Compounds and methods for affecting BCL11 genes

Abstract

Disclosed are compounds and pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof that can be used to affect BCL11 activity in a subject, including methods of making the disclosed compounds. Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier, as well as kits comprising the disclosed compounds or pharmaceutical compositions and, optionally, one or more additional therapeutic agents. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

Description

Attorney Docket No. 331904-2020COMPOUNDSAND METHODS FOR AFFECTING BCL11 GENESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of and priority to U.S. Provisional Application No.63 / 746,469, filed on January 17, 2025 which is incorporated herein by reference in its entirety.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.

[0003] Alterations in the expression of B-cell leukemia / lymphoma 11 transcription factors A and B (BCL11A and BCL11 B) have been associated with a variety of diseases and disorders. For example, altered expression of the BCL11 B gene has been associated with hematological cancers and altered expression of the BCL11A gene has been associated with disorders such as breast cancer, lung cancer, and lymphoid cancers.

[0004] 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, but not limited to, transcription factors and chimeric fusion oncoproteins.

[0005] Despite advances in the understanding and physiology of BCL11 genes, there is still a scarcity of compounds that are both potent, efficacious, and selective inhibitors of the activity of BCL11 genes and also effective in the treatment of disorders associated with BCL11 activity and diseases in which BCL11 is involved. These needs and other needs are satisfied by the present invention.SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds such as such as 3-(1-oxoisoquinolin-2(1 H)-yl)piperidine-2, 6-dione analogs, 3-(4-oxobenzo[d][1 , 2, 3]triazin-3(4H)-yl)piperidine-2 , 6-dione analogs, substituted 3-(4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione analogs, and 3-(1-Attorney Docket No. 331904-2020 oxophthalazin-2(1H)-yl)piperidine-2, 6-dione analogs. The disclosed compounds can affect BCL11 activity via targeted degradation in a subject or target cell. Also, methods of making same, pharmaceutical compositions comprising same, kits comprising the same, and methods of treating disorders associated with BCL11 dysfunction, cereblon dysfunction, and / or uncontrolled cellular proliferation using same. In various further aspects, the disclosed compounds can act to selectively modulate the degradation of BCL11 protein, i.e., the disclosed compounds can act as BCL11 degraders.

[0007] Disclosed are compounds (or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof) having a structure represented by a formula:wherein G can be N or OR10, wherein R10can be hydrogen or an alkyl; wherein J can be N or CH; and wherein R1can be hydrogen or an alkyl. R2can have a structure represented by a formula:wherein x is an integer selected from 1, 2, and 3; wherein L is N or c; wherein R3acan be an aryl and R3bcan be hydrogen or R3aand R3bcan be covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused cycloalkyl; and wherein R3ccan be hydrogen, an alkyl, nitrile, or hydroxy. R5can be an alkyl. M, R4a, and R4bcan be characterized by one of the following:a) M can be N or CR4d, wherein R4dcan be hydrogen, an alkyl, nitrile, or hydroxy; R4acan be hydrogen or an alkyl; and R4bcan be an aryl, a heteroaryl, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an amine, or a fused biaryl; orb) M can be CR4d; R4acan be hydrogen or an alkyl; and R4band R4dcan be covalently bonded and, together with the intermediate carbon, form a four-membered to eight-membered spirocycloalkyl or spiro-heterocycloalkyl.

[0008] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more disclosed compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.Attorney Docket No. 331904-2020

[0009] Also disclosed are methods for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition.

[0010] Also disclosed are methods for inhibiting of BCL11 activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound or at least one disclosed pharmaceutical composition.

[0011] Also disclosed are methods for modulating of cereblon activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound or pharmaceutically acceptable salt thereof.

[0012] Also disclosed are uses of a disclosed compound in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

[0013] Also disclosed are kits comprising at least one disclosed compound or at least one disclosed pharmaceutical composition and one or more of: (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 BCL11 activity; (d) at least one agent known to decrease BCL11 activity; (e) at least one agent known to treat a disorder associated with cereblon activity; (f) at least one agent known to treat a disorder associated with BCL11 activity; (g) at least one agent known to treat a disease of uncontrolled cellular proliferation; or (h) instructions for treating a disorder associated with a BCL11 dysfunction.

[0014] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof; a disclosed product of making, or a pharmaceutically acceptable salt thereof; or a disclosed pharmaceutical composition.

[0015] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a cereblon protein dysfunction in a mammal.

[0016] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a BCL11 dysfunction in a mammal.

[0017] Also disclosed are uses of a disclosed compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a cellular proliferation dysfunction in a mammal, e.g., to inhibit cellular proliferation in a cancer cell, in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0018] Also disclosed are methods for the manufacture of a medicament to modulate the cereblonAttorney Docket No. 331904-2020 protein in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0019] Also disclosed are methods for the manufacture of a medicament to modulate the degradation of BCL11 in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0020] Also disclosed are methods for the manufacture of a medicament to inhibit cellular proliferation, e.g., to inhibit cellular proliferation in a cancer cell, in a mammal comprising combining at least one disclosed compound, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0021] 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. 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.DETAILED DESCRIPTION

[0022] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the 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.

[0023] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0024] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other severalAttorney Docket No. 331904-2020 embodiments without departing from the scope or spirit of the present disclosure.

[0025] 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.

[0026] All publications and patents cited in this specification are cited to disclose and describe the methods and / or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by references as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials described in the cited publications and patents and does not extend to any lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

[0027] 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.

[0028] 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.Attorney Docket No. 331904-2020

[0029] Aspects of the present disclosure will employ, unless otherwise indicated, techniques of molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, blood vessel biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0030] 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.A. Definitions

[0031] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0032] 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.

[0033] 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 “an agent,” “a carrier,” or “a disorder,” include, but are not limited to, two or more such agents, carriers, or disorders, including combinations of agents, carriers, or disorders, and the like.

[0034] Reference to "a / an" chemical compound refers to one or more molecules of the chemical compound rather than being limited to a single molecule of the chemical compound. Furthermore, the one or more molecules may or may not be identical, so long as they fall under the category of the chemical compound.

[0035] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values areAttorney Docket No. 331904-2020 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.

[0036] Where a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. 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. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’ , and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0037] 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.

[0038] 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 inAttorney Docket No. 331904-2020 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.

[0039] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0040] As used herein, “cereblon” and “CRBN” can be used interchangeably, and refer to a protein encoded by the CRBN gene in humans with a cytogenetic location of 3p26.2 and a molecular location of base pairs 3,148,489 to 3,179,716 on chromosome 3 (UCSC Genome Browser on Human Dec.2013 (GRCh38 / hg38) Assembly). The gene structure in humans comprises 11 exons. CRBN is a substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The DCX (DDB1-CUL4-X-box) E3 protein ligase complex is composed at least of CRBN, CUL4A, DDB1, and RBX1. The CRBN protein has two isoforms produced by alternative splicing: Isoform 1 has 442 amino acids and a molecular weight of 50,546 Da; and Isoform 2 has 441 amino acids and a molecular weight of 50,475 Da.

[0041] As used herein, “BCL11” and“B-cell leukemia / lymphoma 11” can be used interchangeably, and refer to a protein encoded by the CRBN BCL11A and BCL11B genes in humans with a cytogenetic location of 2p16.1 and 14p32.2, respectively, and a molecular location of base pairs 60,457,194 to 60,553,654 on chromosome 2 and base pairs 99,635,624 to 99,738,534 on chromosome 14, respectively (UCSC Genome Browser on Human Dec. 2013 (GRCh38 / hg38) Assembly). The BCL11A protein has 835 amino acids with a molecular weight of 91,197 Da, whereas the BCL11B protein has 894 amino acids with a molecular weight of 95,519 Da.

[0042] 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,Attorney Docket No. 331904-2020 intranasal, intracardiac, intraarticular, intracavernous, 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, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0043] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (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, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, andAttorney Docket No. 331904-2020 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 singlestranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0044] 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.

[0045] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0046] As used herein, “attached” can refer to covalent or non-covalent interaction between two orAttorney Docket No. 331904-2020 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, a halogen bonding, electromagnetic interactions, TT-TT interactions, cation-TT interactions, anion-n interactions, polar TT-interactions, and hydrophobic effects.

[0047] 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, nonhuman 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 to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0048] 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 cancer, a disorder or disease associate with uncontrolled cellular proliferation, and / or a disorder or disease associate with BCL11 dysfunction. 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 cancer, a disorder or disease associate with uncontrolled cellular proliferation, and / or a disorder or disease associate with BCL11 dysfunction 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.

[0049] 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 / orAttorney Docket No. 331904-2020 a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0050] 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

[0051] 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.

[0052] 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.

[0053] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeuticAttorney Docket No. 331904-2020 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.

[0054] 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.

[0055] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0056] 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.

[0057] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, / .e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0058] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure 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 ofAttorney Docket No. 331904-2020 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.

[0059] 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 C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0060] The term “pharmaceutically acceptable amide” refers to non-toxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic 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 acidAttorney Docket No. 331904-2020 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.

[0061] 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 fortheir 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).

[0062] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0063] 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.

[0064] 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-lngold-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.).Attorney Docket No. 331904-2020

[0065] In some aspects, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:wherein n is typically an integer. That is, R" is understood to represent five independent substituents, Rn<aRn<b>, Rn<c>, Rn<d>, and R',(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

[0066] 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, f-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0067] 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 groupAttorney Docket No. 331904-2020 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.

[0068] 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.

[0069] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0070] 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.

[0071] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including,Attorney Docket No. 331904-2020 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.

[0072] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0073] 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.

[0074] 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.

[0075] 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,” “bicyclicAttorney Docket No. 331904-2020 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.

[0076] 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.

[0077] 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 asAttorney Docket No. 331904-2020 described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[cf]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0078] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl functional group, i.e., C=O.

[0079] The term “carbonyl” as used herein can refer to a carbonyl functional group C(O) or can be represented by the formula — C(O)A1where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0080] The term “sulfonyl” as used herein is represented by the formula — S(O)(O)A1where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0081] 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.

[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.

[0083] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula — OH.

[0084] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0085] The terms “amine” or “amino” as used herein are represented by the formula — NAW, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0086] The term “arylamino” specifically refers to an amino group that is substituted with one or more aryl groups.

[0087] It is understood, that unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0088] Described herein are compounds that have therapeutic or clinical utility. Also described herein are methods of synthesizing the compounds. Also described herein are methods ofAttorney Docket No. 331904-2020 administering the compounds, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, to a subject in need thereof. In some aspects, the subject can have a need for treatment of a disease or disorder associate with BCL11 dysfunction and / or uncontrolled cellular proliferation. 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. Abbreviations

[0089] BCL11 B-cell leukemia / lymphoma 11

[0090] BCL11A BCL11 transcription factor A

[0091] BCL11B BCL11 transcription factor BC. Compounds.

[0092] In one aspect, disclosed herein are compounds that can affect BCL11 activity, e.g., via targeted protein degradation. In another aspect, the disclosed compounds and / or the products of the disclosed methods of making can affect BCL11 activity. In another aspect, the disclosed compounds and / or the products of the disclosed methods of making can be used in the treatment of a cancer, a disorder or disease associate with uncontrolled cellular proliferation, and / or a disorder or disease associate with BCL11 dysfunction.

[0093] In one aspect, the disclosed compounds have a structure represented by a formula (or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof):where G can be N or CR10, where R10can be hydrogen or an alkyl; J can be N or CH; and R1can be hydrogen or an alkyl. R2can have a structure represented by a formula:where x can be an integer selected from 1 , 2, and 3; L can be N or C; and R3acan be an aryl and R3bcan be hydrogen or R3aand R3bcan be covalently bonded and, together with the bridgeheadAttorney Docket No. 331904-2020 carbons, form a five-membered to eight-membered fused cycloalkyl. R3ccan be hydrogen, an alkyl, nitrile, or hydroxy. R5can be an alkyl. M, R4a, and R4bcan be characterized by one of the following:a) M can be N or CR4d, wherein R4dcan be hydrogen, an alkyl, nitrile, or hydroxy;R4acan be hydrogen or an alkyl; and R4bcan be an aryl, a heteroaryl, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an amine, or a fused biaryl; or b) M can be CR4d; R4acan be hydrogen or an alkyl; and R4band R4dcan be covalently bonded and, together with the intermediate carbon, form a fourmembered to eight-membered spiro-cycloalkyl or spiro-heterocycloalkyl.

[0094] In another aspect, R1can be hydrogen, a C1-C6 acyclic alkyl, or a C1-C4 acyclic alkyl. In another aspect, R10can be a C1-C6 acylic alkyl or a C1-C4 acyclic alkyl.

[0095] In another aspect, R3acan be a C5-C8 aryl (e.g., phenyl) substituted with at least one of a halogen, an alkoxy group, CF3, or OCF3. In another aspect, R3aand R3bcan be covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused heterocycloalkyl substituted with at least one of hydrogen, a C5-C6 heteroaryl, a halogen, CF3, or OCF3.

[0096] In another aspect, M can be N or CR4d, where R4dcan be hydrogen, an alkyl, nitrile, or hydroxy; where R4acan be hydrogen or an alkyl; and where R4bcan be characterized by one of the following:a) R4bcan be a C1-C6 acyclic alkyl, a heterocycloalkyl, — NHR41, or a fused biaryl comprising two C5-C6 aryl rings; where R41is an aryl;b) R4bcan have a structure represented by a formula:where at least one of Za, Zb, Zc, Zd, Zecan be nitrogen and the remainder of Za, Zb, Zc, Zd, and Zecan be, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e;where each of R20a, R20b, R20c, R20d, and R20ecan be independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3; orc) R4bcan have a structure represented by a formula:Attorney Docket No. 331904-2020where each of R20a, R20b, R20c, R20d, and R20ecan be independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3.

[0097] In another aspect, R4bcan be a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, — NHR41, or a fused biaryl comprising two C5-C6 aryl rings; where R41can be a C5-C6 aryl; and where R41can be substituted with hydrogen, a halogen, OCF3, or CF3. In another aspect, R4bcan be a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, or a fused biaryl comprising two C5-C6 aryl rings. In a further aspect, R4bcan be substituted with hydrogen, a C1-C6 acyclic alkyl, a C5-C6 aryl, or a C5-C6 heteroaryl comprising at least one nitrogen heteroatom.

[0098] In another aspect, one of or two of Za, Zb, Zc, Zd, and Zecan be nitrogen and the remainder of Za, Zb, Zc, Zd, and Zecan be, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e.

[0099] In another aspect, each of R20a, R20b, R20°, R20d, and R20ecan be independently selected from hydrogen, a C1-C6 alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, a C5-C6 heterocyloalkenyl comprising at least one nitrogen heteroatom, a C5-C6 heteroaryl comprising at least one nitrogen heteroatom, a C1-C6 alkoxy, — C(O)OR21, — S(O)(O)R22, — NHR23, — C(O)R27, aldehyde, a halogen, OCF3, and CF3; where R21can be a C1-C6 acyclic alkyl; R22can be a C1-C6 acyclic alkyl; R23can be hydrogen or a C5-C6 aryl substituted with at least one of hydrogen, a halogen, CF3, or OCF3; and R27can be a heterocycloalkyl comprising at least one nitrogen heteroatom. In a further aspect, one of R20a, R20b, R20c, R20d, and R20ecan be a C1-C3 alkyl substituted with hydroxy, pyrollidine, piperadine, piperazine, morpholine, imidazole, pyrazole, or — NR24R25and the remainder of R20a, R20b, R20c, R20d, and R20ecan be hydrogen (where any one of the pyrollidine, piperadine, piperazine, morpholine, imidazole, or pyrazole can be further substituted, such as N-methylpiperazine); where R24and R25can be independently selected from hydrogen and a C1-C4 acylic alkyl. In another aspect, R20a, R20b, R20c, R20d, and R20ecan be piperidine, piperazine, morpholine, unsaturated piperidine, or pyridine and the remainder of R20a, R20b, R20c, R20d, and R20ecan be hydrogen. In another aspect, the substituent of R20a, R20b, R20c, R20d, and R20ethat is not hydrogen can be further substituted with hydrogen, a C1-C6 acyclic alkyl, — C(O)OR26, or nitrile; where R26is hydrogen or a C1-C6 acyclic alkyl.

[0100] In another aspect, M can be CR4d; where R4acan be hydrogen or alkyl; and where R4bandAttorney Docket No. 331904-2020 R4dcan be covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl. In another aspect, M can be CR4d; where R4acan be hydrogen or alkyl; and where R4band R4dcan be covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl comprising at least one nitrogen heteroatom, at least one oxygen heteroatom, or a combination thereof. In a further aspect, the four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl formed from R4band R4dcan be substituted with at least one of hydrogen, a C5-C6 heteroaryl, or — NHR44; where R44can be a C5-C6 heteroaryl, optionally comprising at least one nitrogen heteroatom, substituted with at least one of hydrogen, a halogen, CF3, or OCF3.

[0101] In another aspect, R4acan be a C1-C6 alkyl, optionally substituted with hydrogen or hydroxy. In another aspect, R4dcan be a C1-C6 alkyl or a C1-C4 alkyl, either optionally substituted with nitrile.

[0102] In another aspect, R2can be — NHR5, where R5can be an alkyl group substituted with an alkyl or a heterocycloalkyl comprising at least one nitrogen heteroatom. In a further aspect, R5can be an alkyl substituted with a C5-C8 heterocycloalkyl comprising at least one nitrogen heteroatom, where the C5-C8 heterocycloalkyl is optionally further substitutes with an alkyl or an aryl (e.g., phenyl).

[0103] In another aspect, the compound disclosed herein can have a structure represented by any one of the following formulas (or a pharmaceutically acceptable salt, hydrate, solvate, or polymorphAttorney Docket No. 331904-2020Attorney Docket No. 331904-2020Zb, Zc, Zd, and Ze) can represent various elements, functional groups, and / or compounds as disclosed previously.

[0104] In various aspects, it is contemplated herein that the disclosed compounds further comprise their biosteric 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. thia, (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-lnterscience; 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. UnsererZeit 1998, 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”, Cure Med. Chem. 1998, 5, 493-512 (x) Thornber C W, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev. 1979, 8, 563-80.

[0105] 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 replacementAttorney Docket No. 331904-2020 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 embodiment, 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, [1 ,2,4]triazolyl, or an optionally substituted [1,2,4]oxadiazolyl.

[0106] In various aspects, it is contemplated herein that the disclosed compounds further comprise their isotopically-labelled 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 invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of the present invention 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.

[0107] In various aspects, the disclosed compounds can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The stereoisomers can be present in the mixtures in any arbitrary proportions. In some aspects, provided this is possible, the disclosed compounds can be present in the form of the tautomers.

[0108] Thus, methods which are known per se can be used, for example, to separate the disclosed compounds which possess one or more chiral centers and occur as racemates into their optical isomers, i.e., enantiomers or diastereomers. The separation can be effected by means of column separation on chiral phases or by means of recrystallization from an optically active solvent or usingAttorney Docket No. 331904-2020 an optically active acid or base or by means of derivatizing with an optically active reagent, such as an optically active alcohol, and subsequently cleaving off the residue.

[0109] In various aspects, the disclosed compounds can be in the form of a co-crystal. The term “cocrystal” 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.

[0110] 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.

[0111] 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 invention to form solvates and hydrates.

[0112] 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.

[0113] 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, sulphuric 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,Attorney Docket No. 331904-2020 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, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinate, 2-naphthalenesulfonate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Also, basic nitrogen-containing groups can be quatemized 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.

[0114] 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, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may be used 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, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.D. Methods of Making the Compounds.

[0115] In one aspect, the disclosure relates to methods of making compounds that can affect BCL11 activity, which can be useful in the treatment of various disorders, such as disorders of uncontrolled proliferation.Attorney Docket No. 331904-2020

[0116] The compounds of the present disclosure can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0117] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, in addition to other standard manipulations known in the literature or to one skilled in the art. The following examples are provided so that the disclosure might be more fully understood, are illustrative only, and should not be construed as limiting. Compounds are represented in a generic form, with substituents as noted in compound descriptions elsewhere herein, unless indicated otherwise. More specific examples are set forth in the Examples section.

[0118] In one 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.

[0119] In one aspect, compounds of the present disclosure, e.g., compounds of Formula 4A, can be prepared generically as illustrated below.Procedure 1A

[0120] For Procedure 1A, X can be a halogen selected from F, Cl, and Br.

[0121] For Step 1, compounds of Formula 1 and compounds of Formula 2 can be reacted to yield compounds of Formula 3. Briefly, to a mixture comprising a compound of Formula 1, a compound of Formula 2, and a suitable solvent (e.g., DMF), the following is added: suitable coupling agents (e.g., EDCI and HOBt) and a suitable base (e.g., DIEA). The mixture is stirred at a suitable temperature (e.g., 25 °C) for a suitable period of time (e.g., 10 hours). The resulting mixture is poured into water, extracted with a suitable extracting solvent (e.g., ethyl acetate), filtered, and concentrated to give a residue. The residue is titrated with a suitable solvent (e.g., ethyl acetate), filtered, and concentratedAttorney Docket No. 331904-2020 to give a compound of Formula 3.

[0122] For Step 2, compounds of Formula 3 can be treated to yield compounds of Formula 4A. Briefly, to a mixture comprising a compound of Formula 3 and a suitable solvent (e.g., acetic acid), a suitable nitrite (e.g., NaNO2) is added. The mixture is stirred at a suitable temperature (e.g., 25 °C) for a suitable period of time (e.g., 10 hours). The resulting mixture is poured, filtered, and concentrated to give a compound of Formula 4A.

[0123] In another aspect, compounds of the present disclosure, e.g., compounds of Formula 4B, can be prepared generically as illustrated below.Procedure 1B

[0124] For Procedure 1B, X can be a halogen selected from F, Cl, and Br.

[0125] For Step 1 , compounds of Formula 5 can be treated to yield compounds of Formula 6. Briefly, to a mixture comprising a compound of Formula 5 and a suitable solvent (e.g., ethanol), NH2NH2.H2O is added. The mixture is heated to a suitable temperature (e.g., 75 °C) and stirred for a suitable period of time (e.g., 2 hours). The resulting mixture is then allowed to cool to a suitable temperature (e.g., to room temperature). The resulting precipitate is collected by filtration (e.g., vacuum filtration), washed, and dried (e.g., using a vacuum) to yield a compound of Formula 6.

[0126] For Step 2, compounds of Formula 6 and compounds of Formula 7 can be reacted to yield compounds of Formula 4B. Briefly, to a mixture comprising a compound of Formula 6 and a suitable solvent (e.g., DMF), a suitable base (e.g., tert-BuONa) is added. The mixture is stirred at a suitable temperature (e.g., 0 °C) for a suitable period of time (e.g., 30 minutes). After stirring, a compound of Formula 7 is added to the mixture. The mixture is stirred for a suitable period of time (e.g., 10 to 13 hours) at a suitable temperature (e.g., room temperature). The resulting mixture is concentrated under a reduced pressure, purified, and further concentrated to yield a compound of Formula 4B.

[0127] In another aspect, compounds of the present disclosure, e.g., compounds of Formula 4C, can be prepared generically as illustrated below.Attorney Docket No. 331904-2020Procedure 1C

[0128] For Procedure 1 C, X can be a halogen selected from F, Cl, and Br.

[0129] Compounds of Formula 8 and compounds of Formula 9 can be reacted to yield compounds of Formula 4C. Briefly, to a mixture comprising a compound of Formula 8 and a suitable solvent (e.g., DMF) a suitable base (e.g., NaH) is added. The mixture is stirred at a suitable temperature (e.g., 25 °C) for a suitable period of time (e.g., 10 minutes to 1 hour). A compound of Formula 9 is then added to the resulting mixture. The new mixture is then stirred at a suitable temperature (e.g., 25 °C) for a suitable period of time (e.g., 2 hours). The resulting mixture is then quenched, extracted, and concentrated under a reduced pressure. The concentrate is then purified and further concentrated to yield a compound of Formula 4C.

[0130] In another aspect, compounds of the present disclosure, e.g., compounds of Formula A2, can be prepared generically as illustrated below.A1 A2 A3Procedure A

[0131] For Formula A1, X can be selected from F and Br. In another aspect, for Formula A1, X can be F when G is N and X can be Br when G is OR10. R2can have a structure represented by a formula:

[0132] Compounds of Formula A1 and compounds of Formula A2 can be reacted to yield compounds of Formula A3. Briefly, to a mixture comprising a compound of Formula A1 and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula A2 and a suitable base (e.g., DIPEA). The mixture is heated to a suitable temperature (e.g., 90 °C) and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is then filtered, purified, and concentrated to give a compound of Formula A3.

[0133] A specific example of Procedure A is provided below.Attorney Docket No. 331904-2020

[0134] In another aspect, compounds of the present disclosure, e.g., compounds of Formula B4, can be prepared generically as illustrated below.

[0135] In Procedure B, RB1can be an amine, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycloalkyl. R2has a structure represented by a formula:In Formula B2, R2is attached to the rest of the structure either at position 4 (labeled above) in place of R4b, is attached to the fused cycloalkyl formed from R3aand R3b, or is attached to the spirocycloalkyl or spiro-heterocycloalkyl formed from R4aand R4b. In Formula B2, the nitrogen at position 1 (labeled above) is attached to a hydrogen. In Formula B3, RB1is attached to R2at position 4 in place of R4b, is attached to the fused cycloalkyl formed from R3aand R3b, or is attached to the spirocycloalkyl or spiro-heterocycloalkyl formed from R4aand R4b. In Step 2, Formula A1 attaches to R2of Formula B3 at position 1 to form Formula B4.

[0136] For Step 1 , compounds of Formula B1 and compounds of Formula B2 can be reacted to yield compounds of Formula B3. Briefly, to a mixture comprising a compound of Formula B1 and a suitable solvent (e.g., toluene), the following is added: a compound of Formula B2, a suitable ligand (e.g., BINAP), a suitable catalyst (e.g., Pd2(dba)a), and a suitable base (e.g., tert-BuONa). The mixture is heated to reflux and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is filtered, washed, and concentrated. The concentrate is mixed with a suitable solvent (e.g., DCM) and a suitable catalyst (e.g., TFA). The resulting mixture is stirred for a suitable period of time (e.g., 1 hour). The resulting mixture is then concentrated to give a compound of Formula B3.Attorney Docket No. 331904-2020

[0137] For Step 2, compounds of Formula B3 and compounds of Formula 4H can be reacted to yield compounds of Formula B4. Briefly, to a mixture comprising a compound of Formula 4H and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula B3 and a suitable base (e.g., DIPEA). The mixture is heated to a suitable temperature (e.g., 90 °C) and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is then filtered, purified, and concentrated to give a compound of Formula B4.

[0138] A specific example of Procedure B is provided below.

[0139] In another aspect, compounds of the present disclosure, e.g., compounds of Formula C4, can be prepared generically as illustrated below.Procedure C

[0140] For Step 1 , compounds of Formula A1 and compounds of Formula C1 can be reacted to yield compounds of Formula C2. Briefly, to a mixture comprising a compound of Formula A1 and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula C1 and a suitable base (e.g., DIPEA). The mixture is heated to a suitable temperature (e.g., 90 °C) and stirred for a suitable periodAttorney Docket No. 331904-2020 of time (e.g., 5 hours to 20 hours). The resulting mixture is then quenched with water and extracted. The extract is then dried over a suitable drying agent (e.g., Na2SC>4), filtered, and concentrated. The concentrate is mixed with a suitable solvent (e.g., DCM) and a suitable catalyst (e.g., TFA). The resulting mixture is stirred at a suitable temperature (e.g., room temperature) fora suitable period of time (e.g., 2 hours). The resulting mixture is then concentrated to yield a compound of Formula C2.

[0141] For Step 2, compounds of Formula C2 and compounds of Formula C3 can be reacted to yield compounds of Formula C4. Briefly, to a mixture comprising a compound of Formula C2 and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula C3 and a suitable base (e.g., DI PEA). The mixture is heated to a suitable temperature (e.g., 100 °C) and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is then filtered and washed with a suitable solvent (e.g., DMSO). The washed product is then purified and concentrated to yield a compound of Formula C4.

[0142] A specific example of Procedure C is provided below.

[0143] In another aspect, compounds of the present disclosure, e.g., compounds of Formula D4, can be prepared generically as illustrated below.Attorney Docket No. 331904-2020Procedure D

[0144] For Step 1 , compounds of Formula D1 and compounds of Formula D2 can be reacted to yield compounds of Formula D3. Briefly, a compound of Formula D1 is mixed with a compound of Formula D2, a suitable catalyst (e.g., PdCh), a suitable base (e.g., CS2CO3), a suitable solvent (e.g., DME), and water. The mixture is sealed and heated (e.g., using a microwave) to a suitable temperature (e.g., 85 °C) for a suitable period of time (e.g., 2 hours). The resulting mixture is then filtered and washed. The filtrate is then concentration to yield a compound of Formula D3.

[0145] For Step 2, compounds of Formula D3 and compounds of Formula A1 can be reacted to yield compounds of Formula D4. Briefly, to a mixture comprising a compound of Formula A1 and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula D3 and a suitable base (e.g., DIPEA). The mixture is heated to a suitable temperature (e.g., 90 °C) and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is then filtered, purified, and concentrated to give compounds of Formula D4.

[0146] A specific example of Procedure D is provided below.Attorney Docket No. 331904-2020

[0147] In another aspect, compounds of the present disclosure, e.g., compounds of Formula E2, can be prepared generically as illustrated below.Procedure E

[0148] Compounds of Formula E1 and compounds of Formula D3 can be reacted to yield compounds of Formula E2. Briefly, to a mixture comprising a compound of Formula E1 and a suitable solvent (e.g., NMP), the following is added: a compound of Formula D3 and a suitable base (e.g., DIEA). The mixture is heated to a suitable temperature (e.g., 130 °C) and stirred for a suitable period of time (e.g., 5 hours). The resulting mixture is concentrated under reduced pressure, purified, and further concentrated to yield a compound of Formula E2.

[0149] A specific example of Procedure E is provided below.

[0150] In another aspect, compounds of the present disclosure, e.g., compounds of Formula F2, can be prepared generically as illustrated below.Attorney Docket No. 331904-2020Procedure F

[0151] Compounds of Formula F1 and compounds of Formula D3 can be reacted to yield compounds of Formula F2. Briefly, a mixture comprising a compound of Formula F1 , a suitable base (e.g., tert-BuONa), a suitable precatalyst (e.g., P(tert-Bu)3-Pd-G4), and a suitable solvent (e.g., dioxane) is degassed and purged with a suitable gas (e.g., N2) for a suitable number of times (e.g., 3 times). A compound of Formula D3 is then added to the mixture. The mixture is then stirred at a suitable temperature (e.g., 80 °C) for a suitable period of time (e.g., 2 hours) under an inert atmosphere (e.g., N2atmosphere). The resulting mixture is then filtered and concentrated under a reduced pressure. The resulting concentrate is then purified and further concentrated to yield a compounds of Formula F2.

[0152] A specific example of Procedure F is provided below.

[0153] In another aspect, compounds of the present disclosure, e.g., compounds of Formula G4, can be prepared generically as illustrated below.Attorney Docket No. 331904-2020

[0154] In procedure G, R410can be hydrogen, a halogen, OCF3, orCF3.

[0155] For Step 1, compounds of Formula A1 and compounds of Formula G1 can be reacted to yield compounds of Formula G2. Briefly, to a mixture comprising a compound of Formula A1 and a suitable solvent (e.g., DMSO), the following is added: a compound of Formula G1 and a suitable base (e.g., DIPEA). The mixture is heated to a suitable temperature (e.g., 90 °C) and stirred for a suitable period of time (e.g., 5 hours to 20 hours). The resulting mixture is then filtered, purified, and concentrated to give a compound of Formula G2.

[0156] For Step 2, compounds of Formula G2 and compounds of Formula G3 can be reacted to yield compounds of Formula G4. Briefly, to a mixture comprising a compound of Formula G2 and a suitable solvent (e.g., methanol), the following is added: a compound of Formula G3, a suitable reducing agent (e.g., sodium cyanoborohydride), and a suitable acid (e.g., acetic acid). The mixture is heated to a suitable temperature (e.g., 50 °C) and stirred for a suitable period of time (e.g., 2 hours). The resulting mixture is filtered and washed. The filtrate is concentrated, mixed with a suitable solvent (e.g., DMSO), and purified. The purified mixture is then further concentrated to yield a compound of Formula G4.

[0157] A specific example of Procedure G is provided below.

[0158] In another aspect, compounds of the present disclosure, e.g., compounds of Formula J3, can be prepared generically as illustrated below.Procedure J

[0159] In Procedure J, R410can be hydrogen, a halogen, OCF3, or CF3. Variable ml can be an integer from 0 to 23.Attorney Docket No. 331904-2020

[0160] Compounds of Formula J 1 and compounds of Formula J2 can be reacted to yield compounds of Formula J3. Briefly, to a mixture comprising a compound of Formula J1 and a suitable solvent (e.g., methanol), the following is added: a compound of Formula J2, a suitable reducing agent (e.g., sodium cyanoborohydride), and a suitable acid (e.g., acetic acid). The mixture is heated to a suitable temperature (e.g., 50 °C) and stirred fora suitable period of time (e.g., 2 hours). The resulting mixture is filtered and washed. The filtrate is concentrated, mixed with a suitable solvent (e.g., DMSO), and purified. The purified mixture is then further concentrated to yield a compound of Formula J3.

[0161] A specific example of Procedure J is provided below.

[0162] In another aspect, compounds of the present disclosure, e.g., compounds of Formula K3, can be prepared generically as illustrated below.Procedure K

[0163] In Procedure K, R20can be — NHR41, a heterocycloalkenyl, an aryl, or a heteroaryl.

[0164] Compounds of Formula K1 and compounds of Formula K2 can be reacted to yield compounds of Formula K3. Briefly, a compound of Formula K1 is mixed with a compound of Formula K2, a suitable precatalyst (BrettPhos-Pd-G3), a suitable base (e.g., cesium carbonate), and a suitable solvent (e.g., dioxane). The mixture is stirred at a suitable temperature (e.g., 90 °C) for a suitable period of time (e.g., 12 hours) under an inert atmosphere (e.g., N2atmosphere). The resulting mixture is then concentrated under a reduced pressure, purified, and further concentrated to yield a compound of Formula K3.

[0165] A specific example of Procedure K is provided below.

[0166] In another aspect, compounds of the present disclosure, e.g., compounds of Formula L2, can be prepared generically as illustrated below.Attorney Docket No. 331904-2020L1 D3 L2Procedure L

[0167] Compounds of Formula L1 and compounds of Formula D3 can be reacted to yield compounds of Formula L2. Briefly, a compound of Formula L1 is mixed with a compound of Formula D3, a suitable precatalyst (e.g., RuPhos-Pd-G3), a suitable base (e.g., cesium carbonate), and a suitable solvent (e.g., dioxane). The mixture is stirred at a suitable temperature (e.g., 90 °C) for a suitable period of time (e.g., 12 hours) under an inert atmosphere (e.g., N2 atomosphere). The resulting mixture is then concentrated under a reduced pressure, purified, and further concentrated to yield a compound of Formula L2.

[0168] A specific example of Procedure L is provided below.

[0169] Compounds used in the various synthesis procedures outlined above 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 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 Supplementals (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).E. Pharmaceutical Compositions.

[0170] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of aAttorney Docket No. 331904-2020 disclosed method, or a pharmaceutically acceptable salt thereof. 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.

[0171] 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. 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. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially and intratumorally.

[0172] 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.

[0173] 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.

[0174] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable nontoxic 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-Attorney Docket No. 331904-2020 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.

[0175] 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, preferably 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.

[0176] 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, i.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, / V-methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine,Attorney Docket No. 331904-2020 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.

[0177] 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 an 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 the corresponding 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.

[0178] 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 acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0179] 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, theAttorney Docket No. 331904-2020 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 and intimately 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.

[0180] 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.

[0181] 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.

[0182] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics,Attorney Docket No. 331904-2020 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.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilberts. Banker, Christopher T. Rhodes, Eds.).

[0183] 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.

[0184] 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, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0185] 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 additivesAttorney Docket No. 331904-2020 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 C1-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.

[0186] Other auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium 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; maleicAttorney Docket No. 331904-2020 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.

[0187] 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-, triethylcitrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), 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, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates such as Polysorbar 50); sorbitan monooleate.

[0188] 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, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0189] In various aspects, a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn 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.

[0190] 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.

[0191] Tablets may contain the active ingredient in admixture with non-toxic pharmaceuticallyAttorney Docket No. 331904-2020 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.

[0192] 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.

[0193] 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 coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid-methacrylic 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.

[0194] 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.

[0195] 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 dosageAttorney Docket No. 331904-2020 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.

[0196] 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, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulphoxide, triglycerides and the like.

[0197] 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 C1-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.

[0198] 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, polyoxyethylated 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. Polyoxyethylated 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, corn oil. See also Dr.Attorney Docket No. 331904-2020 H. P. Fiedler “Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191-195.

[0199] 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 are: chelate formers such as ethylene diamine tetraacetic acid, nitrilotriacetic acid, diethylene triamine pentaacetic acid and their salts.

[0200] 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).

[0201] 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-, - or y-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-p-cyclodextrin or sulfobutyl-p-cyclodextrin. Also cosolvents such as alcohols may improve the solubility and / or the stability of the compounds according to the present disclosure in pharmaceutical compositions.

[0202] 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.

[0203] 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.

[0204] 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 some 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, polyol (e.g., glycerol, propylene glycolAttorney Docket No. 331904-2020 and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0205] 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 some 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.

[0206] 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.

[0207] 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.

[0208] 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 isAttorney Docket No. 331904-2020 detailed herein below, the compositions of the present invention 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.

[0209] 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.

[0210] 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. Emulsion ointment 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.

[0211] 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 produceAttorney Docket No. 331904-2020 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.

[0212] 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.

[0213] 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.

[0214] 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, i.e. , gelling agents, are crosslinked acrylic acid polymers such as the family 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.

[0215] 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.

[0216] Foam compositions are typically formulated in a single or multiple phase liquid form andAttorney Docket No. 331904-2020 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 alkanol, 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.

[0217] 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 selfadhesiveness can alternatively be used. In both cases, a protective permeable 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.

[0218] Examples of patch configuration which can be utilized with the present invention 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-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.

[0219] 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 invention 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 invention 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, andAttorney Docket No. 331904-2020 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.

[0220] 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. Such 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 invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0221] Another patch system configuration which can be used by the present invention 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 invention 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.

[0222] 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.

[0223] 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.

[0224] 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 andAttorney Docket No. 331904-2020 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] In the treatment conditions which require of modulation of BCL11 or cereblon 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 / kgAttorney Docket No. 331904-2020 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.

[0229] 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.

[0230] 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 containing 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.

[0231] 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.

[0232] The present disclosure is further directed to a method for the manufacture of a medicament for modulating BCL11 activity (e.g., treatment of one or more disorders associated with BCL11 dysfunction, such as a cancer and / or a disorder of uncontrolled cellular proliferation) 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 oneAttorney Docket No. 331904-2020 disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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 a therapeutic agent known to affect cereblon activity, BCL11 activity, treat a disorder associated with cereblon activity or BCL11 activity, or treat a disease or disorder of uncontrolled cellular proliferation. 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 pharmaceuticallyAttorney Docket No. 331904-2020 acceptable carriers or diluents.F. Methods of Using the Compounds.

[0237] In a further aspect, 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. The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compounds disclosed herein or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound will be more efficacious than either as a single agent.1. Methods of T reatment

[0238] In one aspect, the compounds and pharmaceutical compositions disclosed herein are useful for treating, preventing, ameliorating, controlling, or reducing the risk of disorders of uncontrolled cellular proliferation in a subject. The method of treatment of such disorders can include the step of administering to a subject a therapeutically effective amount of at least one compound disclosed herein or administering to a subject a pharmaceutical composition as disclosed herein. The subject can be a mammal, such as a human. In one aspect, the method of treatment can further comprise identifying a subject in need of treatment of a disorder of uncontrolled cellular proliferation. In another aspect, the subject can be diagnosed with a need for treatment prior to the administering step.

[0239] In a further aspect, the disorder of uncontrolled cellular proliferation can be associated with BCL11 dysfunction. The BCL11 dysfunction can be a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof. In another aspect, the disorder can be associated with cereblon activity. In another aspect, the disorder can be a cancer. Examples of BCL11 mutations associated with cancer include BCL11B mutations in the DNA binding zinc finger C2H2-type domains (e.g., C2H2-2, C2H2-3, and / or C2H2-4 domains). Examples of cancer include, but are not limited to, a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma. In a further aspect, the disorder is a hematological cancer, such as chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acuteAttorney Docket No. 331904-2020 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, nonHodgkin lymphoma, or combinations thereof.

[0240] Also disclosed herein is a method for inhibiting BCL11 activity in a subject via targeted degradation of a BCL11 protein (e.g., BCL11A, BCL11B). The method can include the step of administering to the subject a therapeutically effective amount of at least one compound disclosed herein or administering to the subject a pharmaceutical composition disclosed herein. In one aspect, the subject is a mammal, such as a human. In one aspect, the method of inhibition can further comprise identifying a subject in need for inhibition of BCL11 activity. In another aspect, the subject can be diagnosed with a need for inhibition of BCL11 activity prior to the administering step.

[0241] Also disclosed herein is a method for modulating cereblon activity in a subject. The method can include the step of administering to the subject a therapeutically effective amount of at least one compound disclosed herein or administering to the subject a pharmaceutical composition disclosed herein. In one aspect, the subject is a mammal, such as a human. In one aspect, the method of inhibition can further comprise identifying a subject in need for modulating of cereblon activity. In another aspect, the subject can be diagnosed with a need for modulating of cereblon activity prior to the administering step.

[0242] Also disclosed herein is a method for inhibiting of BCL11 activity and / or modulating cereblon activity in at least one cell. The method can include the step of contacting the at least one cell with an effective amount of at least one compound disclosed herein or at least one pharmaceutical composition disclosed herein. The cell can be mammalian, such as human. In one aspect, the cell can be isolated from a subject prior to the contacting step. In another aspect, the contacting can be done via administration to a subject. In one aspect, the method of inhibiting and / or modulating can further comprise identifying a subject in need for inhibiting of BCL11 activity and / or modulating of cereblon activity. In another aspect, the subject can be diagnosed with a need for inhibiting of BCL11 activity and / or modulating of cereblon activity prior to the contacting step.

[0243] In a further aspect, contacting the at least one cell treats a disorder. The disorder can be a cancer. Examples of cancer include, but are not limited to, a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma. In a further aspect, the disorder is a hematological cancer, such as chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), acute lymphoidAttorney Docket No. 331904-2020 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, nonHodgkin lymphoma, or combinations thereof.2. Kits.

[0244] In a further aspect, the present disclosure relates to kits comprising at least one disclosed compound (including a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof) or at least one disclosed pharmaceutical composition and one or more of: (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 BCL11 activity; (d) at least one agent known to decrease BCL11 activity; (e) at least one agent known to treat a disorder associated with cereblon activity; (f) at least one agent known to treat a disorder associated with BCL11 activity; (g) at least one agent known to treat a disease of uncontrolled cellular proliferation; or (h) instructions for treating a disorder associated with a BCL11 dysfunction.

[0245] In one aspect, the agent known to affect (increase or decrease) BCL11 activity can affect BCL11A activity, BCL11B activity, or a combination thereof. In another aspects, the BCL11 dysfunction can be a BCL11A dysfunction, a BCL11B dysfunction, ora combination thereof.

[0246] In one aspect, the disorder associated with cereblon activity, the disorder associated with BCL11 activity, the disease of uncontrolled cellular proliferation, or a combination thereof can be a cancer. Examples of cancer include, but are not limited to, a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma. In a further aspect, the disorder is a hematological cancer, such as 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, nonHodgkin lymphoma, or combinations thereof.

[0247] In various aspects, the disclosed kits can also comprise compounds and / or products copackaged, 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.Attorney Docket No. 331904-2020

[0248] In another aspect, the kit can comprise a plurality of dosage forms of the compound or pharmaceutical composition, such as an oral dosage form, a parenteral injection form, or an intravenous injectable form, as disclosed herein.

[0249] In a further aspect, the kit can comprise instructions for providing the compound or pharmaceutical composition in connection with surgery. The instructions can provide that the surgery be performed prior to or after administering the compound or pharmaceutical composition. In another aspect, the instructions can provide that the surgery be performed at about the same time as the administering of the compound or pharmaceutical composition.

[0250] In another further aspect, the kit can comprise instructions to provide the at least one compound or the pharmaceutical composition in connection with radiotherapy. The instructions can provide that the radiotherapy be performed prior to or after administering the compound or pharmaceutical composition. In another aspect, the instructions can provide that the radiotherapy be performed at about the same time as the administering of the compound or pharmaceutical composition.

[0251] 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.

[0252] 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 invention also features such kits further containing instructions for use.Attorney Docket No. 331904-2020

[0253] In a further aspect, the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. 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.

[0254] 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.3. Manufacture of a Medicament

[0255] In one aspect, the invention relates to a method for the manufacture of a medicament for treatment of a disorder of uncontrolled cellular proliferation in a mammal. The method can include combining a therapeutically effective amount of a disclosed compound or product of a disclosed method of making with a pharmaceutically acceptable carrier or diluent.

[0256] In one aspect, the disorder of uncontrolled cellular proliferation is associated with cereblon activity. In another aspect, the disorder of uncontrolled cellular proliferation is associated with BCL11 dysfunction (e.g., BCL11A dysfunction, BCL11B dysfunction, or a combination thereof). In another aspect, the disorder of uncontrolled cellular proliferation is a cancer. The cancer can be a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, malignant melanoma, or a combination thereof. In a further aspect, the cancer can be a hematological cancer, such as 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, or a combination thereof.G. Aspects

[0257] The following listing of exemplary aspects supports and is supported by the disclosure provided herein.

[0258] Aspect 1. A compound having a structure represented by a formula:Attorney Docket No. 331904-2020wherein G is N or CR10, wherein R10is hydrogen or an alkyl; wherein J is N or CH; wherein R1is hydrogen or an alkyl; wherein R2has a structure represented by a formula:wherein x is an integer selected from 1, 2, and 3; wherein L is N or C; wherein R3ais an aryl and R3bis hydrogen or R3aand R3bare covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused cycloalkyl; wherein R3cis hydrogen, an alkyl, nitrile, or hydroxy; wherein M, R4a, and R4bare characterized by one of the following: a)M is N orCR4d, wherein R4dis hydrogen, an alkyl, nitrile, or hydroxy; R4ais hydrogen or an alkyl; and R4bis an aryl, a heteroaryl, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an amine, or a fused biaryl; or b)M is CR4d; R4ais hydrogen or an alkyl; and R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to eight-membered spiro-cycloalkyl or spiroheterocycloalkyl; and wherein R5is an alkyl; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0259] Aspect 2. The compound of aspect 1, wherein G is N.

[0260] Aspect 3. The compound of aspect 1 or aspect 2, wherein J is N.

[0261] Aspect 4. The compound of any one of aspects 1-3, wherein each of G and J is N.

[0262] Aspect 5. The compound of any one of aspects 1-3, wherein R10is hydrogen.

[0263] Aspect 6. The compound of any one of aspects 1-3, wherein R10is a C1-C6 acyclic alkyl.

[0264] Aspect 7. The compound of any one of aspects 1-3, wherein R10is a C1-C4 acyclic alkyl.

[0265] Aspect 8. The compound of any one of aspects 1-7, wherein R1is hydrogen or a C1-C6 acyclic alkyl.

[0266] Aspect 9. The compound of any one of aspects 1-7, wherein R1is hydrogen.

[0267] Aspect 10. The compound of any one of aspects 1-7, wherein R1is a C1-C4 acyclic alkyl.

[0268] Aspect 11. The compound of any one of aspects 1-10, wherein R2has a structure represented by a formula:Attorney Docket No. 331904-2020

[0269] Aspect 12. The compound of any one of aspects 1-10, wherein R2has a structure represented by a formula:

[0270] Aspect 13. The compound of any one of aspects 1-10, wherein R2has a structure represented by a formula:

[0271] Aspect 14. The compound of any one of aspects 1-12, wherein L is N.

[0272] Aspect 15. The compound of any one of aspects 1-13, wherein R3ais a C5-C8 aryl substituted with at least one of a halogen, an alkoxy group, CF3, or OCF3.

[0273] Aspect 16. The compound of any one of aspects 1-13, wherein R3ais a phenyl substituted with at least one of F, Cl, Br, an alkoxy group, CF3, or OCF3.

[0274] Aspect 17. The compound of any one of aspects 1-16, wherein R3cis hydrogen, nitrile, or hydroxy.

[0275] Aspect 18. The compound of any one of aspects 1-13, wherein R3aand R3bare covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused heterocycloalkyl substituted with at least one of hydrogen, a C5-C6 heteroaryl, a halogen, CF3, or OCF3.

[0276] Aspect 19. The compound of any one of aspects 1-16, wherein M is N or CR4d, wherein R4dis hydrogen, an alkyl, nitrile, or hydroxy; wherein R4ais hydrogen or an alkyl; and wherein R4bis characterized by one of the following: a)R4bis a C1-C6 acyclic alkyl, a heterocycloalkyl, — NHR41, or a fused biaryl comprising two C5-C6 aryl rings; wherein R41is an aryl; b)R4bhas a structure represented by a formula:wherein at least one of Za, Zb, Zc, Zd, Zeis nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare,Attorney Docket No. 331904-2020 respectively, CR20a, CR20b, CR20c, CR20d, and CR20e; wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3; or c)R4bhas a structure represented by a formula:wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3.

[0277] Aspect 20. The compound of aspect 19, wherein R4bis a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, — NHR41, or a fused biaryl comprising two C5-C6 aryl rings; wherein R41is a C5-C6 aryl; and wherein R41is substituted with hydrogen, a halogen, OCF3, or CF3.

[0278] Aspect 21. The compound of aspect 19, wherein R4bis a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, or a fused biaryl comprising two C5-C6 aryl rings.

[0279] Aspect 22. The compound of aspect 21, wherein R4bis substituted with hydrogen, a C1-C6 acyclic alkyl, a C5-C6 aryl, or a C5-C6 heteroaryl comprising at least one nitrogen heteroatom.

[0280] Aspect 23. The compound of aspect 19, wherein one of Za, Zb, Zc, Zd, and Zeis nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e.

[0281] Aspect 24. The compound of aspect 19, wherein two of Za, Zb, Zc, Zd, and Zeare nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e.

[0282] Aspect 25. The compound of any one of aspects 19-24, wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, a C1-C6 alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, a C5-C6 heterocyloalkenyl comprising at least one nitrogen heteroatom, a C5-C6 heteroaryl comprising at least one nitrogen heteroatom, a C1-C6 alkoxy, — C(O)OR21, — S(O)(O)R22, —NHR23, — C(O)R27, aldehyde, a halogen, OCF3, and CF3; wherein R21is a C1-C6 acyclic alkyl; wherein R22is a C1-C6 acyclic alkyl; wherein R23is hydrogen or a C5-C6 aryl substituted with at least one of hydrogen, a halogen, CF3, or OCF3 and; wherein R27is a heterocycloalkyl comprising at least one nitrogen heteroatom.

[0283] Aspect 26. The compound of any one of aspects 19-24, wherein one of R20a, R20b, R20c, R20d, and R20eis a C1-C3 alkyl substituted with hydroxy, pyrollidine, piperadine, piperazine, morpholine, imidazole, pyrazole, or — NR24R25and the remainder of R20a, R20b, R20c, R20d, and R20eare hydrogen;Attorney Docket No. 331904-2020 wherein R24and R25are independently selected from hydrogen and a C1-C4 acylic alkyl.

[0284] Aspect 27. The compound of any one of aspects 19-24, wherein one of R20a, R20b, R20c, R20d, and R20eis piperidine, piperazine, morpholine, unsaturated piperidine, or pyridine and the remainder of R20a, R20b, R20c, R20d, and R20eare hydrogen.

[0285] Aspect 28. The compound of aspect 27, wherein the one of R20a, R20b, R20c, R20d, and R20ethat is not hydrogen is substituted with hydrogen, a C1-C6 acyclic alkyl, — C(O)OR26, or nitrile wherein R26is hydrogen or a C1-C6 acyclic alkyl.

[0286] Aspect 29. The compound of any one of aspects 1-28, wherein M is CR4d; wherein R4ais hydrogen or alkyl; and wherein R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl.

[0287] Aspect 30. The compound of any one of aspects 1-28, wherein M is CR4d; wherein R4ais hydrogen or alkyl; and wherein R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl comprising at least one nitrogen heteroatom, at least one oxygen heteroatom, or a combination thereof.

[0288] Aspect 31. The compound of aspect 29 or 30, wherein the four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl formed from R4band R4dis substituted with at least one of hydrogen, a C5-C6 heteroaryl, or — NHR44; wherein R44is a C5-C6 heteroaryl substituted with at least one of hydrogen, a halogen, CF3, or OCF3.

[0289] Aspect 32. The compound of aspect 31, wherein R44is a C5-C6 heteroaryl comprising at least one nitrogen heteroatom and substituted with at least one of hydrogen, a halogen, CF3, or OCF3.

[0290] Aspect 33. The compound of any one of aspects 1-10, wherein R2has a structure represented by a formula — NHR5.

[0291] Aspect 34. The compound of aspect 33, wherein R5is an alkyl group substituted with an alkyl or a heterocycloalkyl comprising at least one nitrogen heteroatom.

[0292] Aspect 35. The compound of any one of aspects 1-34, wherein M is N.

[0293] Aspect 36. The compound of any one of aspects 1-34, wherein M is CH.

[0294] Aspect 37. The compound of any one of aspects 1-34, wherein M is C.

[0295] Aspect 38. The compound of any one of aspects 1-37, wherein R4ais hydrogen.

[0296] Aspect 39. The compound of any one of aspects 1-37, wherein R4ais a C1-C6 alkyl.

[0297] Aspect 40. The compound of aspect 39, wherein R4ais substituted with hydrogen or hydroxy.

[0298] Aspect 41. The compound of any one of aspects 1-37, wherein R4ais an unsubstituted CI-06 alkyl.Attorney Docket No. 331904-2020

[0299] Aspect 42. The compound of any one of aspects 1-41 , wherein R4dis a C1-C6 alkyl.

[0300] Aspect 43. The compound of any one of aspects 1-41, wherein R4dis an unsubstituted C1-C4 alkyl.

[0301] Aspect 44. The compound of any one of aspects 1-41, wherein R4dis a C1-C4 alkyl substituted with nitrile.

[0302] Aspect 45. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0303] Aspect 46. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0304] Aspect 47. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0305] Aspect 48. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0306] Aspect 49. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020

[0307] Aspect 50. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:>

[0308] Aspect 51. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0309] Aspect 52. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:>

[0310] Aspect 53. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0311] Aspect 54. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020

[0312] Aspect 55. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0313] Aspect 56. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0314] Aspect 57. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0315] Aspect 58. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0316] Aspect 59. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020

[0317] Aspect 60. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0318] Aspect 61. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0319] Aspect 62. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0320] Aspect 63. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0321] Aspect 64. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020

[0322] Aspect 65. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0323] Aspect 66. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0324] Aspect 67. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0325] Aspect 68. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020

[0326] Aspect 69. The compound of any one of aspects 1-44, the compound having a structure represented by a formula:

[0327] Aspect 70. The compound of aspect 1, wherein the compound is selected from a compound have a structure represented by a formula:Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020any combination of the foregoing compounds

[0328] Aspect 71. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of aspects 1-69 and a pharmaceutically acceptable carrier.

[0329] Aspect 72. A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of aspects 1-69 or administering to the mammal the pharmaceutical composition of aspect 70.

[0330] Aspect 73. The method of aspect 71, wherein the mammal is a human.

[0331] Aspect 74. The method of aspect 71, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

[0332] Aspect 75. The method of aspect 71, further comprising the step of identifying a mammal in need of treatment of the disorder.

[0333] Aspect 76. The method of aspect 71 , wherein the disorder of uncontrolled cellular proliferation is associated with BCL11 dysfunction.

[0334] Aspect 77. The method of aspect 75, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

[0335] Aspect 78. The method of aspect 76, wherein the BCL11 dysfunction is a BCL11A dysfunction.

[0336] Aspect 79. The method of aspect 76, wherein the BCL11 dysfunction is a BCL11B dysfunction.

[0337] Aspect 80. The method of aspect 71 , wherein the disorder of uncontrolled cellular proliferation is associated with cereblon activity.

[0338] Aspect 81. The method of aspect 71, wherein the disorder is cancer.Attorney Docket No. 331904-2020

[0339] Aspect 82. The method of aspect 71, wherein the disorder is selected from a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma.

[0340] Aspect 83. The method of aspect 81, wherein the disorder is a hematological cancer.

[0341] Aspect 84. The method of aspect 82, 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.

[0342] Aspect 85. The method of aspect 81, wherein the disorder is breast cancer.

[0343] Aspect 86. A method for inhibiting of BCL11 activity via targeted degradation of a BCL11 protein in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of aspects 1-69 or administering to the mammal the pharmaceutical composition of aspect 70.

[0344] Aspect 87. The method of aspect 85, wherein the mammal is a human.

[0345] Aspect 88. The method of aspect 85, wherein the mammal has been diagnosed with a need for inhibition of BCL11 activity prior to the administering step.

[0346] Aspect 89. The method of aspect 85, further comprising the step of identifying a mammal in need for inhibition of BCL11 activity.

[0347] Aspect 90. The method of aspect 85, wherein the BCL11 is BCL11 A.

[0348] Aspect 91. The method of aspect 85, wherein the BCL11 is BCL11B.

[0349] Aspect 92. A method for modulating of cereblon activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of aspects 1-69 or administering to the mammal a therapeutically effective amount of the pharmaceutical composition of aspect 70.

[0350] Aspect 93. The method of aspect 91, wherein the mammal is a human.

[0351] Aspect 94. The method of aspect 91 or aspect 92, wherein the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step.

[0352] Aspect 95. The method of any one of aspects 91-93, further comprising the step of identifying a mammal in need for modulating of cereblon activity.

[0353] Aspect 96. A method for inhibiting of BCL11 activity in at least one cell, comprising the stepAttorney Docket No. 331904-2020 of contacting the at least one cell with an effective amount of at least one compound of any of aspects 1-69 or at least one pharmaceutical composition of aspect 70.

[0354] Aspect 97. The method of aspect 95, wherein the cell is mammalian.

[0355] Aspect 98. The method of aspect 96, wherein the cell is human.

[0356] Aspect 99. The method of any one of aspects 95-97, wherein the cell has been isolated from a mammal prior to the contacting step.

[0357] Aspect 100. The method of any one of aspects 95-98, wherein contacting is via administration to a mammal.

[0358] Aspect 101. The method of any one of aspects 95-99, wherein the mammal has been diagnosed with a need for inhibiting of BCL11 activity prior to the contacting step.

[0359] Aspect 102. The method of any one of aspects 95-100, wherein the mammal has been diagnosed with a need for treatment of a disorder related to BCL11 activity prior to the contacting step.

[0360] Aspect 103. The method of any one of aspects 95-100, wherein the BCL11 is BCL11A, BCL11B, or both.

[0361] Aspect 104. A method for modulating of cereblon activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one compound of any of aspects 1-69 or at least one pharmaceutical composition of aspect 70.

[0362] Aspect 105. The method of aspect 103, wherein the cell is mammalian.

[0363] Aspect 106. The method of aspect 104, wherein the cell is human.

[0364] Aspect 107. The method of any one of aspects 103-105, wherein the cell has been isolated from a mammal prior to the contacting step.

[0365] Aspect 108. The method of any one of aspects 103-106, wherein contacting is via administration to a mammal.

[0366] Aspect 109. The method of any one of aspects 103-107, wherein the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step.

[0367] Aspect 110. The method of any one of aspects 103-108, wherein the mammal has been diagnosed with a need for treatment of a disorder related to cereblon activity prior to the administering step.

[0368] Aspect 111. A kit comprising at least one compound of any of aspects 1-69 or the pharmaceutical composition of aspect 70; and one or more of: 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 BCL11 activity; d)at least one agent known to decrease BCL11 activity; e)at least one agent known to treat a disorder associated with cereblon activity; f)at least one agent known toAttorney Docket No. 331904-2020 treat a disorder associated with BCL11 activity; g)at least one agent known to treat a disease of uncontrolled cellular proliferation; or h)instructions for treating a disorder associated with a BCL11 dysfunction.

[0369] Aspect 112. The kit of aspect 110, wherein the at least one compound and the at least one agent are co-formulated.

[0370] Aspect 113. The kit of aspect 110, wherein the at least one compound and the at least one agent are co-packaged.

[0371] Aspect 114. The kit of any one of aspects 110-112, wherein the BCL11 is BCL11A.

[0372] Aspect 115. The kit of any one of aspects 110-112, wherein the BCL11 is BCL11B.

[0373] Aspect 116. The kit of any one of aspects 110-114, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

[0374] Aspect 117. The kit of aspect 115, wherein the BCL11 dysfunction is a BCL11 A dysfunction.

[0375] Aspect 118. The kit of aspect 115, wherein the BCL11 dysfunction is a BCL11 B dysfunction.

[0376] Aspect 119. The kit of any one of aspects 110-117, further comprising instructions to provide the compound in connection with surgery.

[0377] Aspect 120. The kit of aspect 118, wherein the instructions provide that surgery is performed prior to the administering of at least one compound.

[0378] Aspect 121. The kit of aspect 118, wherein the instructions provide that surgery is performed after the administering of at least one compound.

[0379] Aspect 122. The kit of aspect 118, wherein the instructions provide that the administering of at least one compound is to effect presurgical debulking of a tumor.

[0380] Aspect 123. The kit of aspect 118, wherein the instructions provide that surgery is performed at about the same time as the administering of at least one compound.

[0381] Aspect 124. The kit of any one of aspects 110-122, further comprising instructions to provide the at least one compound or the pharmaceutical composition in connection with radiotherapy.

[0382] Aspect 125. The kit of aspect 123, wherein the instructions provide that radiotherapy is performed prior to the administering of at least one compound or the pharmaceutical composition.

[0383] Aspect 126. The kit of aspect 123, wherein the instructions provide that radiotherapy is performed after the step of the administering of at least one compound or the pharmaceutical composition.

[0384] Aspect 127. The kit of aspect 123, wherein the instructions provide that radiotherapy is performed at about the same time as the step of the administering of at least one compound or the pharmaceutical composition.

[0385] Aspect 128. The kit of any one of aspects 110-126, further comprising a plurality of dosageAttorney Docket No. 331904-2020 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.

[0386] Aspect 129. The kit of aspect 127, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-formulated.

[0387] Aspect 130. The kit of aspect 127, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-packaged.

[0388] Aspect 131. The kit of any one of aspects 127-129, wherein the dosage forms are formulated for oral administration and / or intravenous administration.

[0389] Aspect 132. The kit of aspect 130, wherein the dosage forms are formulated for oral administration.

[0390] Aspect 133. The kit of aspect 130, wherein the dosage forms are formulated for intravenous administration.

[0391] Aspect 134. The kit of any one of aspects 127-129, 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.

[0392] Aspect 135. The kit of any one of aspects 127-129, 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.

[0393] Aspect 136. Use of a compound at least one compound of any of aspects 1-69 in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

[0394] Aspect 137. The use of aspect 135, wherein the disorder of uncontrolled cellular proliferation is associated with cereblon activity.

[0395] Aspect 138. The use of aspect 135, wherein the disorder of uncontrolled cellular proliferation is associated with BCL11 dysfunction.

[0396] Aspect 139. The use of aspect 137, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

[0397] Aspect 140. The use of aspect 138, wherein the BCL11 dysfunction is a BCL11A dysfunction.

[0398] Aspect 141. The use of aspect 138, wherein the BCL11 dysfunction is a BCL11B dysfunction.

[0399] Aspect 142. The use of any one of aspects 135-140, wherein the disorder is cancer.

[0400] Aspect 143. The use of aspect 141, wherein the disorder is selected from a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer,Attorney Docket No. 331904-2020 and malignant melanoma.

[0401] Aspect 144. The use of aspect 142, wherein the disorder is a hematological cancer.

[0402] Aspect 145. The use of aspect 143, 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.

[0403] Aspect 146. The use of aspect 141, wherein the disorder is breast cancer.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] 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.H. Examples

[0409] 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,Attorney Docket No. 331904-2020 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. Synthesis Routes for a Subset of Disclosed Compounds

[0410] The following synthesis procedure is a specific example of Procedure 1A discussed previously.

[0411] Step 1. To a solution of 2-amino-5-fluorobenzoic acid (15.0 g, 96.7 mmol, 1.00 eq) and 3-aminopiperidine-2, 6-dione (17.5 g, 106 mmol, 1.10 eq, HCI) in DMF (150 ml_) was added EDCI (20.3 g, 106 mmol, 1.10 eq), HOBt (14.3 g, 106 mmol, 1.10 eq) and DIEA (37.4 g, 290 mmol, 50.5 ml_, 3.00 eq) at 25 °C for 10 hrs. LCMS showed desired MS was detected. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (100 ml_), filtered and concentrated to give a residue. The residue was triturated with ethyl acetate (100 mL), filtered and concentrated to give 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-fluorobenzamide (24.0 g, 90.4 mmol, 93.5% yield) as gray solid.

[0412] Step 2. To a solution of 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-fluorobenzamide (24.0 g, 90.4 mmol, 1.00 eq) in AcOH (480 mL) was added NaNO2(7.49 g, 108 mmol, 1.20 eq) at 25 °C for 10 hrs. The reaction mixture was poured into water (2000 mL), filtered and concentrated to give a residue. The residue was triturated with ice NaHCCh (50.0 mL), filtered and concentrated to give 3-(6-fluoro-4-oxobenzo[d][1, 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (10.0 g, 39.9% yield, 99.8% purity) as an off-white solid.

[0413] The following synthesis procedure is a specific example of Procedure 1B discussed previously.

[0414] Step 1. To a solution of compound 5-fluoro-2-formylbenzoic acid (2 g, 11.90 mmol, 1 eq) in EtOH (10 mL) was added NH2NH2.H2O (2.74 g, 54.73 mmol, 2.66 mL, 4.60 eq) at 25 °C. The mixture was stirred at 75 °C for 2 hours. LCMS showed the desired mass was detected. The mixture was cooled to room temperature. The resulting white precipitate was collected by vacuum filtration,Attorney Docket No. 331904-2020 washed with ethanol (6 ml_) and dried under high vacuum to provide the crude. 7-fluoro-2H-phthalazin-1-one (1.04 g, 6.34 mmol, 53.26% yield) was obtained as a white solid.

[0415] Step 2. To a solution of 7-fluoro-2H-phthalazin-1-one (500 mg, 3.05 mmol, 1 eq) in DMF (5 mL) was added t-BuONa (585.51 mg, 6.09 mmol, 2 eq) at 0 °C. After stirring for 30 minutes, 3-bromopiperidine-2, 6-dione (1.05 g, 5.48 mmol, 1.8 eq) was added in reaction mixture and stirred for 11.5 hours at 25 °C. LCM showed the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude of two batches were combined and purified by prep-HPLC. Desired fractions were concentrated to give 3-(7-fluoro-1-oxophthalazin-2(1 H)-yl)piperidine-2, 6-dione (320 mg, 1.16 mmol, 19.08% yield) was obtained as a purple solid.

[0416] The following synthesis procedure is a specific example of Procedure 1C discussed previously.

[0417] To a solution of 7-bromoisoquinolin-1-ol (0.5 g, 2.23 mmol, 1 eq) in DMF (5 mL) was added NaH (178.51 mg, 4.46 mmol, 60% purity, 2 eq). The mixture was stirred at 25 °C for 0.5 hours, then 3-bromopiperidine-2, 6-dione (642.74 mg, 3.35 mmol, 1.5 eq) was added to the mixture and stirred at 25°C for 2 hours. LCMS showed the desired mass was detected. The reaction mixture was quenched by addition sat. NH4C1 10 mL, and then extracted with EtOAc (10 mL * 2). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by prep- HPLC. Desire fractions were concentrated to give 3-(7-bromo-1-oxoisoquinolin-2(1 H)-yl)piperidine-2, 6-dione (0.5 g, 1.49 mmol, 66.85% yield) was obtained as a white solid.

[0418] The following synthesis procedure is a specific example of Procedure A discussed previously.

[0419] To a stirring solution of 3-(6-fluoro-4-oxobenzo[d][1 , 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (20 mg, 0.072 mmol) in DMSO (0.750 mL, 0.1M) was added 4-(4-(trifluoromethoxy)phenyl)piperidine (26.6 mg, 0.109 mmol) and DIPEA (39.0 pl, 0.217 mmol). The reaction mixture was heated to 90°C and stirred overnight. UPLC showed reaction was complete and crude mixture was filtered through a syringe filter and purification was performed on the Shimazu purification / analytical LC / UV / ELSD system. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(4-Attorney Docket No. 331904-2020 (trifluoromethoxy)phenyl)piperidin-1-yl)benzo[d][1 , 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (4.8 mg, 9.57 pmol, 13.22 % yield) as a white solid.

[0420] The following synthesis procedure is a specific example of Procedure B discussed previously.

[0421] Step 1. To a solution of 1-bromo-3-(trifluoromethyl)benzene (20 mg, 0.089 mmol) in toluene (444 pl) was added tert-butyl piperazine-1-carboxylate (33.1 mg, 0.178 mmol) followed by BINAP (2.77 mg, 4.44 pmol), Pd2(dba)3(4.07 mg, 4.44 pmol), and sodium tert-butoxide (11.96 mg, 0.124 mmol). The reaction mixture was heated to reflux and stirred overnight. UPLC showed reaction was complete and reaction mixture was filtered through a plug of Celite and washed with EtOAc. The filtrate was concentrated then was taken up in DCM (500 pl) and TFA (250 pL) was added. The reaction mixture was stirred for 1 hour when UPLC showed reaction complete. The crude reaction mixture was concentrated to dryness to give1-(3-(trifluoromethyl)phenyl)piperazine (15 mg, 0.065 mmol, 73.3 % yield) and was carried on without further purification.

[0422] Step 2. To a stirring solution of 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2, 6-dione (11.88 mg, 0.043 mmol) in DMSO (0.430 mL, 0.1M) was added 4-(4-(trifluoromethoxy)phenyl)piperidine (26.6 mg, 0.109 mmol) and DIPEA (62.0 pl, 0.344 mmol). The reaction mixture was heated to 90°C and stirred overnight. UPLC showed reaction was complete and crude mixture was filtered through a syringe filter and purification was performed on the Shimazu purification / analytical LC / UV / ELSD system. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)benzo[d][1 , 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (16.2 mg, 33 pmol, 77 % yield) as a white solid.

[0423] The following synthesis procedure is a specific example of Procedure C discussed previously.

[0424] Step 1. To a stirring solution of 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2, 6-dione (400 mg, 1.448 mmol) in DMSO (14.481 mL) was added tert-butyl piperazine-1-carboxylate (405 mg, 2.172 mmol) followed by DI PEA (0.780 mL, 4.34 mmol) and the reaction was heated to 90°C overnight. UPLC showed reaction was complete and the crude reaction mixture wasAttorney Docket No. 331904-2020 quenched with H20 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to dryness. The crude material was taken up in DCM (10 ml_) and TFA (2 mL) was added and mixture was stirred at RT for 2hrs. The reaction mixture was concentrated to dryness to give 3-(4-oxo-6-(piperazin-1-yl)benzo[d][1, 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (450 mg, 1.314 mmol, 91 % yield) as a beige solid. The product was taken on without further purification.

[0425] Step 2. To a solution of 3-(4-oxo-6-(piperazin-1-yl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine- 2, 6-dione (10 mg, 0.029 mmol) in DMSO (292 pl) was added 2-fluoro-5-(trifluoromethyl)pyridine (4.82 mg, 0.029 mmol) followed by DIPEA (25.5 pl, 0.146 mmol). The reaction mixture was heated to 100°C and stirred overnight. UPLC showed the reaction was complete and reaction mixture was filtered through a pad of Celite and washed with DMSO (0.75 mL). Purification was performed on the Shimazu purification / analytical LC / UV / ELSD system. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine- 2,6-dione (2.9 mg, 5.95 pmol, 20.4% yield) as a white solid.

[0426] The following synthesis procedure is a more detailed specific example of Procedure D discussed previously

[0427] Step 1. To a microwave vial containing 4-(4-bromophenyl)piperidine (20 mg, 0.083 mmol) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (19.16 mg, 0.083 mmol) followed by PdCI2(dppf) (6.09 mg, 8.33 pmol), Cs2CC>3 (81 mg, 0.250 mmol), DME (694 pl), and H2O (139 pl). The reaction was sealed and heated in microwave at 85°C for 2 hrs. UPLC showed reaction complete and crude mixture was filtered through a pad of Celite and washed with EtOAc. Filtrate was concentrated and taken on without further purification.

[0428] Step 2. To a stirring solution of 3-(6-fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine- 2, 6-dione (20 mg, 0.072 mmol) in DMSO (0.750 mL, 0.1M) was added 3-(4-(piperidin-4-yl)phenyl)isonicotinonitrile (19.07 mg, 0.072 mmol) and DIPEA (39.0 pl, 0.217 mmol). The reaction mixture was heated to 90°C and stirred overnight. UPLC showed reaction was complete and crude mixture was filtered through a syringe filter and purification was performed on the Shimazu purification / analytical LC / UV / ELSD system. Desired fractions were concentrated to give 3-(4-(1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)piperidin-4-yl)phenyl)isonicotinonitrile (4.2 mg, 8.08 pmol, 11.16 % yield) as a white solid.

[0429] The following synthesis procedure is a specific example of Procedure E discussed previously.Attorney Docket No. 331904-2020

[0430] To a solution of 3-(7-fluoro-1-oxophthalazin-2(1 H)-yl)piperidine-2, 6-dione (160 mg, 581.32 pmol, 1 eq) in NMP (3 ml_) was added DIPEA (225.39 mg, 1.74 mmol, 303.77 pL, 3 eq) and 4-[4-(trifluoromethoxy)phenyl]piperidine (142.56 mg, 581.32 pmol, 1 eq). The mixture was stirred at 130 °C for 5 hours. LCMS showed the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC. Desired fractions were concentrated to give 3-(1-oxo-7-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)phthalazin-2(1H)piperidine-2, 6-dione (22.6 mg, 41.31 pmol, 7.11% yield, 98.15% purity, HCI) was obtained as a yellow solid.

[0431] The following synthesis procedure is a specific example of Procedure F discussed previously

[0432] A mixture of 3-(7-bromo-1-oxoisoquinolin-2(1H)-yl)piperidine-2, 6-dione (193.32 mg, 686.26 pmol, 1 eq, HCI), t-BuONa (131.90 mg, 1.37 mmol, 2 eq), P(t-Bu)3Pd G4 (40.22 mg, 68.63 pmol, 0.1 eq) in Dioxane (5 ml_) was degassed and purged with N2for 3 times. 4-[4-(trifluoromethoxy)phenyl]piperidine (252.45 mg, 1.029 mmol, 1.5 eq) was then added and then the mixture was stirred at 80 °C for 2 hours under N2atmosphere. LCMS showed the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC. Desired fractions were concentrated to give 3-(1-oxo-7-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)isoquinolin-2(1H)-yl)piperidine-2, 6-dione (17.8 mg, 34.63 pmol, 5.05% yield, 97.18% purity) was obtained as a white solid.

[0433] The following synthesis procedure is a specific example of Procedure G discussed previously.

[0434] Step 1. Follows Procedure A.

[0435] Step 2. To a solution of 3-(4-oxo-6-(4-oxopiperidin-1-yl)benzo[d][1,2,3]triazin-3(4H)-Attorney Docket No. 331904-2020 yl)piperidine-2, 6-dione (30 mg, 0.084 mmol) in MeOH (836 pl) was added aniline (7.86 mg, 0.084 mmol) followed by sodium cyanoborohydride (90.7 mg, 0.084 mmol) on silica beads (1.08g / mmol) and AcOH (8.36 pl). The reaction mixture was heated to 50°C and stirred for 2 hrs. UPLC determined reaction was complete and the mixture was filtered by fritted funnel and washed with EtOAc. Filtrate was concentrated then taken up in DMSO and purified by reverse phase chromatography. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(phenylamino)piperidin-1-yl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2, 6-dione (3.5 mg, 8.09 pmol, 9.59 % yield) as a white powder.

[0436] The following synthesis procedure is a specific example of Procedure J discussed previously.

[0437] To a solution of 3-(4-oxo-6-(piperazin-1-yl)benzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (20 mg, 0.058 mmol) in MeOH (578 pl) was added 4-(trifluoromethoxy)benzaldehyde (11.11 mg, 0.058 mmol) followed by sodium cyanoborohydride (62.3 mg, 0.058 mmol) on silica beads (1.08g / mmol) and AcOH (5.78 pl). The reaction mixture was heated to 50°C and stirred for 2 hrs. UPLC determined reaction was complete and the mixture was filtered by fritted funnel and washed with EtOAc. Filtrate was concentrated then taken up in DMSO and purified by reverse phase chromatography. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(4-(trifluoromethoxy)benzyl)piperazin-1-yl)benzo[d][1 , 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (11 mg, 21 pmol, 36.5% yield) as a white powder.

[0438] The following synthesis procedure is a specific example of Procedure K discussed previously.

[0439] To a vial equipped with a stir bar was added 3-(6-(4-(4-bromophenyl)piperazin-1-yl)-4-oxobenzo[d][1, 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (20 mg, 0.040 mmol), 2- (trifluoromethoxy)aniline (10.7mg, 0.060 mmol), BrettPhos Pd G3 (3.65 mg, 0.0042 mmol) and cesium carbonate (39.3 mg, 0.121 mmol), followed by Dioxane (0.402 mL). The mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(4-((2-(trifluoromethoxy)phenyl)amino)phenyl)piperazin-1-Attorney Docket No. 331904-2020 yl)benzo[d][1, 2, 3]triazin-3(4H)-yl)piperidine-2, 6-dione (2.5 mg, 4.21 pmol, 10.47% yield) as a white powder.

[0440] The following synthesis procedure is a specific example of Procedure L discussed previously.

[0441] To a vial equipped with a stir bar was added 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)piperidine-2, 6-dione (20 mg, 0.059 mmol), 4-(4-(trifluoromethoxy)phenyl)piperidine (36.5 mg, 0.149 mmol), RuPhos-Pd-G3 (4.98 mg, 0.0059 mmol) and cesium carbonate (58.2 mg, 0.178 mmol), followed by Dioxane (0.595 ml_). The mixture was stirred at 90 °C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Desired fractions were concentrated to give 3-(4-oxo-6-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)quinazolin-3(4H)-yl)piperidine-2, 6-dione (1.1 mg, 2.198 pmol, 3.69% yield) as a white powder.2. Example Compounds

[0442] Table 1 provides a list of examples of disclosed compounds, along with which synthesis procedure can be used to synthesize the compounds and results from Cereblon (CRBN) fluorescence polarization (FP) assays, Western blot tests, and cell viability assays (Jurkat CellTiter-Glo® (CTG)). The CRBN FP EC50 values in Table 1 are binned such that M1= (0 pM to 1 pM), M2= (greater than 1 pM to 5 pM), M3= (greater than 5 pM to 20 pM), and M4= (greater than 20 pM to 100 pM). The CTG EC50 values are binned such that Z1= (0 pM to 1 pM), Z2= (greater than 1 pM to 3 pM), Z3= (greater than 3 pM to 10 pM), and Z4= (greater than 10 pM to 50 pM).

[0443] CRBN Fluorescence Polarization Assay. In this competitive fluorescent polarization assay Cy5 conjugated lenalidomide analog (Cy5-O-Len) was used as the fluorescent probe. The assay cocktail was prepared by combining 6XHis-CRBN-DDB1 protein (200 nM) and Cy5-O-Len probe (30 nM) in 20 mM HEPES pH 7, 150 mM NaCI, 0.005% Tween-20 assay buffer. Compounds were transferred to a Corning 3821 BC black 384-well assay plate from a dose-response plate using a Labcyte Echo 655 Acoustic Liquid Handler (Beckman Coulter, USA). Then 20 mL of the assay cocktail was dispensed to wells of the assay plate with a Multidrop Combi Reagent Dispenser (Thermo Scientific, USA). The plates were incubated in the dark for 1.5 hours at room temperature and then read on an Envision plate reader (PerkinElmer, USA). ECso values were determined using a proprietary software RISE (Robust Investigation of Screening Experiments), developed in houseAttorney Docket No. 331904-2020 on the Pipeline Pilot platform (Biovia, v. 21.2.0).

[0444] Cell Viability Assay (CTG). Jurkat cells were maintained in RPMI 1640 medium containing 10% fetal bovine serum (HyClone), penicillin / -streptomycin (100 U / mL), and glutamine (100 pM). For high throughput screening, 30 nl of compound solutions were transferred to barcoded 384-well assay plates (Corning, Cat#3570BC) using Echo liquid handler 655 (Beckman Coulter). Then, 30 ul of medium containing Jurkat cells (2,500 cells) were added to assay plates using Matrix WellMate (Thermo scientific) and assay plates were incubated at 37°C in 5% CO2for 72 hours. Then, 25 ul of CellTiter-Glo (Promega) were added to the cells and the luminescence was measured by 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.

[0445] Western Blot. Three million cells were incubated for 5 hours with MG of a final concentration on 5uM. The cells were collected by centrifugation at 250xg for 1 minute and subsequently washed with PBS. The cells were lysed with 50ul of RIPA buffer with IxHALT protease inhibitor cocktail. The lysate was clarified with centrifugation at 18000xg. Clarified lysate was suspended in 1xSDS loading buffer and boiled for 1 minute. 10ul of the prepared sample is run on SDS-PAGE. The gel was transferred to a nitrocellulose membrane. The membrane is blocked by 5% milk in TBST buffer. The membrane is incubated in BCL11B antibody overnight. The membrane is washed and treated with HRP-conjugated secondary antibody. The membrane is developed with an ECL reagent, and chemiluminescence is recorded on BioRad ChemiDoc.Table 1.Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020Attorney Docket No. 331904-2020

[0446] It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

Attorney Docket No. 331904-2020CLAIMSWhat is claimed is:

1. A compound having a structure represented by a formula:wherein G is N or CR10, wherein R10is hydrogen or an alkyl;wherein J is N or CH;wherein R1is hydrogen or an alkyl;wherein R2has a structure represented by a formula:wherein x is an integer selected from 1 , 2, and 3;wherein L is N or C;wherein R3ais an aryl and R3bis hydrogen or R3aand R3bare covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused cycloalkyl;wherein R3cis hydrogen, an alkyl, nitrile, or hydroxy;wherein M, R4a, and R4bare characterized by one of the following:a) M is N or CR4d, wherein R4dis hydrogen, an alkyl, nitrile, or hydroxy; R4ais hydrogen or an alkyl; and R4bis an aryl, a heteroaryl, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an amine, or a fused biaryl; or b) M is CR4d; R4ais hydrogen or an alkyl; and R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to eightmembered spiro-cycloalkyl or spiro-heterocycloalkyl; and wherein R5is an alkyl;or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

2. The compound of claim 1, wherein G is N.

3. The compound of claim 1 or claim 2, wherein J is N.Attorney Docket No. 331904-2020 4. The compound of any one of claims 1-3, wherein each of G and J is N.

5. The compound of any one of claims 1-3, wherein R10is hydrogen.

6. The compound of any one of claims 1-3, wherein R10is a C1-C6 acyclic alkyl.

7. The compound of any one of claims 1-3, wherein R10is a C1-C4 acyclic alkyl.

8. The compound of any one of claims 1-7, wherein R1is hydrogen or a C1-C6 acyclic alkyl.

9. The compound of any one of claims 1-7, wherein R1is hydrogen.

10. The compound of any one of claims 1-7, wherein R1is a C1-C4 acyclic alkyl.

11. The compound of any one of claims 1-10, wherein R2has a structure represented by a formula:

12. The compound of any one of claims 1-10, wherein R2has a structure represented by a formula:

13. The compound of any one of claims 1-10, wherein R2has a structure represented by a formula:

14. The compound of any one of claims 1-12, wherein L is N.

15. The compound of any one of claims 1-13, wherein R3ais a C5-C8 aryl substituted with at least one of a halogen, an alkoxy group, CF3, or OCF3.

16. The compound of any one of claims 1-13, wherein R3ais a phenyl substituted with at least one of F, Cl, Br, an alkoxy group, CF3, or OCF3.

17. The compound of any one of claims 1-16, wherein R3cis hydrogen, nitrile, or hydroxy.

18. The compound of any one of claims 1-13, wherein R3aand R3bare covalently bonded and, together with the bridgehead carbons, form a five-membered to eight-membered fused heterocycloalkyl substituted with at least one of hydrogen, a C5-C6 heteroaryl, a halogen, CF3, or OCF3.

19. The compound of any one of claims 1-16, wherein M is N or CR4d, wherein R4dis hydrogen, an alkyl, nitrile, or hydroxy; wherein R4ais hydrogen or an alkyl; and wherein R4bis characterized by one of the following:a) R4bis a C1-C6 acyclic alkyl, a heterocycloalkyl, — NHR41, or a fused biaryl comprising twoAttorney Docket No. 331904-2020 C5-C6 aryl rings;wherein R41is an aryl;b) R4bhas a structure represented by a formula:"wherein at least one of Za, Zb, Zc, Zd, Zeis nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e;wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3; orc) R4bhas a structure represented by a formula:wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, an alkyl, a heterocycloalkyl, a heterocycloalkenyl, an aryl, a heteroaryl, an alkoxy, an ester, sulfonyl, an amine, an arylamino, a carbonyl, aldehyde, a halogen, OCF3, and CF3.

20. The compound of claim 19, wherein R4bis a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, — NHR41, or a fused biaryl comprising two C5-C6 aryl rings;wherein R41is a C5-C6 aryl; andwherein R41is substituted with hydrogen, a halogen, OCF3, or CF3.

21. The compound of claim 19, wherein R4bis a C1-C3 acyclic alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, or a fused biaryl comprising two C5-C6 aryl rings.

22. The compound of claim 21, wherein R4bis substituted with hydrogen, a C1-C6 acyclic alkyl, a C5-C6 aryl, or a C5-C6 heteroaryl comprising at least one nitrogen heteroatom.

23. The compound of claim 19, wherein one of Za, Zb, Zc, Zd, and Zeis nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e.

24. The compound of claim 19, wherein two of Za, Zb, Zc, Zd, and Zeare nitrogen and the remainder of Za, Zb, Zc, Zd, and Zeare, respectively, CR20a, CR20b, CR20c, CR20d, and CR20e.Attorney Docket No. 331904-2020 25. The compound of any one of claims 19-24, wherein each of R20a, R20b, R20c, R20d, and R20eis independently selected from hydrogen, a C1-C6 alkyl, a C5-C6 heterocyloalkyl comprising at least one nitrogen heteroatom, a C5-C6 heterocyloalkenyl comprising at least one nitrogen heteroatom, a C5-C6 heteroaryl comprising at least one nitrogen heteroatom, a C1-C6 alkoxy, — C(O)OR21, — S(O)(O)R22, — NHR23, — C(O)R27, aldehyde, a halogen, OCF3, and CF3;wherein R21is a C1-C6 acyclic alkyl;wherein R22is a C1-C6 acyclic alkyl;wherein R23is hydrogen or a C5-C6 aryl substituted with at least one of hydrogen, a halogen, CF3, or OCF3and;wherein R27is a heterocycloalkyl comprising at least one nitrogen heteroatom.

26. The compound of any one of claims 19-24, wherein one of R20a, R20b, R20c, R20d, and R20eis a C1- C3 alkyl substituted with hydroxy, pyrollidine, piperadine, piperazine, morpholine, imidazole, pyrazole, or — NR24R25and the remainder of R20a, R20b, R20c, R20d, and R20eare hydrogen;wherein R24and R25are independently selected from hydrogen and a C1-C4 acylic alkyl.

27. The compound of any one of claims 19-24, wherein one of R20a, R20b, R20°, R20d, and R20eis piperidine, piperazine, morpholine, unsaturated piperidine, or pyridine and the remainder of R20a, R20b, R20c, R20d, and R20eare hydrogen.

28. The compound of claim 27, wherein the one of R20a, R20b, R20c, R20d, and R20ethat is not hydrogen is substituted with hydrogen, a C1-C6 acyclic alkyl, — C(O)OR26, or nitrilewherein R26is hydrogen or a C1-C6 acyclic alkyl.

29. The compound of any one of claims 1-28, wherein M is CR4d; wherein R4ais hydrogen or alkyl;and wherein R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl.

30. The compound of any one of claims 1-28, wherein M is CR4d; wherein R4ais hydrogen or alkyl;and wherein R4band R4dare covalently bonded and, together with the intermediate carbon, form a four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl comprising at least one nitrogen heteroatom, at least one oxygen heteroatom, or a combination thereof.

31. The compound of claim 29 or 30, wherein the four-membered to six-membered spiro-cycloalkyl or spiro-heterocycloalkyl formed from R4band R4dis substituted with at least one of hydrogen, a C5-C6 heteroaryl, or — NHR44;wherein R44is a C5-C6 heteroaryl substituted with at least one of hydrogen, a halogen, CF3, or OCF3.

32. The compound of claim 31 , wherein R44is a C5-C6 heteroaryl comprising at least one nitrogen heteroatom and substituted with at least one of hydrogen, a halogen, CF3, or OCF3.Attorney Docket No. 331904-2020 33. The compound of any one of claims 1-10, wherein R2has a structure represented by a formula — NHR5.

34. The compound of claim 33, wherein R5is an alkyl group substituted with an alkyl or a heterocycloalkyl comprising at least one nitrogen heteroatom.

35. The compound of any one of claims 1-34, wherein M is N.

36. The compound of any one of claims 1-34, wherein M is CH.

37. The compound of any one of claims 1-34, wherein M is C.

38. The compound of any one of claims 1-37, wherein R4ais hydrogen.

39. The compound of any one of claims 1-37, wherein R4ais a C1-C6 alkyl.

40. The compound of claim 39, wherein R4ais substituted with hydrogen or hydroxy.

41. The compound of any one of claims 1-37, wherein R4ais an unsubstituted C1-C6 alkyl.

42. The compound of any one of claims 1-41, wherein R4dis a C1-C6 alkyl.

43. The compound of any one of claims 1-41, wherein R4dis an unsubstituted C1-C4 alkyl.

44. The compound of any one of claims 1-41, wherein R4dis a C1-C4 alkyl substituted with nitrile.

45. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

46. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

47. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

48. The compound of any one of claims 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-202049. The compound of any one of claims 1-44, the compound having structure represented by a formula:

50. The compound of any one of claims 1-44, the compound having structure represented by a formula:

51. The compound of any one of claims 1-44, the compound having structure represented by a formula:

52. The compound of any one of claims 1-44, the compound having structure represented by a formula:

53. The compound of any one of claims 1-44, the compound having structure represented by a formula:Attorney Docket No. 331904-202054. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

55. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

56. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

57. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

58. The compound of any one of claims 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-202059. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

60. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

61. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

62. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

63. The compound of any one of claims 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-202064. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

65. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

66. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

67. The compound of any one of claims 1-44, the compound having a structure represented by a formula:Attorney Docket No. 331904-2020 68. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

69. The compound of any one of claims 1-44, the compound having a structure represented by a formula:

70. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-69 and a pharmaceutically acceptable carrier.

71. A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1-69 or administering to the mammal the pharmaceutical composition of claim 70.

72. The method of claim 71, wherein the mammal is a human.

73. The method of claim 71, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

74. The method of claim 71, further comprising the step of identifying a mammal in need of treatment of the disorder.

75. The method of claim 71, wherein the disorder of uncontrolled cellular proliferation is associated with BCL11 dysfunction.

76. The method of claim 75, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

77. The method of claim 76, wherein the BCL11 dysfunction is a BCL11A dysfunction.

78. The method of claim 76, wherein the BCL11 dysfunction is a BCL11B dysfunction.

79. The method of claim 71, wherein the disorder of uncontrolled cellular proliferation is associated with cereblon activity.

80. The method of claim 71, wherein the disorder is cancer.Attorney Docket No. 331904-2020 81. The method of claim 71, wherein the disorder is selected from a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma.

82. The method of claim 81, wherein the disorder is a hematological cancer.

83. The method of claim 82, 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.

84. The method of claim 81, wherein the disorder is breast cancer.

85. A method for inhibiting of BCL11 activity via targeted degradation of a BCL11 protein in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1-69 or administering to the mammal the pharmaceutical composition of claim 70.

86. The method of claim 85, wherein the mammal is a human.

87. The method of claim 85, wherein the mammal has been diagnosed with a need for inhibition of BCL11 activity prior to the administering step.

88. The method of claim 85, further comprising the step of identifying a mammal in need for inhibition of BCL11 activity.

89. The method of claim 85, wherein the BCL11 is BCL11A.

90. The method of claim 85, wherein the BCL11 is BCL11B.

91. A method for modulating of cereblon activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of any of claims 1- 69 or administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 70.

92. The method of claim 91, wherein the mammal is a human.

93. The method of claim 91 or claim 92, wherein the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step.

94. The method of any one of claims 91-93, further comprising the step of identifying a mammal in need for modulating of cereblon activity.

95. A method for inhibiting of BCL11 activity in at least one cell, comprising the step of contactingAttorney Docket No. 331904-2020 the at least one cell with an effective amount of at least one compound of any of claims 1-69 or at least one pharmaceutical composition of claim 70.

96. The method of claim 95, wherein the cell is mammalian.

97. The method of claim 96, wherein the cell is human.

98. The method of any one of claims 95-97, wherein the cell has been isolated from a mammal prior to the contacting step.

99. The method of any one of claims 95-98, wherein contacting is via administration to a mammal.

100. The method of any one of claims 95-99, wherein the mammal has been diagnosed with a need for inhibiting of BCL11 activity prior to the contacting step.

101. The method of any one of claims 95-100, wherein the mammal has been diagnosed with a need for treatment of a disorder related to BCL11 activity prior to the contacting step.

102. The method of any one of claims 95-100, wherein the BCL11 is BCL11A, BCL11 B, or both.

103. A method for modulating of cereblon activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one compound of any of claims 1-69 or at least one pharmaceutical composition of claim 70.

104. The method of claim 103, wherein the cell is mammalian.

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

106. The method of any one of claims 103-105, wherein the cell has been isolated from a mammal prior to the contacting step.

107. The method of any one of claims 103-106, wherein contacting is via administration to a mammal.

108. The method of any one of claims 103-107, wherein the mammal has been diagnosed with a need for modulating of cereblon activity prior to the administering step.

109. The method of any one of claims 103-108, wherein the mammal has been diagnosed with a need for treatment of a disorder related to cereblon activity prior to the administering step.

110. A kit comprising at least one compound of any of claims 1-69 or the pharmaceutical composition of claim 70; and one or more of: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 BCL11 activity;d) at least one agent known to decrease BCL11 activity;e) at least one agent known to treat a disorder associated with cereblon activity;f) at least one agent known to treat a disorder associated with BCL11 activity;g) at least one agent known to treat a disease of uncontrolled cellular proliferation; orAttorney Docket No. 331904-2020 h) instructions for treating a disorder associated with a BCL11 dysfunction.

111. The kit of claim 110, wherein the at least one compound and the at least one agent are coformulated.

112. The kit of claim 110, wherein the at least one compound and the at least one agent are copackaged.

113. The kit of any one of claims 110-112, wherein the BCL11 is BCL11 A.

114. The kit of any one of claims 110-112, wherein the BCL11 is BCLUB.

115. The kit of any one of claims 110-114, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

116. The kit of claim 115, wherein the BCL11 dysfunction is a BCL11 A dysfunction.

117. The kit of claim 115, wherein the BCL11 dysfunction is a BCL11 B dysfunction.

118. The kit of any one of claims 110-117, further comprising instructions to provide the compound in connection with surgery.

119. The kit of claim 118, wherein the instructions provide that surgery is performed prior to the administering of at least one compound.

120. The kit of claim 118, wherein the instructions provide that surgery is performed after the administering of at least one compound.

121. The kit of claim 118, wherein the instructions provide that the administering of at least one compound is to effect presurgical debulking of a tumor.

122. The kit of claim 118, wherein the instructions provide that surgery is performed at about the same time as the administering of at least one compound.

123. The kit of any one of claims 110-122, further comprising instructions to provide the at least one compound or the pharmaceutical composition in connection with radiotherapy.

124. The kit of claim 123, wherein the instructions provide that radiotherapy is performed prior to the administering of at least one compound or the pharmaceutical composition.

125. The kit of claim 123, wherein the instructions provide that radiotherapy is performed after the step of the administering of at least one compound or the pharmaceutical composition.

126. The kit of claim 123, wherein the instructions provide that radiotherapy is performed at about the same time as the step of the administering of at least one compound or the pharmaceutical composition.

127. The kit of any one of claims 110-126, 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.Attorney Docket No. 331904-2020 128. The kit of claim 127, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-formulated.

129. The kit of claim 127, wherein each dose of the at least one compound or the pharmaceutical composition and the at least one agent are co-packaged.

130. The kit of any one of claims 127-129, wherein the dosage forms are formulated for oral administration and / or intravenous administration.

131. The kit of claim 130, wherein the dosage forms are formulated for oral administration.

132. The kit of claim 130, wherein the dosage forms are formulated for intravenous administration.

133. The kit of any one of claims 127-129, 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.

134. The kit of any one of claims 127-129, 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.

135. Use of a compound at least one compound of any of claims 1-69 in the manufacture of a medicament for the treatment of a disorder of uncontrolled cellular proliferation in a mammal.

136. The use of claim 135, wherein the disorder of uncontrolled cellular proliferation is associated with cereblon activity.

137. The use of claim 135, wherein the disorder of uncontrolled cellular proliferation is associated with BCL11 dysfunction.

138. The use of claim 137, wherein the BCL11 dysfunction is a BCL11A dysfunction, a BCL11B dysfunction, or a combination thereof.

139. The use of claim 138, wherein the BCL11 dysfunction is a BCL11A dysfunction.

140. The use of claim 138, wherein the BCL11 dysfunction is a BCL11B dysfunction.

141. The use of any one of claims 135-140, wherein the disorder is cancer.

142. The use of claim 141 , wherein the disorder is selected from a hematological cancer, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, and malignant melanoma.

143. The use of claim 142, wherein the disorder is a hematological cancer.

144. The use of claim 143, 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), acuteAttorney Docket No. 331904-2020 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.

145. The use of claim 141 , wherein the disorder is breast cancer.

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