suspension which is in direct contact with the release liner. The component responsible for skin adhesion is incorporated in an overlay and forms a concentric configuration around the semisolid matrix.

[0317] Pharmaceutical compositions of the present disclosure 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.

[0318] Pharmaceutical compositions containing a compound of the present disclosure, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0319] The pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.Attorney Docket No. 19116.0070P1

[0320] The disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U. S. Food and Drug Administration for prescription drugs, or the approved product insert. Pharmaceutical compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0321] The exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compounds of the present disclosure.

[0322] Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0323] In the treatment conditions which require of modulation of cereblon protein an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level willAttorney Docket No. 19116.0070P1be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0324] In the treatment conditions which require of modulation of PPIL4 activity an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0325] In the treatment conditions which require of inhibition of cellular proliferation an appropriate dosage level will generally be about 0.01 to 1000 mg per kg patient body weight per day and can be administered in single or multiple doses. In various aspects, the dosage level will be about 0.1 to about 500 mg / kg per day, about 0.1 to 250 mg / kg per day, or about 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 1000 mg / kg per day, about 0.01 to 500 mg / kg per day, about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form ofAttorney Docket No. 19116.0070P1tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0326] Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day. In various aspects, such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.

[0327] A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or multiple times per day, or one time-release capsule or tablet taken once a day and having a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

[0328] It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

[0329] The present disclosure is further directed to a method for the manufacture of a medicament for modulating cereblon protein (e.g, treatment of one or more disorders associated with a cereblon function or dysfunction, such as a cancer) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compoundAttorney Docket No. 19116.0070P1or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament is useful for modulation of cereblon protein.

[0330] The present disclosure is further directed to a method for the manufacture of a medicament for modulating PPIL4 (e.g., treatment of one or more disorders associated with a cereblon function or dysfunction, such as a cancer) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament is useful for modulation of PPIL4 protein.

[0331] The present disclosure is further directed to a method for the manufacture of a medicament for inhibiting cellular proliferation (e.g., treatment of one or more disorders associated with a cereblon function or dysfunction, such as a cancer) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one aspect, the present disclosure further relates to a method for manufacturing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament is useful for inhibiting cellular proliferation.

[0332] The disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.

[0333] 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.

[0334] As already mentioned, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier. Additionally, the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.Attorney Docket No. 19116.0070P1

[0335] As already mentioned, the present disclosure also relates to a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for a disclosed compound or the other drugs may have utility as well as to the use of such a composition for the manufacture of a medicament. The present disclosure also relates to a combination of disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and an additional therapeutic agent, e.g., an inhibitor of cellular proliferation or anti-cancer therapeutic. The present disclosure also relates to such a combination for use as a medicine. The present disclosure also relates to a product comprising (a) disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and (b) an additional therapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the modulatory effect of the disclosed compound and the additional therapeutic agent. The different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.D. METHODS OF MAKING THE COMPOUNDS

[0336] In one aspect, the disclosure relates to the disclosed synthetic manipulations. In a further aspect, the disclosed compounds comprise the products of the synthetic methods described herein. In a further aspect, the disclosed compounds comprise a compound produced by a synthetic method described herein. In a still further aspect, the disclosure comprises a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In a still further aspect, the disclosure comprises a method for manufacturing a medicament comprising combining at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.

[0002] 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,Attorney Docket No. 19116.0070P1exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0003] 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.

[0337] It is contemplated that each disclosed method can further comprise additional steps, manipulations, and / or components. It is also contemplated that any one or more step, manipulation, and / or component can be optionally omitted from the disclosure. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed compositions, kits, and uses.

[0338] The synthetic methods and schemes are provided with specificity in the Examples herein below, but the skilled artisan can appreciate that the specifically disclosed methods can be modified and readily adapted to prepare the disclosed compounds as appropriate. That is, it is contemplated that each disclosed method can further comprise additional steps, manipulations, and / or components. It is also contemplated that any one or more step, manipulation, and / or component can be optionally omitted from the disclosure. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.1. ROUTE I

[0004] In one aspect, the disclosed compounds can be prepared as shown below.Attorney Docket No. 19116.0070P1SCHEME 1A.

[0005] Compounds are represented in generic form, wherein X is a halogen and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME IB.1.4

[0339] In one aspect, compounds of type 1.6 and similar compounds can be prepared according to reaction Scheme IB above. Thus, compounds of type 1.6 can be prepared by a coupling reaction between an appropriate amine or aniline, e.g., 1.4 as shown above, and an appropriate aryl bromide, e.g, 1.5 as shown above. Appropriate amines, anilines, and aryl bromides are commercially available or prepared by methods known to one skilled in the art. The coupling reaction is carried out in the presence of an appropriate catalyst, e.g., BrettPhos and BrettPhos Pd G3, and an appropriate base, e.g, potassium carbonate, in an appropriate solvent, e.g., dimethylsulfoxide, at an appropriate temperature, e.g., 90 °C, for an appropriate period of time, e.g., 12 hours. 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 and 1.2) can be substituted in the reaction to provide substituted analogs similar to Formula 1.3.Attorney Docket No. 19116.0070P12. ROUTE II

[0006] In one aspect, the disclosed compounds can be prepared as shown below.SCHEME 2A.2.2

[0007] Compounds are represented in generic form, wherein R is a C1-C3 alkyl and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 2B.NaCNBH3,AcOH, MeOH, 50°C

[0340] In one aspect, compounds of type 2.6 and similar compounds can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by deprotection of an appropriate protected amine, e.g., 2.4 as shown above, followed by a reductive amination. The deprotection is carried out in the presence of an appropriate deprotecting agent, e.g., trifluoroacetic acid (TFA), in an appropriate solvent, e.g., dichloromethane, for an appropriate period of time, e.g., 1 hr, at an appropriate temperature, e.g., room temperature. The reductive amination is carried out in the presence of an appropriate aldehyde, e.g., 2.5 as shown above, and an appropriate reducing agent, e.g., sodium cyanoborohydride, and an appropriate acid, e.g., acetic acid, in an appropriate protic solvent, e.g., methanol, at an appropriate temperature, e.g., 50 °C. As can be appreciated by one skilled in the art, the above reactionAttorney Docket No. 19116.0070P1provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2) can be substituted in the reaction to provide substituted analogs similar to Formula 2.3.E. METHODS OF USING THE COMPOUNDS1. METHODS OF TREATMENT

[0341] In various aspects, the present disclosure provides methods of treatment comprising administration of a therapeutically effective amount of a disclosed compound or pharmaceutical composition as disclosed herein above to a subject in need thereof. In a further aspect, the compound has a structure represented by a formula:wherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4Attorney Docket No. 19116.0070P1aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C 1 -C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof. In a further aspect, the at least one disclosed compound is administered to the subject orally.

[0342] Thus, in various aspects, disclosed are methods for treating a disorder of uncontrolled cellular proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0343] In various aspects, disclosed are methods for treating a disorder associated with a kinase dysfunction in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0344] In various aspects, disclosed are methods for treating a disorder associated with a PPIL4 dysfunction in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0345] In various aspects, disclosed are methods for treating T cell acute lymphoblastic leukemia in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.Attorney Docket No. 19116.0070P1

[0346] In various aspects, disclosed are methods for treating an immunologic disease or pathological condition involving an immunologic component in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one disclosed pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0347] In a further aspect, the present disclosure provides any of the above methods wherein the at least one disclosed compound or a pharmaceutically acceptable salt thereof is administered to the subject or mammal orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially, or intratumorally.

[0348] In a further aspect, the present disclosure provides for any of the above methods wherein the at least one disclosed compound or a pharmaceutically acceptable salt thereof, is administered to the subject or mammal orally.

[0349] In various aspects, the mammal is a human.

[0350] In various aspects, the mammal has been diagnosed with a need for treatment of the disorder of uncontrolled cellular proliferation prior to the administering step.

[0351] In various aspects, the method further comprises the step of identifying a mammal in need of treatment of the disorder of uncontrolled cellular proliferation.

[0352] In various aspects, the disorder of uncontrolled cellular proliferation is associated with a PPIL4 dysfunction.

[0353] In various aspects, the disorder of uncontrolled cellular proliferation is a cancer. In a further aspect, the disorder of uncontrolled cellular proliferation is a cancer, e.g., a cancer is selected from a brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell cancer, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, malignant melanoma, colorectal cancer, endometrial carcinoma, thyroid cancer, rhabdosarcoma, and combinations thereof. In a still further aspect, the cancer is a hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML),Attorney Docket No. 19116.0070P1juvenile myelomonocyte leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, Burkett’s lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof. In a further aspect, the disorder of uncontrolled cellular proliferation is T cell acute lymphoblastic leukemia.

[0354] In various aspects, the cancer is a pediatric cancer.

[0355] In various aspects, the cancer is medulloblastoma.

[0356] In various aspects, the cancer is acute lymphoblastic leukemia (ALL).

[0357] In various aspects, the cancer is selected from a brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell cancer, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, malignant melanoma, colorectal cancer, endometrial carcinoma, thyroid cancer, rhabdosarcoma, and combinations thereof.

[0358] In various aspects, the cancer is selected from lung cancer, ovarian cancer, and brain cancer. In a further aspect, the lung cancer is selected from small-cell lung cancer, non-small cell lung cancer, and combinations thereof.

[0359] In various aspects, the cancer is a kidney cancer. In a further aspect, the kidney cancer is a kidney clear cell carcinoma.

[0360] In various aspects, the cancer is a brain cancer. In a further aspect, the brain cancer is selected from a glioblastoma, medullablastoma, glioma, and combinations thereof.

[0361] In various aspects, the cancer is a bladder cancer. In a further aspect, the bladder cancer is a bladder urothelial carcinoma.

[0362] In various aspects, the cancer is a liver cancer. In a further aspect, the liver cancer is a hepatic carcinoma.

[0363] In various aspects, the cancer is a hematological cancer. In a further aspect, the hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocyte leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin’s lymphoma, nonAttorney Docket No. 19116.0070P1Hodgkin’s lymphoma, hairy cell lymphoma, Burkett’s lymphoma, Hodgkin lymphoma, nonHodgkin lymphoma, and combinations thereof.

[0364] In various aspects, the method further comprises the step of administering a therapeutically effective amount of at least one agent known to treat a cancer, e.g., uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5 -fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0365] In various aspects, the at least one agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or combinations thereof.

[0366] In various aspects, the DNA methyltransferase inhibitor is 5-aza-2’-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3 -gallate, procaine, or combinations thereof.

[0367] In various aspects, the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rocilinostat, apicidin, or combinations thereof.Attorney Docket No. 19116.0070P1

[0368] In various aspects, the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or combinations thereof.

[0369] In various aspects, the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.

[0370] In various aspects, the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent or other chemotherapeutic agent.

[0371] In various aspects, the antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0372] In various aspects, the antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0373] In various aspects, the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0374] In various aspects, the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0375] In various aspects, the mTor inhibitor is everolimus, sirolimus, temsirolimus, or combinations thereof.

[0376] In various aspects, the other chemotherapeutic agent is an anthracycline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or combinations thereof. In aAttorney Docket No. 19116.0070P1further aspect, the anthracycline is daunorubicin, idarubicin, or combinations thereof. Tn a still further aspect, the purine analog is cladribine, fludarabine, clofarabine, or combinations thereof.

[0377] In various aspects, the at least one compound, the at least one pharmaceutical composition, and the at least one agent are administered sequentially.

[0378] In various aspects, the at least one compound, the at least one pharmaceutical composition, and the at least one agent are administered simultaneously.

[0379] In various aspects, the at least one compound, the at least one pharmaceutical composition, and the at least one agent are co-formulated.

[0380] In various aspects, the at least one compound, the at least one pharmaceutical composition, and the at least one agent are co-packaged.2. IN VIVO METHODS

[0381] In various aspects, the present disclosure provides in vivo methods comprising administration of a therapeutically effective amount of a disclosed compound or pharmaceutical composition as disclosed herein above to a mammal in need thereof. In a further aspect, the compound has a structure represented by a formula:N HNwherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. In a further aspect, the compound has a structure represented by a formula:Attorney Docket No. 19116.0070P1wherein X1is selected from -N= -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0382] Thus, in various aspects, disclosed are methods for modulating cereblon activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0383] In various aspects, disclosed are methods for modulating PPIL4 activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or administering to the mammal a therapeutically effective amount of at least one pharmaceutical composition. In a further aspect, the at least one disclosed compound is administered to the mammal orally.

[0384] In a further aspect, the present disclosure provides any of the above methods wherein the at least one disclosed compound or a pharmaceutically acceptable salt thereof is administered to the subject or mammal orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially, or intratum orally.

[0385] In a further aspect, the present disclosure provides for any of the above methods wherein the at least one disclosed compound or a pharmaceutically acceptable salt thereof, is administered to the subject or mammal orally.

[0386] In various aspects, the mammal is a human.Attorney Docket No. 19116.0070P1

[0387] In various aspects, the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step. In various further aspects, the mammal has been diagnosed with a need for modulating PPIL4 activity prior to the administering step.

[0388] In various aspects, the method further comprises the step of identifying a mammal in need for modulating of cereblon activity. In various further aspects, the method further comprises the step of identifying a mammal in need for modulating PPIL4 activity.

[0389] In various aspects, modulating of cereblon activity comprises modulating the degradation of PPIL4. In various further aspects, modulating the degradation of PPIL4 decreases levels of PPIL4 in a cell.

[0390] In various aspects, modulating the PPIL4 activity comprises modulating PPIL4 protein levels in a cell. In various further aspects, modulating PPIL4 protein levels are decreased compared to a cell that is not exposed to the at least one compound or the pharmaceutical composition.

[0391] In a further aspect, the disclosed methods for modulating cereblon activity in a mammal comprising the step of administering to the mammal further comprise the step of administering a therapeutically effective amount of at least one agent known to treat a cancer, e.g., uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17a-ethinylestradiol, diethyl stilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxy progesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine,Attorney Docket No. 19116.0070P1hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.3. IN VITRO METHODS

[0392] In various aspects, the present disclosure provides in vitro methods comprising contacting a cell with an effective amount of a disclosed compound or pharmaceutical composition as disclosed herein. In a further aspect, the compound has a structure represented by a formula:wherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1isAttorney Docket No. 19116.0070P1selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof.

[0393] In a further aspect, the present disclosure provides methods for modulating cereblon activity in at least one cell, the method comprising contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof; or at least one disclosed pharmaceutical composition.

[0394] In a further aspect, the present disclosure provides methods for modulating PPIL4 activity in at least one cell, the method comprising contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof; or at least one disclosed pharmaceutical composition.

[0395] In various aspects, the cell is mammalian. In various further aspects, the cell is human.

[0396] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0397] In various aspects, contacting is via administration to a mammal.

[0398] In various aspects, the mammal has been diagnosed with a need for treatment of a disorder related to cereblon activity prior to the administering step.

[0399] In a further aspect, the disclosed methods for modulating cereblon activity in at least one cell further comprise the step of contacting the at least one cell with an effective amount of at least one agent known to treat a cancer, e.g., uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17a-ethinylestradiol, di ethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone,Attorney Docket No. 19116.0070P1triamcinolone, chi orotriani sene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafme, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0400] In various aspects, the compound inhibits cell proliferation with an EC50 of less than about 1 pM when determined in a cell viability assay using MHHCALL4 cells as described herein; and / or wherein the compound exhibits PPIL4 degradation with an DC50 of less than about 1 pM using an antibody -free endogenous protein detection assay (HiBit) as described herein. In various further aspects, the compound inhibits cell proliferation with an EC50 of less than about 0.1 pM; and / or wherein the compound exhibits cereblon binding with an IC50 of less than about 0.1 pM. In various further aspects, the compound inhibits cell proliferation with an EC50 of less than about 25 nM; and / or wherein the compound exhibits cereblon binding with an IC50 of less than about 25 nM. In various further aspects, the compound inhibits cell proliferation with an EC50 of less than about 10 nM; and / or wherein the compound exhibits cereblon binding with an IC50 of less than about 10 nM. In various further aspects, the compound inhibits cell proliferation with an EC50 of less than about 5 nM; and / or wherein the compound exhibits cereblon binding with an IC50 of less than about 5 nM. In various further aspects, the compound inhibits cell proliferation with an EC50 of less than about 1 nM; and / or wherein the compound exhibits cereblon binding with an IC50 of less than about 1 nM.4. USE OF COMPOUNDS AND MANUFACTURE OF A MEDICAMENT

[0401] In a further aspect, the present disclosure pertains to uses of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a cereblon dysfunction in a mammal.

[0402] In a further aspect, the present disclosure pertains to uses of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a PPIL4 dysfunction in a mammal.Attorney Docket No. 19116.0070P1

[0403] In a further aspect, the present disclosure pertains to uses of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

[0404] In a further aspect, the present disclosure pertains to uses of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an immunologic disease or pathological condition involving an immunologic component.

[0405] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0406] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0407] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0408] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation such as, for example, cancer (e.g., medulloblastoma and / or acute lymphoblastic leukemia (ALL).F. KITS

[0409] In a further aspect, the present disclosure relates to kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, and / or at least one disclosedAttorney Docket No. 19116.0070P1pharmaceutical composition. In a further aspect, the compound has a structure represented by a formula:wherein XI is selected from — (C-CH3) —, — (CH) — and — (N) —; wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic. In a further aspect, the compound has a structure represented by a formula:wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C^Cy1, -OCy1, -O(C1-C4 alkyl)Cy1, and -(CH2)nCy1; wherein n is an integer selected from 0, 1, and 2; and wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5, or a pharmaceutically acceptable salt thereof.

[0410] In a further aspect, the present disclosure relates to kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof and one or more of: (a) at least one agent known to increase cereblon activity; (b) at least one agent known to decreaseAttorney Docket No. 19116.0070P1cereblon activity; (c) at least one agent known to increase a kinase activity; (d) at least one agent known to decrease kinase activity; (e) at least one agent known to increase cellular proliferation; (!) at least one agent known to decrease cellular proliferation; (g) at least one agent known to exacerbate an immunologic disease or pathological condition involving an immunologic component; (h) at least one agent known to treat an immunologic disease or pathological condition involving an immunologic component; (i) at least one agent known to treat a disorder associated with cereblon activity; (j) at least one agent known to treat a disorder associated with kinase activity; (k) instructions for treating a disorder of uncontrolled cellular proliferation; or (I) instructions for treating a immunologic disease or pathological condition involving an immunologic component.

[0411] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds can conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. In further aspects, a kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, a kit can contain instructions for preparation and administration of the compositions. The kit can be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

[0412] In a further aspect, the disclosed kits can be packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). Such packaging promotes products and increases patient compliance with drug regimens. Such packaging can also reduce patient confusion. The present disclosure also features such kits further containing instructions for use.Attorney Docket No. 19116.0070P1

[0413] In a further aspect, the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers fdled with one or more of the ingredients of the pharmaceutical compositions of the disclosure. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0414] In various aspects, the disclosed kits can also comprise compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0415] Thus, in various aspects, the at least one compound or the at least one product and the at least one agent are co-formulated.

[0416] In various aspects, the at least one compound or the at least one product and the at least one agent are co-packaged.

[0417] In various aspects, the kit further comprises instructions to provide the compound in connection with surgery. In various further aspects, the instructions provide that surgery is performed prior to the administering of at least one compound. In various further aspects, the instructions provide that surgery is performed after the administering of at least one compound. In various further aspects, the instructions provide that the administering of at least one compound is to effect presurgical debulking of a tumor. In various further aspects, the instructions provide that surgery is performed at about the same time as the administering of at least one compound.

[0418] In various aspects, the kit further comprises instructions to provide the at least one compound or the pharmaceutical composition in connection with radiotherapy. In various further aspects, the instructions provide that radiotherapy is performed prior to the administering of at least one compound. In various further aspects, the instructions provide that radiotherapy is performed after the step of the administering of at least one compound. In various further aspects, the instructions provide that radiotherapy is performed at about the same time as the step of the administering of at least one compound.Attorney Docket No. 19116.0070P1

[0419] In various aspects, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound or the pharmaceutical composition and the at least one agent. In various further aspects, each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-formulated. In various further aspects, each dose of the at least one compound or the pharmaceutical composition and the at least one agent are copackaged.

[0420] In various aspects, the dosage forms are formulated for oral administration and / or intravenous administration. In various further aspects, the dosage forms are formulated for oral administration. In various further aspects, the dosage forms are formulated for intravenous administration.

[0421] In various aspects, the dosage form for the at least one compound or the pharmaceutical composition is formulated for oral administration and the dosage form for the at least one agent is formulated for intravenous administration.

[0422] In various aspects, the dosage form for the at least one compound or the pharmaceutical composition is formulated for intravenous administration and the dosage form for the at least one agent is formulated for oral administration.

[0423] It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making, the disclosed methods of using or treating, and / or the disclosed compositions.G. RESEARCH TOOLS

[0424] The disclosed compounds and pharmaceutical compositions have activity as modulators of cereblon protein. In a further aspect, the disclosed compounds and pharmaceutical compositions have activity as modulators PPIL4 expression and / or activity. In a still further aspect, the disclosed compounds and pharmaceutical compositions have activity as inhibitors of cellular proliferation. As such, the disclosed compounds are also useful as research tools.

[0425] Accordingly, one aspect of the present disclosure relates to a method of using a compound of the disclosure as a research tool, the method comprising conducting a biological assay using a compound of the disclosure. Compounds of the disclosure can also be used to evaluate new chemical compounds. Thus another aspect of the disclosure relates to a method ofAttorney Docket No. 19116.0070P1evaluating a test compound in a biological assay, comprising: (a) conducting a biological assay with a test compound to provide a first assay value; (b) conducting the biological assay with a compound of the disclosure to provide a second assay value; wherein step (a) is conducted either before, after or concurrently with step (b); and (c) comparing the first assay value from step (a) with the second assay value from step (b). Exemplary biological assays include a cereblon assay or a PPIL4 assay that can be conducted in vitro or in a cell culture system as disclosed herein, or alternatively, an assay of cellular proliferation using a cell-line and cellular proliferation assay as disclosed herein.

[0426] Still another aspect of the disclosure relates to a method of studying a biological system, e.g., a model animal for a clinical condition, or biological sample comprising a cereblon protein the method comprising: (a) contacting the biological system or sample with a compound of the disclosure; and (b) determining the effects caused by the compound on the biological system or sample. A further aspect of the disclosure relates to a method of studying a biological system, e.g., a model animal for a clinical condition, or biological sample comprising a PPIL4 the method comprising: (a) contacting the biological system or sample with a compound of the disclosure; and (b) determining the effects caused by the compound on the biological system or sample. In various aspects, the disclosed compounds are useful as chemical probes for the study of PPIL4in vitro and in vivo.

[0427] From the foregoing, it will be seen that aspects herein are well adapted to attain all the ends and objects hereinabove set forth together with other advantages, which are obvious and which are inherent to the structure.

[0428] While specific elements and steps are discussed in connection to one another, it is understood that any element and / or steps provided herein is contemplated as being combinable with any other elements and / or steps regardless of explicit provision of the same while still being within the scope provided herein.

[0429] It will be understood that certain features and subcombinations are of utility and may be employed without reference to other features and subcombinations. This is contemplated by and is within the scope of the claims.

[0430] Since many possible aspects may be made without departing from the scope thereof, it is to be understood that all matter herein set forth or shown in the accompanying drawings and detailed description is to be interpreted as illustrative and not in a limiting sense.Attorney Docket No. 19116.0070P1

[0431] 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. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0432] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.H. EXAMPLES

[0433] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.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.1. EXEMPLARY COMPOUNDS

[0434] Table 1 shows the molecular SMILES codes and molecular weights of exemplary PPIL4 degraders. The exemplary compounds in Table 1 were synthesized, purified, and then characterized as described herein. The synthesis was confirmed using standard analytical techniques as described. Note that compound no. 4 is also referred to as SJ42872.Attorney Docket No. 19116.0070P1TABLE 1.Molecular No. MOLSMILESWt.CCl=Nc2ccc(Nc3cccc(CN4CCCC4)c3)cc2C(=O)NlC5CCC(=O)NC5= 1 445.513580CNlCCN(CCl)c2cccc(Nc3ccc4N=NN(C5CCC(=O)NC5=O)C(=O)c4c3 2 447.4897)c2CCl=Nc2ccc(Nc3ccc4NC(=O)COc4c3)cc2C(=O)NlC5CCC(=O)NC5= 3 433.4167604 CNlCCN(CCl)c2cccc(Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C(=O)c 460.52822 (SJ42872) 4c3)c25 COc 1 ccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3 c2)cc 1 392.40796 CC 1 =Nc2ccc(Nc3 ccc4ccccc4c3)cc2C(=O)Nl C5 CCC(=O)NC 5=0 412.4406CCl=Nc2ccc(Nc3ccc4OCC(=O)Nc4c3)cc2C(=O)NlC5CCC(=O)NC5= 7 433.4167608 CCl=Nc2ccc(Nc3ccc(cc3)C#N)cc2C(=O)NlC4CCC(=O)NC4=O 387.391389 COclccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3c2)cclF 410.39836Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.10 CC1=NC2CCC(NC3CCC(C1)C(C1)C3)CC2C(=O)N1C4CCC(=O)NC4=O 431.2720411 CCl=Nc2ccc(Nc3cccc(c3)C(F)(F)F)cc2C(=O)NlC4CCC(=O)NC4=O 430.3798912 CCl=Nc2ccc(Nc3ccc(Cl)cc3)cc2C(=O)NlC4CCC(=O)NC4=O 396.82698CNlCCN(CCl)c2ccc(Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C(=O)c4 13 460.52822 c3)cc214 CCl=Nc2ccc(Nc3ccc(cc3)C4CC4)cc2C(=O)NlC5CCC(=O)NC5=O 402.44578CC(=O)Nclccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3c2)cc 15 419.433241CC(=O)Nclcccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3c2)c 16 419.433241CCl=Nc2ccc(Nc3ccc(OCCN4CCOCC4)cc3)cc2C(=O)NlC5CCC(=O) 17 491.53896NC5=O18 CCl=Nc2ccc(Nc3cccc(F)c3)cc2C(=O)NlC4CCC(=O)NC4=O 380.3723819 CCl=Nc2ccc(Nc3ccccc3F)cc2C(=O)NlC4CCC(=O)NC4=O 380.3723820 CCl=Nc2ccc(Nc3ccc(cc3)C(F)(F)F)cc2C(=O)NlC4CCC(=O)NC4=O 430.37989Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.21 CCl=Nc2ccc(Nc3cccnc3)cc2C(=O)NlC4CCC(=O)NC4=O 363.3699822 CC 1 =Nc2ccc(Nc3 ccccc3 )cc2C(=O)N 1 C4CCC(=O)NC4=O 362.38192CCl=Nc2ccc(Nc3cccc(c3)N4CCOCC4)cc2C(=O)NlC5CCC(=O)NC5= 23 447.4864024 CCl=Nc2ccc(Nc3cccc(F)c3C)cc2C(=O)NlC4CCC(=O)NC4=O 394.3989625 COc 1 ccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3 c2)nc 1 393.3959626 CC 1 =Nc2ccc(Nc3 cc(C)nn3 C)cc2C(=O)N 1 C4CCC(=O)NC4=O 380.400527 CC|-Nc2ccc(Nc3cc(CI)ccn3)cc2C(-O)NIC4CCC(-O)NC4-O 397.8150428 CCl=Nc2ccc(Nc3cccc(c3)c4ccccn4)cc2C(=O)NlC5CCC(=O)NC5=O 439.4659429 CCl=Nc2ccc(Nc3cccc4cccc(Cl)c34)cc2C(=O)NlC5CCC(=O)NC5=O 446.8856630 CCl=Nc2ccc(Nc3cccc(Cl)c3)cc2C(=O)NlC4CCC(=O)NC4=O 396.8269831 COc 1 cc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3 c2)cc(OC)c 1 422.4338832 CCl=Nc2ccc(Nc3ccc(OC(F)(F)F)cc3)cc2C(=O)NlC4CCC(=O)NC4=O 446.37929Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.33 CCl=Nc2ccc(Nc3ccon3)cc2C(=O)NlC4CCC(=O)NC4=O 353.332134 CCl=Nc2ccc(Nc3ncc(C)s3)cc2C(=O)NlC4CCC(=O)NC4=O 383.4242835 CCl=Nc2ccc(Nc3ccncc3)cc2C(=O)NlC4CCC(=O)NC4=O 363.3699836 CCl=Nc2ccc(Nc3ccc(Oc4ccccc4)cc3)cc2C(=O)NlC5CCC(=O)NC5=O 454.4772837 CCl=Nc2ccc(Nc3ccc(Cc4ccncc4)cc3)cc2C(=O)NlC5CCC(=O)NC5=O 453.4925238 CCl=Nc2ccc(Nc3ccccc3CN4CCCC4)cc2C(=O)NlC5CCC(=O)NC5=O 445.51358CC(C)CNlCCN(CCl)c2cccc(Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O) 39 502.60796C(=O)c4c3)c240 Clc 1 cccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)c 1 383.7884641 O=ClCCC(N2N=Nc3ccc(Nc4ccccc4CN5CCCC5)cc3C2=O)C(=O)Nl 432.47506CCl=Nc2ccc(Nc3ccccc3CN4CCCCC4)cc2C(=O)NlC5CCC(=O)NC5= 42 459.540160CCl=Nc2ccc(Nc3cccc(c3)N4CCN(Cc5ccccc5)CC4)cc2C(=O)NlC6CC 43 536.62418C(=O)NC6=OAttorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.CC(C)N1 CCN(CC1 )c2cccc(Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C( 44 488.58138=O)c4c3)c245 O=ClCCC(N2N=Nc3ccc(Nc4ccc5ccccc5c4)cc3C2=O)C(=O)Nl 399.4020846 COc 1 ccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)cc IF 397.35984CClCCCN(Cc2cccc(Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C(=O)c4c 47 473.566743)c2)Cl48 CCl=Nc2ccc(Nc3cccc(c3)N4CCCC4)cc2C(=O)NlC5CCC(=O)NC5=O 431.48749 CCl=Nc2ccc(Nc3ccccc3F)cc2C(=O)NlC4CCC(=O)NC4=O 380.3723850 Cclccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)ccl 363.36998CCl=Nc2ccc(Nc3cccc(CN4CCCCC4)c3)cc2C(=O)NlC5CCC(=O)NC5 51 459.54016=0CNlCCN(CCl)c2ccc(Nc3ccc4N=NN(C5CCC(=O)NC5=O)C(=O)c4c3) 52 447.4897 cc2CCl=Nc2ccc(Nc3ccccc3CN4CCOCC4)cc2C(=O)NlC5CCC(=O)NC5= 53 461.512980Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.CNlCCN(Cc2ccccc2Nc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C(=O)c4c 54 474.55483)CC155 O=ClCCC(N2C=Nc3ccc(Nc4ccccc4CN5CCCC5)cc3C2=O)C(=O)Nl 431.487CCl=Nc2ccc(Nc3ccc(CN4CCOCC4)cc3)cc2C(=O)NlC5CCC(=O)NC5 56 461.51298=0CCl=Nc2ccc(Nc3ccccc3CN4CCSCC4)cc2C(=O)NlC5CCC(=O)NC5= 57 477.578580FC(F)(F)clnc2cc(Nc3ccc4N=NN(C5CCC(=O)NC5=O)C(=O)c4c3)ccc2 58 457.36547[nH]lCCl=Nc2ccc(Nc3cccc(c3)N4CCNCC4)cc2C(=O)NlC5CCC(=O)NC5= 59 446.501640CC 1 =Nc2ccc(Nc3 ccccc3 C(=O)N4CCCC4)cc2C(=O)N 1 C5CCC(=0)NC 60 459.49715=061 CCl=Nc2ccc(Nc3cccc(Cc4ccccc4)c3)cc2C(=O)NlC5CCC(=O)NC5=O 452.50446CCl=Nc2ccc(Nc3cccc(CN4CCCC4=O)c3)cc2C(=O)NlC5CCC(=O)NC 62 459.49715=0Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.63 CN(c 1 ccc(C)cc 1 )c2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3 c2 390.43508CCOclccc(Nc2ccc3N=C(C)N(C4CCC(=O)NC4=O)C(=O)c3c2)cclCN 64 489.566145CCCC5CCl=Nc2ccc(Nc3ccccc3CN4CCCC4=O)cc2C(=O)NlC5CCC(=O)NC5 65 459.4971=0CCl=Nc2ccc(Nc3ccc(CN4CCCC4)cc3)cc2C(=O)NlC5CCC(=O)NC5= 66 445.51358067 O=C 1 CCC(N2N=Nc3 ccc(Nc4nc5 ccccc5 [nH]4)cc3 C2=O)C(=O)N 1 389.3675CCl=Nc2ccc(Nc3cccc(c3)C(=O)N4CCCCC4)cc2C(=O)NlC5CCC(=O) 68 473.52368NC5=O69 O=ClCCC(N2N=Nc3ccc(Nc4ccccc4)cc3C2=O)C(=O)Nl 349.343470 FC(F)(F)c 1 cccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)c 1 417.3413771 O=ClCCC(N2N=Nc3ccc(Nc4cccnc4)cc3C2=O)C(=O)Nl 350.3314672 Clclccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)ccl 383.7884673 Fc 1 cccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)c 1 367.33386Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.74 O=C 1 CCC(N2N=Nc3 ccc(Nc4ccc(cc4)C#N)cc3 C2=O)C(=O)N 1 374.3528675 COclcc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)cc(OC)cl 409.3953676 Fc 1 ccccc 1NC2CCC3N=NN(C4CCC(=O)NC4=O)C(=O)C3 c2 367.3338677 FC(F)(F)Oc 1 ccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)cc 1 433.3407778 O=ClCCC(N2N=Nc3ccc(Nc4ccc5OCOc5c4)cc3C2=O)C(=O)Nl 393.352979 O=ClCCC(N2N=Nc3ccc(Nc4ccc(Oc5ccccc5)cc4)cc3C2=O)C(=O)Nl 441.4387680 O=ClCCC(N2N=Nc3ccc(Nc4cccc(c4)c5nccs5)cc3C2=O)C(=O)Nl 432.4551481 CCnlnc(C)cclNc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2 381.3885682 O-CICCC(N2N-Nc3ccc(Nc4cccc(c4)c5ccccn5)cc3C2-O)C(-O)NI 426.42742CC(C)(C)OC(=O)NlCCC(CCl)c2ccc(Nc3ccc4N=NN(C5CCC(=O)NC 83 532.590885=O)C(=O)c4c3)cc284 O=ClCCC(N2N=Nc3ccc(Nc4ccc(cc4)C5CC5)cc3C2=O)C(=O)Nl 389.4072685 CC(=O)Nclcccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)cl 406.39472Attorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.O=ClCCC(N2N=Nc3ccc(Nc4ccc(OCCN5CCOCC5)cc4)cc3C2=O)C(= 86 478.50044O)N187 CC(=O)Nc 1 ccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)cc 1 406.3947288 FC(F)(F)clccc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)ccl 417.3413789 O=ClCCC(N2N=Nc3ccc(Nc4cccc(c4)N5CCOCC5)cc3C2=O)C(=O)Nl 434.4478890 O=ClCCC(N2N=Nc3ccc(Nc4ccc(Cc5ccncc5)cc4)cc3C2=O)C(=O)Nl 440.45491 Clclccnc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3c2)cl 384.7765292 COc 1 ccc(Nc2ccc3 N-NN(C4CCC(-O)NC4-O)C(-O)c3 c2)nc 1 380.3574493 Cc 1 cnc(Nc2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2)s 1 370.3857694 CN(c 1 ccc(C)cc 1 )c2ccc3N=NN(C4CCC(=O)NC4=O)C(=O)c3 c2 377.39656CCl=Nc2ccc(Nc3ccc(cc3)C4CCN(CC4)C(=O)OC(C)(C)C)cc2C(=O)N 95 545.62941C5CCC(=O)NC5=OCCl=Nc2ccc(Nc3cccc(c3)C(=O)N4CCCC4)cc2C(=O)NlC5CCC(=O)N 96 459.4971C5=OAttorney Docket No. 19116.0070P1Molecular No. MOL SMILESWt.CCl=Nc2ccc(Nc3cccc(CN4C(=O)c5ccccc5C4=O)c3)cc2C(=O)NlC6C 97 521.52342CC(~0)NC6-0CC 1 =Nc2ccc(Nc3 cc(CN4CCCC4)ccc3 C)cc2C(=O)Nl C5CCC(=O)NC5 98 459.54016=0CC1CCCCN1CC2CCCC(NC3CCC4N=C(C)N(C5CCC(=O)NC5=O)C( 99 473.56674=O)C4C3)C2COclccc(CN2CCCC2)cclNc3ccc4N=C(C)N(C5CCC(=O)NC5=O)C(= 100 475.53956O)c4c32. BIOLOGICAL PROPERTIES OF EXEMPLARY COMPOUNDS

[0435] The assay results for PPIL4 degradation were characterized via a PPIL4 Hibit assay described below. The results are presented in Table 2.TABLE 2.HIBIT MolecularNo. LCMS2Rt Category1 3Wt.1 B 446.2 0.73 445.513582 A 448.2 0.81 447.48973 C 434.1 0.85 433.416764 (SI42872) A 461.5 0.68 460.528225 B 393.1 1.15 392.40791HIBIT Category A: < 0.1 gM; B: 0.1 gM - 1 gM; C: 1 gM- 10 gM; D: > 10 gM.2LCMS (M+H) from mass spectrometry3LCMS retention time in minutesAttorney Docket No. 19116.0070P1HIBIT MolecularNo. LCMS2Rt Category1 3Wt.6 A 413.2 1.47 412.44067 C 434.1 0.94 433.416768 B 388.1 1.10 387.391389 B 411.1 1.19 410.3983610 B 432.1 1.57 431.2720411 B 431.1 1.50 430.3798912 B 397.1 1.40 396.8269813 B 461.2 0.65 460.5282214 B 403.2 1.45 402.4457815 C 420.2 0.82 419.4332416 C 420.2 0.90 419.4332417 C 492.2 0.69 491.5389618 A 381.1 1.27 380.3723819 B 381.1 1.22 380.3723820 B 431.1 1.49 430.3798921 C 364.1 0.49 363.3699822 B 363.1 1.20 362.3819223 B 448.2 1.07 447.486424 B 395.1 1.37 394.3989625 B 394.1 0.82 393.3959626 C 381.2 0.77 380.400527 D 398.1 1.11 397.8150428 B 440.2 0.95 439.4659429 C 447.1 1.50 446.8856630 A 397.1 1.40 396.8269831 B 423.2 1.24 422.4338832 C 447.1 1.54 446.3792933 D 354.1 0.83 353.332134 C 384.1 0.92 383.4242835 D 364.1 0.43 363.3699836 D 455.2 1.61 454.4772837 D 454.2 0.77 453.4925238 A 446.5 0.70 445.5135839 A 503.7 0.80 502.6079640 A 384.1 1.41 383.7884641 A 433.7 0.71 432.4750642 A 460.7 0.73 459.5401643 A 537.7 0.89 536.6241844 A 489.7 0.74 488.5813845 A 400.1 1.51 399.4020846 B 398.1 1.26 397.3598447 B 474.6 0.80 473.5667448 B 432.6 1.32 431.487Attorney Docket No. 19116.0070P1HIBIT MolecularNo. LCMS2Rt Category1 3Wt.49 B 381.1 1.22 380.3723850 B 364.1 1.39 363.3699851 B 460.5 0.72 459.5401652 B 448.2 0.75 447.489753 B 462.6 0.67 461.5129854 B 475.7 0.80 474.554855 B 432.5 0.69 431.48756 B 462.6 0.58 461.5129857 B 478.6 0.74 477.5785858 B 458.1 1.14 457.3654759 C 447.6 0.67 446.5016460 C 460.6 1.09 459.497161 C 453.4 1.61 452.5044662 C 460.4 1.01 459.497163 C 391.4 1.49 390.4350864 C 490.6 0.86 489.5661465 C 460.6 1.12 459.497166 C 446.4 0.65 445.5135867 D 390.1 0.74 389.367568 D 474.6 1.18 473.5236869 D 350.1 1.25 349.343470 D 418.1 1.57 417.3413771 D 351.1 0.55 350.3314672 D 384.1 1.43 383.7884673 D 368.1 1.36 367.3338674 D 375.1 1.16 374.3528675 D 410.1 1.36 409.3953676 D 368.1 1.21 367.3338677 D 434.1 1.60 433.3407778 D 394.1 1.20 393.352979 D 442.1 1.63 441.4387680 D 433.1 1.38 432.4551481 D 382.2 1.00 381.3885682 D 427.1 1.08 426.4274283 D 533.2 1.79 532.5908884 D 390.1 1.59 389.4072685 D 407.1 0.95 406.3947286 D 479.2 0.77 478.5004487 D 407.1 0.95 406.3947288 D 418.1 1.58 417.3413789 D 435.2 1.24 434.4478890 D 441.2 0.85 440.45491 D 385.1 1.36 384.77652Attorney Docket No. 19116.0070P1HIBIT MolecularNo. LCMS2Rt Category1 3Wt.92 D 381.1 1.13 380.3574493 D 371.1 1.15 370.3857694 D 378.1 1.62 377.3965695 D 546.6 1.67 545.629496 D 460.4 1.04 459.497197 D 522.5 1.37 521.5234298 D 460.6 0.72 459.5401699 D 474.6 0.72 473.56674100 D 476.6 0.73 475.539563. CHEMICAL SYNTHESIS AND CHARACTERIZATION OF EXEMPLARY COMPOUNDSa. GENERAL EXPERIMENTAL

[0436] All reagents and solvents were obtained from commercially available sources and were used without further purification. Reactions were set up in air and carried out under nitrogen atmosphere. Parallel synthesis was accomplished using MiniBlock XT synthesizers purchased from Mettler-Toledo AutoChem placed on a stirring hot plate. Library compounds were filtered using a 96 well Thomson 2mL filter plate (25 pm) containing Celite 545 into a Waters 96 well 2 ml receiving plate prior to purification. Automated weighing was done using a Bohdan Balance Automator (Mettler-Toldeo AutoChem) and parallel evaporations were carried out using a Genevac HT-24. HPLC analyses were accomplished using an UPLC / UV / ELSD / SQD (Single Quadrupole Detector) with stationary phase: BEH C18, 1.7 pm, solvents: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, detector types: PDA (210 to 400 nm) and ELSD.

[0437] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker NMR spectrometer at 500 MHz for 1H-NMR spectra and 125 MHz for 13C-NMR spectra. Chemical shifts (ppm) are reported relative to the solvent peak. Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, quadruplet; m, multiplet. Coupling constants (J) are expressed in Hertz. The purity of final compounds was performed on an Acquity UPLC BEH C18 1.7 pm, 2.1 x 50 mm column (Waters Corporation, Milford, MA) using an Acquity ultra performance liquid chromatography system. The flow rate was 0.7 mL / min. The sample injection volume was 3 pL. The UPLC column was maintained at 50 °CAttorney Docket No. 19116.0070P1and the gradient program started at 90% A (0.1% formic acid in MilliQ H2O), changed to 95% B (0.1% formic acid in Acetonitrile) over 2.5 min, held for 0.35 minutes, then to 90% A over 0.05 minutes.b. GENERAL BUCHWALD-HARTWIG AMINATION PROTOCOL

[0438] To a reaction tube equipped with a stir bar was added corresponding bromide 3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione, or 3-(6-bromo-4-oxobenzo[d][l, 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione, or 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione (0.060 mmol, 1.0 equiv), corresponding aniline (0.12 mmol, 2 equiv), BrettPhos Pd G3 (7.8 pmol, 0.13 equiv), BrettPhos (7.8 pmol, 0.13 equiv) and potassium carbonate (0.18 mmol, 3.0 equiv), followed by anhydrous 1,4-Dioxane (1 mL). The mixture was stirred at 90 °C for 12 hr under N₂ atmosphere and checked by UPLC. Upon completion, reaction mixture was diluted with 500 pl of EtOAc, added Si-Diol and Si-Thiol resins (25 mg of each) and stirred for about an hour. The resulting suspension was fdtered through SPE fdter tubes containing a small amount of Celite 545 and then concentrated. The residue was dissolved in DMSO and filtered. The celite was washed with 200 pl additional DMSO. Pre-purifi cation analysis in the UPLC was done with water / acetonitrile / 0.1% formic acid. Library purification was performed on the Waters purification / analytical LC / UV / ELSD system and parallel evaporations were carried out using a TurboVap® LV evaporator.c. SYNTHESIS OF 3-(2-METHYL-6-((3-(4-METHYLPIPERAZIN-1-YL)PHENYL)AMINO)- 4-OXOQUINAZOLIN-3(4H)-YL)PIPERIDINE-2, 6-DIONE

[0439] To a reaction tube equipped with a stir bar was added 3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione (20.0 mg, 0.057 mmol, 1.0 equiv), 3-(4-methylpiperazin-l-yl)aniline (21.9 mg, 0.11 mmol, 2 equiv), BrettPhos Pd G3 (6.7 mg, 7.4 pmol, 0.13 equiv), BrettPhos (4.0 mg, 7.4 pmol, 0.13 equiv) and potassium carbonate (23.7 mg, 0.17 mmol, 3.0 equiv), followed by anhydrous 1,4-Dioxane (1 mL). The mixture was stirred at 90 °C for 12 hr under N₂ atmosphere and checked by UPLC. Upon completion, reaction mixture was diluted with 500 pl of EtOAc, added Si-Diol and Si-Thiol resins (25 mg of each) and stirred for about an hour. The resulting suspension was filtered through SPE filter tubes containing a small amount of Celite 545 and then concentrated. The residue was dissolved in DMSO and filtered.Attorney Docket No. 19116.0070P1The celite was washed with 200 pl additional DMSO. Pre-purifi cation analysis in the UPLC was done with water / acetonitrile / 0.1 % formic acid. Library purification was performed on the Waters purification / analytical LC / UV / ELSD system and parallel evaporations were carried out using a TurboVap® LV evaporator to afford 3-(2-methyl-6-((3-(4-methylpiperazin-l-yl)phenyl)amino)-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione (5.1 mg, 0.011 mmol, 19%) as a white solid. 1H NMR (500 MHz, DMSO) 5 10.93 (s, 1H), 8.37 (s, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.06 (t, J = 8.0 Hz, 1H), 6.64 - 6.52 (m, 2H), 6.51 -6.45 (m, 1H), 5.14 (dd, J = 11.6, 5.7 Hz, 1H), 3.03 (dd, J = 6.4, 3.7 Hz, 4H), 2.80 - 2.69 (m, 1H), 2.63 - 2.45 (m, 5H), 2.37 (t, J = 5.0 Hz, 4H), 2.14 (s, 3H), 2.07 (ddd, J = 11.3, 5.7, 3.4 Hz, 1H). LCMS (m / z) M+H = 461.5.d. SYNTHESIS OF 3-(2-METHYL-4-OXO-6-((2-(PYRROLIDIN-1- YLMETHYL)PHENYL)AMINO)QUINAZOLIN-3(4H)-YL)PIPERIDINE-2, 6-DIONE

[0440] To a microwave vial equipped with a stir bar was added 3-(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione (50.0 mg 0.14 mmol, 1.0 equiv), 2-(pyrrolidin-l-ylmethyl)aniline (27.7 mg, 0.16 mmol, 1.1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos, 10.7 mg, 0.019 mmol, 0.13 equiv), Tris(dibenzylideneacetone)dipalladium (17.0 mg, 0.019 mmol, 0.13 equiv) and potassium carbonate (39.5 mg, 0.29 mmol, 2.0 equiv), followed by DMSO (2 mb). The reaction was heated to 150 °C in a microwave reactor for 30 min. The reaction mixture was checked by UPLC and fdtered through a pile of celite. Pre-purification analysis in the UPLC was done with water / acetonitrile / 0.1 % formic acid. Purification was performed on the Waters purification / analytical LC / UV / ELSD system and evaporations were carried out using a TurboVap® LV evaporator to afford 3-(2-methyl-4-oxo-6-((2-(pyrrolidin-l-ylmethyl)phenyl)amino)quinazolin-3(4H)-yl)piperidine-2, 6-dione (12.0 mg, 19%, Purity > 95%).1H NMR (600 MHz, MeOD) 58.43 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1 H), 7.36 - 7.23 (m, 4H), 7.04 - 6.99 (m, 1 H), 5.14 (dd, J = 11.2, 5.8 Hz, 1H), 3.98 (s, 2H), 2.87 (br s, 4H), 2.82-2.66 (m, 2H), 2.65-2.60 (m, 1 H), 2.57 (s, 3H), 2.15 - 2.08 (m, 1 H), 1.85 (q, J = 3.5 Hz, 4H). LCMS (m / z) M+H = 446.5.Attorney Docket No. 19116.0070P1e. SYNTHESIS OF COMPOUND NOS.39, 43, 44, AND 59

[0441] To a reaction vial with / 7-butyl 4-(3-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)piperazine-l -carboxylate (0.046 mmol, 1 equiv) in DCM (ImL) was added TFA (0.92 mmol, 20 equiv) and stirred Ih when UPLC. Crude reaction mixture was concentrated, dissolved in DMSO and purified by Waters purification / analytical LC / UV / ELSD. Evaporations were carried out using a TurboVap® LV evaporator. Crude material was used for the next step without further purification.

[0442] To a reaction vial with 3-(2-methyl-4-oxo-6-((3-(piperazin-l-yl)phenyl)amino)quinazolin-3(4H)-yl)piperidine-2, 6-dione (0.045 mmol, 1 equiv) and corresponding aldehyde or ketone (0.045 mmol, 1 equiv) in MeOH (1 mL) was added sodium cyanotrihydroborate (0.045 mmol, 1 equiv) followed by 1 drop of acetic acid. The reaction was heated to 50 °C overnight. The resulting suspension was filtered through SPE filter tubes containing a small amount of Celite 545 and then concentrated. The residue was dissolved in DMSO and filtered. Pre-purification analysis in the UPLC was done with water / acetonitrile / 0.1% formic acid. Library purification was performed on the Waters purification / analytical LC / UV / ELSD system and parallel evaporations were carried out using a TurboVap® LV evaporator.

[0443] All remaining compounds were synthesized using the general protocols described above.4. BIOLOGICAL ASSAY PROTOCOLS

[0444] PPIL4 HiBiT Assay A homozygous PPIL4 C-terminal HiBiT knock-in clonal cell line was generated using CRISPR / Cas9 to insert HiBiT at the C-terminus of the endogenous PPIL4 loci in HEK293 cells at the Center for Advanced Genome Engineering at St. Jude.

[0445] PPIL4 HiBiT cells were plated at 2,500 cells / well density in 384-well white solid bottom assay plates (Corning, Cat. # 3570BC) in 30 uL volume in DMEM media (ATCC, 30-2002) containing 10% FBS (R& D Systems, SI 1550H) and incubated overnight at 37 °C and 5% CO2. After overnight incubation, cells were treated with compounds in a dose-response format using Echo 655 Acoustic Liquid Handler (Beckman Coulter). After 4 h incubation at 37 °C and 5% CO2, the level of HiBiT tagged-PPIL4 was evaluated by addition of Nano-Gio Live CellAttorney Docket No. 19116.0070P1Assay reagent (Promega, Cat. #N2013) to the plates according to the manufacturer’s instruction followed by incubation for 10 min before the luminescence signal was read using EnVision plate reader (PerkinElmer). The luminescence data was analyzed using our in-house developed data analysis pipeline, Robust Investigation of Screening Experiments (RISE), based on the Pipeline Pilot platform (Accelrys, v.8.5.0). This analysis determined the compound DC50 values using a four-parameter dose-response model. The results are summarized in Table 2.5. ADDITIONAL PROTOCOLSa. CELL LINES AND NORMAL HEMATOPOIETIC CELL SAMPLES

[0446] The B-progenitor ALL cell lines used in this study include the MHH-C ALL-4 (CRLF2-rearranged; JAK2 I682F), KOPN-49 (CRLF 1 -rearranged; JAK2 R683G), NALM-6 (DUX4-rearranged), MHH-CALL-2 (near haploid), SUP-B15 (BCR-ABL1), NALM-16 (Hypodiploid), 697 (TCF3-PBX1) and REH (ETV6-RUNX1); MHH -CALL-4 with CRBN knock down were also utilized (PMID: 37172201). Cell lines were maintained in RPMI 1640 medium containing 10% or 20% fetal bovine serum (HyClone), penicillin / -streptomycin (100 U / mL), and glutamine (100 pM). Human (h)CD34+ cells were purified from cord blood using hCD34 MicroBeads (Miltenyi Biotec) and expanded as described previously (PMID: 37172201). Normal human peripheral blood mononuclear cells were isolated by Ficoll-Paque density gradient centrifugation from apheresis rings obtained from anonymous healthy blood donors. The donors provided informed consent for the research use of leftover specimens, which was approved by the Institutional Review Board of St Jude Children's Research Hospital.

[0447] The Group 3 medulloblastoma (MB) cell lines used in this study included HDMB03 (provided by Dr. Till Milde), D283 (ATCC HTB-185), D425 (Millipore, SCC290), and the human microglial cell line HMC3 (ATCC CRL-3304). A CRBN-knockout derivative of HDMB03 (HDMB03-CRBN KO) was generated in-house using CRISPR / Cas9-mediated gene disruption. MS neurospheres were isolated from mouse brain tissue. Cells were cultured under lineage-appropriate conditions: HDMB03 and MS neurospheres in Neurobasal medium, D283 in EMEM, D425 in Neurocult medium, and HMC3 in EMEM. All media were supplemented with penicillin-streptomycin (100 U / mL), and L-glutamine (2 mM).Attorney Docket No. 19116.0070P1

[0448] All human cell lines and neurosphere cultures were routinely screened and confirmed to be free of Mycoplasma spp. contamination using the Universal Mycoplasma Detection Kit (ATCC). Cell identity for all human cell lines was verified by short tandem repeat (STR) profiling using a PowerPlex Fusion System (Promega).b. MICE

[0449] Female NSG (NOD. Cg-Prkdcscid I12rgtmlWjl / SzJ) mice were obtained from St Jude animal research center. Female CD 1 -nude (NU / NU) mice (Charles River Laboratories, strain code #O86NU / NUCD1) were obtained from Charles River Laboratories. All experimental work was carried out according to Office of Laboratory Animal Welfare guidelines and was approved by Institutional Animal Care and Use Committee of St Jude Children’s Research Hospital.c. IMMUNOBLOT ANALYSIS

[0450] Cells were washed twice with ice-cold PBS and lysed in RIPA lysis buffer (Sigma) freshly supplemented with Halt™ Protease Inhibitor Cocktail (ThermoFisher) for 15 minutes on ice. The cell pellet was removed by centrifugation at 13,000 g at 4 °C for 15 minutes. Protein concentration was measured by BCA assay (Thermo Fisher Scientific). Proteins were denatured in NuPAGE LDS 4X sample buffer supplemented with reducing agents (Invitrogen).Typically, 10-20 pg of total protein was loaded per lane on a 4%-12% NuPAGE Bis-Tris gradient gel (Invitrogen) and analyzed by standard immunoblotting. The blotting images were obtained with Li-COR Odyssey CLx and band density was analyzed by Image Studio v4 software (LI-COR Biotechnology, Lincoln, NE). Primary antibodies used were: PPIL4 (Proteintech, 12538-1-AP), ACTB (Santa Cruz Biotechnology, SC-47778), HSC70 (Santa Cruz Biotechnology, SC- 7298).d. CYTOTOXICITY ASSAY

[0451] For manual cytotoxicity assay, a total of 2x 105cells were seeded at 100 pL per well in 96-well assay plates (Coming #3603). Assays were performed in triplicate; compounds to be tested were added to assay plates from DMSO stock solutions. The assay plates were incubated at 37 °C in 5% CO2 for 72 hours. Cells were then incubated for 4 hours with resazurin (Sigma)Attorney Docket No. 19116.0070P1solution and read on a Synergy HT plate reader (BioTek Instruments, Winooski, VT). Data were plotted and analyzed with GraphPad Prism software v8 using nonlinear regression curve fitting.

[0452] For high throughput screening, 30 nl of compound solutions were transferred to barcoded 384-well assay plates (Coming, Cat#3570BC) using Echo liquid handler 655 (Beckman Coulter). Then, 30 pl of medium containing cells were added to assay plates using Matrix WellMate (Thermo scientific) and assay plates were incubated at 37 °C in 5% CO2 for 72 hours. Then, 25 pl of CellTiter-Glo (Promega) were added to the cells and the luminescence was measured by an EnVision plate reader (PerkinElmer). High-throughput assay data were analyzed using our in-house Robust Interpretation of Screening Experiments (RISE) application written in Pipeline Pilot (Biovia, V17.2.0) in R (PMID: 34110416).e. IN VIVO PHARMACOKINETIC STUDIES

[0453] Non-tumor bearing female CD1 female mice, aged 8-12 weeks were dosed by i.p. injections with single doses of compound SJ42872 at 30, 60 and 100 mg / kg, respectively.Compound SJ42872 was suspended in 80 % v / v of (20 % w / v SBE-b-CD in water) & QS by Milli Q water (pH=5), with a final dosing volume of 10 ml / kg. For each dose, three mice were injected with a single dose and blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours by retro-orbital eye bleed technique. Blood samples (~30 pL) were collected and concentration levels of compound SJ42872 were determined by liquid chromatography and mass spectrometry.f. IN VIVO PHARMACODYNAMIC STUDIES

[0454] For pharmacodynamics studies, female NSG (NOD. Cg- / 7A / cscld^r^^ / SzI) mice were monitored weekly bioluminescence imaging as described before after engraftment (PMID: 37172201). When average luminescence reached above IxlO10photons per second and hCD45% in blood was above 5% by flow cytometry, mice were dosed by i.p. injection with 60 and 100 mg / kg of compound SJ42872 daily or twice daily for 3, 5 and 7 days. Twelve or twenty-four hours after the last dose, mice were euthanized and cells were collected from bone marrow and spleen. For immunoblotting, leukemia cells from bone marrow and spleen were purified by hCD19 MicroBeads (Miltenyi Biotec) and total protein was extracted using RIPA buffer supplemented with Halt Protease Inhibitor Cocktail (ThermoFisher).Attorney Docket No. 19116.0070P1g. / V VIVO EFFICACY STUDIES

[0455] Female NSG ( OD. Cg- / VA / cSLld / / 27,gtmlwjl / SzJ) mice aged 8 to 12 weeks were used for xenotransplantation. NSG mice were inoculated by tail vein injection with IxlO6PDX (E27009) cells transduced with a lentiviral vector containing the firefly luciferase and yellow fluorescent protein genes (CL20SF2-Luc2aYFP). Leukemia burden was determined by weekly bioluminescence imaging using a Xenogen IVIS-200 system and Living Image software (Caliper Life Sciences). Treatment was commenced when the luminescence signal of whole body averaged ~lxl08photons per second. Mice were dosed by i.p. with compound SJ42872 (60 mg / kg BID, 100 mg / kg QD and 100 mg / kg BID) for 28 days. At the end of the study, cells from spleen, bone marrow, and blood were harvested and stained with mouse CD45-APC-Cy7 (Cat# 3557659, BD Biosciences), human CD45-BV405 (Cat# 564047, BD Biosciences), or human CD19-PE (Cat# 349209, BD Biosciences) antibodies and analyzed by flow cytometry to determine the percentage of hCD45+ cells. Efficacy was determined by linear regression and 2-way analysis of variance using Prism (GraphPad Software, version 8.4.2).h. BRAIN TISSUE BINDING (EQUILIBRIUM DIALYSIS)

[0456] Drugs were prepared at 10 mM in DMSO. Dulbecco's phosphate buffered saline (DPBS; pH 7.4) was obtained from Invitrogen (Carlsbad, CA). Single-Use RED (rapid equilibrium dialysis, Thermo Fisher, Cat#: 90006) devices were obtained from Thermo scientific (Rockford, IL). Mouse brain homogenate was obtained from BioIVT (Westbury, NY).

[0457] Sample preparation for brain tissue binding was modified from the methods of Di et. Al. (PMID: 21474681). The Teflon base plate with the RED inserts was used without any pretreatment. Mouse brain homogenate was thawed and mixed with DPBS at 1:9 ratio (BraimDPBS v:v). Each compound was added to the brain homogenate at substrates concentration of IpM (1 pL of 0.4 mM (diluted in DMSO) in 400 pL of mouse brain homogenate (0.25% DMSO)). Appropriate volume of brain homogenate was placed into the sample chamber (indicated by the colored ring) and the corresponding volume of DPBS was added into the adjacent chamber to achieve the same level (height) between the two chambers. The plate was sealed and incubated at 37°C on an orbital shaker for 4 hours. After incubation, the seal was removed from the RED. 50pL aliquots were sampled from each side of the insert and dispensed into a 96-well deep plate.Attorney Docket No. 19116.0070P1An equal volume of blank brain homogenate or DPBS was added to the well to create analytically identical sample matrices (matrix matching). 200pL of acetonitrile containing 40 ng / ml warfarin (internal standard) was added to the samples. The plates were sealed and mixed, and then were centrifuged at 4000rpm for 20min. Supernatants were transferred to the analytical plates and mixed with MillQ water at 1 to 1 ratio (v:v)

[0458] The compound concentrations were quantified in both buffer and brain homogenates chambers via peak areas relative to the internal standard. The unbound fraction of the compound bound to diluted brain homogenate was calculated with the following equation: fu,b,d= Concentration buffer chamber / concentration b...

Claims

1. Attorney Docket No. 19116.0070P12.CLAIMS3.What is claimed is:

1. A compound having a structure represented by a formula:

6. 8.wherein X1is selected from — (C-CH3) —, — (CH) —, and — (N) —;9.wherein R1is an unsaturated, partially saturated, or saturated polycyclic or monocyclic ring structure having from 4 to 12 ring atoms; and10.wherein the ring structure can be substituted or unsubstituted and homocyclic or heterocyclic;11.or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R1is a six-membered ring which can be substituted or unsubstituted and homocyclic or heterocyclic;13.optionally, wherein the six-membered ring is part of a polycyclic ring structure.

3. The compound according to claim 1, wherein R1is a five-membered ring which can be substituted or unsubstituted and homocyclic or heterocyclic;15.optionally, wherein the five-membered ring is part of a polycyclic ring structure.

4. The compound according to claim 2 or claim 3, wherein the five or six-membered ring is part of a polycyclic ring structure.

5. The compound according to claim 1, having a structure represented by the formula:Attorney Docket No. 19116.0070P119. 21.wherein R1is selected from a moiety having a structure represented by any one of the following formulas:

23. 25.wherein X1is — (C-CH3)-, — (CH) —,or — (N) —;26.wherein any — C(R2)(R2a) —, when present, can be substituted for an — N(R3) — or — O —;27.wherein any — C(R2) —, when present, can be substituted for an — N —;28.wherein each R2and R2a, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and te / 7-butyl, — SFs, — CN, — N3, — NH2, — OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — C1-C3 alkanediyl) — O — (C1-C3 alkyl), — O — (C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, sulfonamide, methylsulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3 alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3 alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl;29.wherein any two occurrences of R2are optionally covalently bonded and, together with the intermediate atoms, comprise a 4- to 7-membered cycle;30.wherein each R3, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and / c77-butyl; Attorney Docket No. 19116.0070P131.or a pharmaceutically acceptable salt thereof6. The compound of claim 5, wherein X1is — (C-CH3) —.

7. The compound of claim 5, wherein X1is — (CH) —.

8. The compound of claim 5, wherein X1is — (N) —.

9. The compound of claim 5, wherein each occurrence of R2is hydrogen.

10. The compound of claim 5, wherein each occurrence of R2ais hydrogen.

11. The compound of claim 5, wherein each occurrence of R3is hydrogen.

12. The compound of claim 5, wherein each R2is independently selected from hydrogen, — F, — Cl, — OCF3, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy.

13. The compound of claim 5, wherein each R2is selected from hydrogen, — F, — Cl, and C1-C3 alkyl.

14. The compound of claim 1, having a structure represented by a formula:

42. 44.wherein R1is selected from a moiety having a structure represented by any one of the following formulas:

46. 48.wherein X1is — (C-CH3) —, — (CH) —, or — (N) —; Attorney Docket No. 19116.0070P149.wherein any — C(R2)(R2a) —, when present, can be substituted for an — N(R3) — or — O —;50.wherein any — C(R2) —, when present, can be substituted for an — N —;51.wherein each R2, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, — SFs, — CN, -N3, -NH2I — OH, — NC, — SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, — O — (C1-C3 alkanediyl) — O — (C1-C3 alkyl), — (C1-C3 alkanediyl) — O — (Cl-C3 alkyl), — O — (C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, sulfonamide, methylsulfonamide, C2-C7 heterocycle, — (C1-C3 alkanediyl) — (C2-C7 heterocycle), — (C1-C3 alkanediyl) — phenyl, — (C1-C3 alkanediyl) — O — phenyl, — (C1-C3 alkanediyl) — O — (C1-C3 alkanediyl) — phenyl, — O — phenyl, — NH — phenyl, and phenyl;52.wherein any two occurrences of R2are optionally covalently bonded and, together with the intermediate atoms, comprise a 4- to 7-membered cycle;53.wherein each R3, when present, is independently selected from hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl;54.or a pharmaceutically acceptable salt thereof15. The compound of claim 14, wherein X1is — (C-CH3) —.

16. The compound of claim 14, wherein X1is — (N) —.

17. The compound of claim 14, wherein each occurrence of R2is hydrogen.

18. The compound of claim 14, wherein each occurrence of R2ais hydrogen.

19. The compound of claim 14, wherein each occurrence of R3is hydrogen.

20. The compound of claim 14, wherein each R2is independently selected from hydrogen, — F, — Cl, — OCF3, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy.

21. The compound of claim 14, wherein each R2is selected from hydrogen, — F, — Cl, and C1-C3 alkyl.Attorney Docket No. 19116.0070P162.The compound of claim 5 or 14, wherein each occurrence of R2is independently selected from hydrogen, — F, —Cl, — Br, — SF5, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2CI, — CHCh, — CCI3, — CH2Br, — CHBr2, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, — CH2CH2CI, — CH2CHCI2, — CH2CCI3, — CH2CH2Br, — CH2CHBr2, — CH2CBr3, — OCH2F, — OCHF2, — OCF3, — OCH2CI, — OCHCI2, — OCCI3, — OCH2Br, — OCHBr2, — OCBr3, — OCH2CH2F, — OCH2CHF2, — OCH2CF3, — OCH2CH2CI, — OCH2CHCI2, — OCH2CCI3, — OCH2CH2Br, — OCH2CHBr2, — OCH2CBr3, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3I — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

23. The compound of claim 5 or 14, wherein one occurrence of R2is hydrogen.

24. The compound of claim 5 or 14, wherein two occurrences of R2are hydrogen.

25. The compound of claim 5 or 14, wherein three occurrences of R2, when present, are hydrogen.

26. The compound of claim 5 or 14, wherein four occurrences of R2, when present, are hydrogen.

27. The compound of claim 5 or 14, wherein one occurrence of R2is selected from — F, — Cl, — Br, — SFs, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2CI, —CHCh, — CCI3, — CH2Br, — CHBr2, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, — CH2CH2CI, — CH2CHC12, — CH2CC13, — CH2CH2Br, — CH2CHBr2, — CH2CBr3, — OCH2F, — OCHF2, — OCF3, — OCH2CI, — OCHCk, — OCCI3, — OCH2Br, — OCHBrc, — OCBn, — OCH2CH2F, — OCH2CHF2, — OCH2CF3, — OCH2CH2CI, — OCH2CHCI2, — OCH2CCI3, — OCH2CH2Br, — OCH2CHBr2, — OCH2CBr3, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3, — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl; and68.wherein each of the other occurrences of R2are hydrogen.

28. The compound of claim 5 or 14, wherein two occurrences of R2are each independently selected from — F, —Cl, — Br, — SFs, — CN, — N3, — CN, — CH2F, — CHF2, — CF3, — CH2CI, — CHCI2, — CCI3, — CH2Br, — CHBr2, — CBr3, — CH2CH2F, — CH2CHF2, — CH2CF3, —Attorney Docket No. 19116.0070P170.CH2CH2CI, — CH2CHCI2, — CH2CCI3, — CH2CH2Br, — CH2CHBr2, — CH2CB1-3, — OCH2F, — OCHF2, — OCF3, — OCH2CI, — OCHCh, — OCCI3, — OCH2B1-, — OCHBn, — OCBn, — OCH2CH2F, — OCH2CHF2, — OCH2CF3, — OCH2CH2CI, — OCH2CHCI2, — OCH2CCI3, — OCH2CH2Br, — OCH2CHBr2, — OC& CBn, — OCH3, — OCH2CH3, — CH2OH, — (CH2)2OH, — NHCH3, — NHCH2CH3, — N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl; and71.wherein each of the other occurrences of R2, if present, are hydrogen.

29. The compound of claim 1, having a structure represented by a formula:

74. 76.wherein X1is selected from -N=, -C(H)=, and -C(CH3)=; and77.wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -78.

79. CCOKy1, -OCy1, -O(C1-C4 alkyOCy1, and -(CT^nCy1;80.wherein n is an integer selected from 0, 1, and 2; and81.wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and -CH2C6H5,82.or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29, wherein n is 0.Attorney Docket No. 19116.0070P131. The compound of claim 29, wherein n is i.

32. The compound of claim 29, wherein X1is -N=.

33. The compound of claim 29, wherein X1is -C(CH3)=.

34. The compound of claim 29, wherein R1is selected from a C6-C10 aryl and a C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -C(O)Cy\ -O88.

89. Cy1, -O(C1-C4 alkyl)Cy1, and -(CH^nCy1.

35. The compound of claim 29, wherein R1is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy lkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -91.

92. C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH^nCy1.

36. The compound of claim 29, wherein R1is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -94.

95. C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH^nCy1.

37. The compound of claim 29, wherein R1is a C6 aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -97.

98. C(O)Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1.

38. The compound of claim 29, wherein R1is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4Attorney Docket No. 19116.0070P1100.alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(CO)(C1-C4 alkyl), -101.

102. C^Cy1, -OCy1, -O(C1-C4 alky^Cy1, and -(Ob^Cy1.

39. The compound of claim 29, wherein R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, a pyridinyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -104.

105. CCOXV, -OCy1, -O(C1-C4 alky^Cy1, and -(CH2)nCy1.

40. The compound of claim 29, wherein R1is a C2-C9 heteroaryl selected from a thiazolyl, a pyrazolyl, an isoxazolyl, a pyridinyl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, Cl-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, =0, -CO2(C1-C4 alkyl), -NH(C0)(C 1 -C4 alkyl), -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)Cy’, and -(CH2)nCy'.

41. The compound of claim 29, wherein R1is selected from a C6-C10 cycloalkyl, a C5-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C9 heteroaryl, and is monosubstituted with a group selected from -C(O)CyJ, -OCy1, -O(C1-C4 alkyl)C108.

109. y\ and -(CH^nCy1.

42. The compound of claim 29, wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from C1-C4 alkyl, =0, -CO2(C1-C4 alkyl), and-CTbCeHs.

43. The compound of claim 29, wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0 or 1 methyl group.

44. The compound of claim 29, wherein Cy1is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is unsubstituted.

45. The compound of claim 1, wherein the compound is:Attorney Docket No. 19116.0070P1114.VlH115. / 117. 119.or a pharmaceutically acceptable salt thereof.

46. The compound of claim 1, wherein the compound is:

122. 124.or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1, wherein the compound is selected from:

127.

128. Attorney Docket No. 19116.0070P1129.tf H130.

131. Attorney Docket No. 19116.0070P1133.

134. Attorney Docket No. 19116.0070P1135.or a pharmaceutically acceptable salt thereof48. The compound of claim 1, wherein the compound is selected from:

138. 140.or a pharmaceutically acceptable salt thereof49. The compound of claim 1, wherein the compound is selected from:

143. 145.or a pharmaceutically acceptable salt thereof.

50. A compound represented by a structure according to any one of the structures in Table A or a pharmaceutically acceptable salt thereof.Attorney Docket No. 19116.0070P151. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any of claims 1-50, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

52. The pharmaceutical composition of claim 51, further comprising at least one agent known to treat a cancer.

53. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is a hormone therapy agent; an alkylating agent, an anti metabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent, other chemotherapeutic agent, or combinations thereof.

54. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is a hormone therapy agent is selected from one or more of the group consisting of leuprolide, tamoxifen, raloxifene, megestrol, fulvestrant, triptorelin, medroxyprogesterone, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histrelin, fluoxymesterone, estramustine, flutamide, toremifene, degarelix, nilutamide, abarelix, and testolactone, or a pharmaceutically acceptable salt thereof.

55. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is an antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.

56. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is an antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5 -fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

57. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is an alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan,Attorney Docket No. 19116.0070P1154.lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt.

58. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is a mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt.

59. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is a mTor inhibitor agent is selected from one or more of the group consisting of everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

60. The pharmaceutical composition of claim 52, wherein the at least one agent known to treat a cancer is selected from uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5 -fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17?-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chi orotriani sene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

61. A method for treating a disorder of uncontrolled cellular proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at leastAttorney Docket No. 19116.0070P1159.one compound of any of claims 1 -50, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60.

62. The method of claim 61, wherein the mammal is a human.

63. The method of claim 61, wherein the mammal has been diagnosed with a need for treatment of the disorder of uncontrolled cellular proliferation prior to the administering step.

64. The method of claim 63, further comprising the step of identifying a mammal in need of treatment of the disorder of uncontrolled cellular proliferation.

65. The method of claim 61, wherein the disorder of uncontrolled cellular proliferation is associated with a PPIL4 dysfunction.

66. The method of claim 61, wherein the disorder of uncontrolled cellular proliferation is a cancer.

67. The method of claim 66, wherein the cancer is a pediatric cancer.

68. The method of claim 66 or claim 67, wherein the cancer is medulloblastoma.

69. The method of claim 66 or claim 67, wherein the cancer is acute lymphoblastic leukemia (ALL).

70. The method of claim 66, wherein the cancer is selected from a brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell cancer, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, malignant melanoma, colorectal cancer, endometrial carcinoma, thyroid cancer, rhabdosarcoma, and combinations thereof.

71. The method of claim 66, wherein the cancer is selected from lung cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, hematological cancer, and brain cancer.

72. The method of claim 71, wherein the lung cancer is selected from small-cell lung cancer, non-small cell lung cancer, and combinations thereof.Attorney Docket No. 19116.0070P173. The method of claim 71, wherein the kidney cancer is a kidney clear cell carcinoma.

74. The method of claim 71, wherein the brain cancer is selected from a glioblastoma, medullablastoma, glioma, and combinations thereof.

75. The method of claim 71, wherein the bladder cancer is a bladder urothelial carcinoma.

76. The method of claim 71, wherein the liver cancer is a hepatic carcinoma.

77. The method of claim 71, wherein the hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoid leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocyte leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, hairy cell lymphoma, Burkett’s lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

78. The method of any one of claims 61-77, further comprising the step of administering a therapeutically effective amount of at least one agent known to treat a cancer.

79. The method of claim 78, wherein the at least one agent is selected from uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepilone, mithramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, teniposide 17a-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone,Attorney Docket No. 19116.0070P1178.levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

80. The method of claim 78, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or combinations thereof.

81. The method of claim 80, wherein the DNA methyltransferase inhibitor is 5-aza-2’-deoxycytidine, 5 -azacytidine, zebularin, epigallocatechin-3 -gallate, procaine, or combinations thereof.

82. The method of claim 80, wherein the HDAC-inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mocetinostat, belinostat, dacinostat, givinostat, tubastatin A, pracinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tacedinaline, rocilinostat, apicidin, or combinations thereof.

83. The method of claim 80, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or combinations thereof.

84. The method of claim 80, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.

85. The method of claim 80, wherein the cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent or other chemotherapeutic agent.

86. The method of claim 85, wherein the antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

87. The method of claim 85, wherein the antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5 -fluorouracil, capecitabine, hydroxyurea, mercaptopurine,Attorney Docket No. 19116.0070P1187.pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

88. The method of claim 85, wherein the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

89. The method of claim 85, wherein the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

90. The method of claim 85, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or combinations thereof.

91. The method of claim 85, wherein the other chemotherapeutic agent is an anthracy cline, cytarabine, a purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or combinations thereof.

92. The method of claim 91, wherein the anthracy cline is daunorubicin, idarubicin, or combinations thereof.

93. The method of claim 91, wherein the purine analog is cladribine, fludarabine, clofarabine, or combinations thereof.

94. The method of any one of claims 78-93, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one agent are administered sequentially.

95. The method of any one of claims 78-93, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one agent are administered simultaneously.Attorney Docket No. 19116.0070P196. The method of any one of claims 78-93, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one agent are co-formulated.

97. The method of any one of claims 78-93, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one agent are co-packaged.

98. A method for modulating cereblon activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1-50, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60.

99. The method of claim 98, wherein the mammal is a human.

100. The method of claim 98, wherein the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step.

101. The method of claim 98, further comprising the step of identifying a mammal in need for modulating of cereblon activity.

102. The method of claim 98, wherein the modulating of cereblon activity comprises modulating the degradation of PPIL4.

103. The method of claim 98, wherein the modulating the degradation of PPIL4 decreases levels of PPIL4 in a cell.

104. A method for modulating PPIL4 activity in a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60.

105. The method of claim 104, wherein the mammal is a human.

106. The method of claim 104, wherein the mammal has been diagnosed with a need for modulating PPIL4 activity prior to the administering step.Attorney Docket No. 19116.0070P1107. The method of claim 104, further comprising the step of identifying a mammal in need for modulating PPIL4 activity.

108. The method of claim 104, wherein the modulating the PPIL4 activity comprises modulating PPIL4 protein levels in a cell.

109. The method of claim 108, wherein the modulating PPIL4 protein levels are decreased compared to a cell that is not exposed to the at least one compound or the pharmaceutical composition.

110. A method for modulating of cereblon activity in at least one cell, the method contacting the at least one cell with an effective amount of at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60.

111. The method of claim 110, wherein the cell is mammalian.

112. The method of claim 110, wherein the cell is human.

113. The method of claim 110, wherein the cell has been isolated from a mammal prior to the contacting step.

114. The method of claim 110, wherein contacting is via administration to a mammal.

115. The method of claim 110, wherein the mammal has been diagnosed with a need for treatment of a disorder related to cereblon activity prior to the administering step.

116. A method for modulating of PPIL4 activity in at least one cell, the method comprising contacting the at least one cell with an effective amount of at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60.

117. The method of claim 116, wherein the cell is mammalian.

118. The method of claim 116, wherein the cell is human.Attorney Docket No. 19116.0070P1119. The method of claim 116, wherein the cell has been isolated from a mammal prior to the contacting step.

120. The method of claim 116, wherein contacting is via administration to a mammal.

121. The method of claim 120, wherein the mammal has been diagnosed with a need for treatment of a disorder related to cereblon activity prior to the administering step.

122. The method of claim any one of claims 61-121, wherein the compound inhibits cell proliferation with an ECso of less than about 1 pM when determined in a cell viability assay using MHHCALL4 cells as described herein; and / or wherein the compound exhibits PPIL4 degradation with an DCso of less than about 1 pM using an antibody -free endogenous protein detection assay (HiBit) as described herein.

123. The method of claim 122, wherein the compound inhibits cell proliferation with an ECso of less than about 0.1 pM; and / or wherein the compound exhibits cereblon binding with an ICso of less than about 0.1 pM.

124. The method of claim 122, wherein the compound inhibits cell proliferation with an ECso of less than about 25 nM; and / or wherein the compound exhibits cereblon binding with an ICso of less than about 25 nM.

125. The method of claim 122, wherein the compound inhibits cell proliferation with an ECso of less than about 10 nM; and / or wherein the compound exhibits cereblon binding with an ICso of less than about 10 nM.

126. The method of claim 122, wherein the compound inhibits cell proliferation with an ECso of less than about 5 nM; and / or wherein the compound exhibits cereblon binding with an ICso of less than about 5 nM.

127. The method of claim 122, wherein the compound inhibits cell proliferation with an ECso of less than about 1 nM; and / or wherein the compound exhibits cereblon binding with an ICso of less than about 1 nM.Attorney Docket No. 19116.0070P1128. A kit comprising at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof, and one or more selected from:229.(a) at least one agent known to increase cereblon activity;230.(b) at least one agent known to decrease cereblon activity;231.(c) at least one agent known to increase PPIL4 activity;232.(d) at least one agent known to decrease PPIL4 activity;233.(e) at least one agent known to increase cellular proliferation;234.(f) at least one agent known to decrease cellular proliferation;235.(g) at least one agent known to treat a disorder associated with cereblon activity;236.(h) at least one agent known to treat a disorder associated with PPIL4 activity;237.(i) at least one agent known to treat a disorder of uncontrolled cellular proliferation; and238.(j) instructions for treating a disorder of uncontrolled cellular proliferation.

129. The kit of claim 128, wherein the at least one compound or the at least one product and the at least one agent are co-formulated.

130. The kit of claim 128, wherein the at least one compound or the at least one product and the at least one agent are co-packaged.

131. The kit of any one of claims 128-130, further comprising instructions to provide the compound in connection with surgery.

132. The kit of claim 131, wherein the instructions provide that surgery is performed prior to the administering of at least one compound.Attorney Docket No. 19116.0070P1133. The kit of claim 131, wherein the instructions provide that surgery is performed after the administering of at least one compound.

134. The kit of claim 131, wherein the instructions provide that the administering of at least one compound is to effect presurgical debulking of a tumor.

135. The kit of claim 131, wherein the instructions provide that surgery is performed at about the same time as the administering of at least one compound.

136. The kit of any one of claims 128-131, further comprising instructions to provide the at least one compound or the pharmaceutical composition in connection with radiotherapy.

137. The kit of claim 136, wherein the instructions provide that radiotherapy is performed prior to the administering of at least one compound.

138. The kit of claim 136, wherein the instructions provide that radiotherapy is performed after the step of the administering of at least one compound.

139. The kit of claim 136, wherein the instructions provide that radiotherapy is performed at about the same time as the step of the administering of at least one compound.

140. The kit of any one of claims 128-139, further comprising a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of the at least one compound or the pharmaceutical composition and the at least one agent.

141. The kit of claim 140, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-formulated.

142. The kit of claim 140, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-packaged.

143. The kit of claim 140, wherein the dosage forms are formulated for oral administration and / or intravenous administration.

144. The kit of claim 140, wherein the dosage formas are formulated for oral administration.Attorney Docket No. 19116.0070P1145. The kit of claim 140, wherein the dosage forms are formulated for intravenous administration.

146. The kit of claim 140, wherein the dosage form for the at least one compound or the pharmaceutical composition is formulated for oral administration and the dosage form for the at least one agent is formulated for intravenous administration.

147. The kit of claim 140, wherein the dosage form for the at least one compound or the pharmaceutical composition is formulated for intravenous administration and the dosage form for the at least one agent is formulated for oral administration.

148. Use of a compound at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60 or combinations thereof in the manufacture of a medicament for the treatment of a disorder associated with a cereblon dysfunction in a mammal.

149. Use of a compound at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60 or combinations thereof in the manufacture of a medicament for the treatment of a disorder associated with a PPIL4 dysfunction in a mammal.

150. Use of a compound at least one compound of any of claims 1-50 or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of any one of claims 51-60 or combinations thereof in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

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