Substituting N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analog as a modulator of cereblon protein

Abstract

In one aspect, the disclosure relates to substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindolin-5-yl)arylsulfonamide analogs useful as modulators of cereblon (CRBN) activity, methods of making same, pharmaceutical compositions containing same, and methods of using same to treat various clinical conditions and disorders, e.g., disorders of uncontrolled cell proliferation, e.g., cancers that may be associated with cereblon protein dysfunction and / or GSPT1 dysfunction. In various further aspects, the disclosed compounds can selectively modulate the degradation of GSPT1 protein, i.e., the disclosed compounds can act as GSPT1 degraders. This Abstract is intended as a research tool for purposes of searching in a particular technical field and is not intended to limit the disclosure.

Description

Detailed description of the invention

[0001]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63 / 082,365, filed on 23 September 2020, which is incorporated in its entirety by reference herein.

[0002] [background]

[0002] Cancer is primarily characterized by an increase in the number of abnormal cells originating from a given normal tissue, invasion of adjacent tissue by these abnormal cells, or lymphatic or blood-borne transmission (metastasis) of malignant cells to regional lymph nodes and distant sites. There is a great need for new methods, treatments, and compositions that can be used to treat patients with cancer.

[0003]

[0003] Proteolysis plays some role in various cellular functions; namely, the concentration of regulatory proteins is regulated by their breakdown into smaller peptides to maintain cellular health and productivity. Cereblon is a protein that forms an E3 ubiquitin ligase complex that ubiquitinates various other proteins. Specifically targeting proteolysis offers the interesting prospect of targeting oncogeneic proteins that are currently untreatable by drug discovery, such as transcription factors and chimeric fusion oncogeneic proteins.

[0004]

[0004] Despite advances in research on the clinical improvement of cancer, there is still a lack of potent, effective, and selective modulators of proteolysis, such as compounds that are potent and selective modulos of cereblon. These and other needs are met by the present disclosure.

[0005] [overview]

[0005] In accordance with the purposes of this disclosure, as embodied and broadly described herein, this disclosure relates in one aspect to a substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analog useful as a modulator of cereblon (CRBN) activity, a method for producing the same, a pharmaceutical composition comprising the same, and a method for using the same to treat various clinical conditions and disorders, e.g., disorders of uncontrolled cell proliferation, e.g., cancers that may be associated with cereblon protein dysfunction. In various further embodiments, the disclosed compound can act to selectively modulate the degradation of the GSPT1 protein, i.e., the disclosed compound can act as a GSPT1 degrader. In further embodiments, the disclosed compound is shown to be selective for GSPT1 degradation by at least 5 times compared to IKZF1 degradation.

[0006]

[0006] Compounds having a structure represented by the following formula: [ka] (In the formula, n is an integer selected from 0, 1, and 2, and A 1 and A 2 Each of these is independently selected from -(C=O)- and -CH2-, where A 1 and A 2 At least one of them is -(C=O)-, and R 1is (a) a 5- to 10-membered aryl or heteroaryl optionally substituted by a group selected from halogen, ─SF5, ─CN, ─N3, ─NH2, ─OH, ─CN, ─SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, and (b) a 5- to 10-membered cycloalkyl optionally substituted by a group selected from halogen, ─SF5, ─CN, ─N3, ─NH2, ─OH, ─CN, ─SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl) or a pharmaceutically acceptable salt thereof is disclosed.

[0007]

[0007] A compound having a structure represented by the following formula: [Chemical formula] (wherein n is an integer selected from 0, 1, and 2, and each of A 1 and A 2 is independently selected from -(C=O)- and -CH2-, provided that at least one of A 1 and A 2 is -(C=O)-, and R 1(a) 5-10 membered aryl or heteroaryl compounds optionally substituted with groups selected from halogens, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxys, C1-C3 haloalkyls, C1-C3 aminoalkyls, C1-C3 alkylaminos, C1-C3 hydroxyalkyls, -O-(C1-C3 haloalkyls), C3-C8 cycloalkyls, C1-C6 alkyls, and phenyls, as well as (b) halogens, -SF5, -CN, - Also disclosed are pharmaceutically acceptable salts thereof (selected from 5-10 membered cycloalkyls optionally substituted with groups selected from N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl), provided that the compounds have the following structures: [ka] (In the formula, R 20a R is selected from bromo, methyl, -CF3, and -OCF3. 20b , R 20c , R 20d and R 20e Each of these is independently selected from hydrogen, halogen, and methyl (or a pharmaceutically acceptable salt thereof), and a compound having a structure represented by the following formula: [ka] or not a pharmaceutically acceptable salt thereof.

[0008]

[0008] Compounds having a structure represented by the following formula: [ka] (In the formula, R 1a R is selected from bromo, methyl, -CF3, and -OCF3.1b , R 1c , R 1d and R 1e Each of these (independently selected from hydrogen, halogen, and methyl) or a pharmaceutically acceptable salt thereof is also disclosed.

[0009]

[0009] Compounds having a structure represented by the following formula: [ka] Alternatively, pharmaceutically acceptable salts thereof are also disclosed.

[0010]

[0010] Pharmaceutical compositions comprising one or more disclosed compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier are also disclosed.

[0011]

[0011] Also disclosed is a method for treating a disorder of uncontrolled cell proliferation in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0012]

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

[0013]

[0013] Also disclosed is a method for regulating cereblon activity in at least one cell, comprising the step of contacting at least one cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0014]

[0014] Also disclosed is a method for modulating GSPT1 activity in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0015]

[0015] Also disclosed is a method for regulating GSPT1 activity in at least one cell, comprising the step of contacting at least one cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0016]

[0016] The use of the disclosed compound or a pharmaceutically acceptable salt thereof, the disclosed product or a pharmaceutically acceptable salt thereof, or the disclosed pharmaceutical composition is also disclosed.

[0017]

[0017] The use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating disorders associated with cereblon protein dysfunction in mammals is also disclosed.

[0018]

[0018] The use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating disorders associated with GSPT1 dysfunction in mammals is also disclosed.

[0019]

[0019] Disclosed is the use of a disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for treating a disorder associated with impaired cell proliferation in mammals, for example, for inhibiting the proliferation of cancer cells in mammals, the use comprising the step of combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0020]

[0020] Also disclosed is a method for producing a pharmaceutical for modulating cereblon protein in mammals, comprising the step of combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0021]

[0021] Also disclosed is a method for producing a pharmaceutical for modulating the degradation of GSPT1 in mammals, comprising the step of combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0022]

[0022] Also disclosed is a method for producing a pharmaceutical product that inhibits cell proliferation in mammals, for example, for inhibiting the proliferation of cancer cells, comprising the step of combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0023]

[0023] Also disclosed are a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition, and one or more of the following: (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 GSPT1 activity, (d) at least one agent known to decrease GSPT1 activity, (e) at least one agent known to increase cell proliferation, (f) at least one agent known to decrease cell proliferation, (g) at least one agent known to treat disorders related to cereblon activity, (h) at least one agent known to treat disorders related to GSPT1 activity, (i) at least one agent known to treat disorders of uncontrolled cell proliferation, and / or (j) instructions for treating disorders of uncontrolled cell proliferation.

[0024]

[0024] Also disclosed are a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition, and one or more of the following: (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 cell proliferation, (d) at least one agent known to decrease cell proliferation, (e) at least one agent known to treat disorders related to cereblon activity, (f) at least one agent known to treat disorders of uncontrolled cell proliferation, and / or (g) instructions for treating disorders of uncontrolled cell proliferation.

[0025]

[0025] Also disclosed are a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition, and one or more of the following: (a) at least one agent known to increase GSPT1 activity, (b) at least one agent known to decrease GSPT1 activity, (c) at least one agent known to increase cell proliferation, (d) at least one agent known to decrease cell proliferation, (e) at least one agent known to treat disorders related to GSPT1 activity, (f) at least one agent known to treat disorders of uncontrolled cell proliferation, and / or (g) instructions for treating disorders of uncontrolled cell proliferation.

[0026]

[0026] While aspects of this disclosure may be described and claimed in certain legal classes, such as system legal classes, this is for convenience only, and those skilled in the art will understand that each aspect of this disclosure may be described and claimed in any legal class. Unless otherwise specified, no method or aspect described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Therefore, if a claim for a method does not specifically state in the claim or description that the steps should be limited to a particular order, no order should ever be inferred in any way. This applies to any possible non-express grounds for interpretation, including logical matters relating to the arrangement of steps or operational flows, plain meaning derived from grammatical structure or punctuation, or the number or type of aspects described herein.

[0027]

[0027] Many aspects of this disclosure can be better understood by referring to the following drawings. The components in the drawings are not necessarily to scale, and instead the focus is on clearly illustrating the principles of this disclosure. Furthermore, in the drawings, similar reference numerals indicate corresponding parts through several figures. [Brief explanation of the drawing]

[0028] [Figure 1] This shows prior art thalidomide analogs that induce the degradation of different disease-related proteins. Checkmarks indicate the targets degraded by each IMiD. [Figure 2A] Representative data on the effect of treatment with compounds 1 and 5 at gradually increasing concentrations over 3 days on the viability of MV4-11 cells under the described conditions are shown. [Figure 2B]Representative data on the effect of treatment with compound 1 and 5 at increasingly high concentrations over 3 days on the viability of MV4-11 cells under the described conditions are shown. Figure 2A shows the effect of treatment with compound 1 and 5 at increasingly high concentrations over 3 days on the viability of MV4-11 cells in the absence and presence of lenalidomide (10 μM). Figure 2B shows the effect of treatment with compound 1 and 5 at increasingly high concentrations over 3 days on the viability of wild-type MV4-11 cells compared to CRBN- / -MV4-11 cells. [Figure 3A] Representative data on the effects of treatment with gradually increasing concentrations of compounds 1 and 5 on GSPT1 and IKZF1 levels in MV4-11 cells are shown. [Figure 3B] Representative data on the effects of treatment with gradually increasing concentrations of compounds 1 and 5 on GSPT1 and IKZF1 levels in MV4-11 cells are shown. [Figure 3C] Representative data on the effects of treatment with gradually increasing concentrations of compounds 1 and 5 on GSPT1 and IKZF1 levels in MV4-11 cells are shown. [Figure 3D]Representative data on the effects of treatment with gradually increasing concentrations of compounds 1 and 5 on GSPT1 and IKZF1 levels in MV4-11 cells are shown. Immunoblot images are shown above the graphs, and the band intensities quantified from these immunoblots are plotted on each graph. The immunoblots are labeled to show the detected proteins, namely GSPT1 and IKZF1 proteins, in contrast to a GAPDH control. Each lane of the immunoblot is labeled to show the concentration of a given compound used to treat MV4-11 cells. Figure 3A shows the data obtained for MV4-11 cells treated with compound 1 over 4 hours. Figure 3B shows the data obtained for MV4-11 cells treated with compound 5 over 4 hours. Figure 3C shows the data obtained for MV4-11 cells treated with compound 1 over 24 hours. Figure 3D shows the data obtained for MV4-11 cells treated with compound 5 over 24 hours. Resolution values ​​were calculated using band intensities quantified from immunoblotting and DC50 values ​​calculated based on the mean of at least two independent experiments. [Figure 4] Representative data obtained from TMT-proteomics experiments using compound 1 (10 nM) at 24 hours are shown. The dataset shown represents the mean of n=4 replicates. The upper left region of the plot shows proteins downregulated by more than 1.5 times (dotted line on the Y axis at -Log10 P=3) with a p-value of less than 0.001. As shown, the results for GSPT1, GSPT2, IKZF3, CK1a, and IKZF1 are highlighted within the dataset. [Figure 5] As shown, representative pharmacokinetic data obtained using compound 1 in CD1 mice after a single intravenous (IV) and oral (PO) administration are presented. The dose levels shown are: 3 mg / kg IV and 10 mg / kg PO. Formulation vehicle: 5% v / v NMP: 5% v / v solute HS-15 and 90% v / v normal physiological saline solution. Pharmacokinetic parameters obtained from this study are shown below the graph. [Figure 6] Representative Western blot data obtained using compound 2 for GSPT1 and IKZF1 levels in MV4-11 cells are shown. The immunoblot is labeled to show the detected proteins, namely GSPT1 and IKZF1 proteins, in contrast to a GAPDH control. Each lane of the immunoblot is labeled to show the concentration of a given compound used to treat MV4-11 cells. [Figure 7] Representative Western blot data obtained using wild-type and cereblon-deficient MV4-11 cell lines (clone 4B12) are shown, demonstrating the detection of CRBN protein compared to a GAPDH control. [Figure 8] In comparison to the DMSO control treatment, representative data on the caspase activation of compounds 1 and 5 at 4, 8, and 24 hours after treatment are shown for the concentrations indicated. [Figure 9A] Representative data on the effects of treatment with the prior art compound CC-90009 at gradually increasing concentrations on GSPT1 and IKZF1 levels in MV4-11 cells are shown. [Figure 9B] Representative data on the effects of treatment with the prior art compound CC-90009 at increasing concentrations on GSPT1 and IKZF1 levels in MV4-11 cells are shown. Immunoblot images are shown above the graphs, and the band intensities quantified from these immunoblots are plotted on each graph. The immunoblots are labeled to show the detected proteins, namely GSPT1 and IKZF1 proteins, in contrast to the GAPDH control. Each lane of the immunoblot is labeled to show the concentration of a given compound used to treat MV4-11 cells. Figure 9A shows the data obtained for 4 hours of treatment of MV4-11 cells with compound CC-90009. Figure 9B shows the data obtained for 24 hours of treatment of MV4-11 cells with compound CC-90009.

[0029] [Detailed explanation]

[0037] Additional benefits of this disclosure are partially described in the following description, partially evident from that description, or can be learned through the practice of this disclosure. These benefits will be realized and achieved through the elements and combinations specifically indicated in the attached claims. It should be understood that both the general description above and the detailed description below are illustrative and descriptive only and do not limit the claimed disclosure.

[0030]

[0038] Those skilled in the art, who are interested in the teachings presented in the foregoing description and the accompanying drawings, will likely recognize many modifications and other embodiments of the disclosed compositions and methods. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and adaptations of the embodiments described herein. These variations and adaptations are included in the teachings of this disclosure and are intended to be included within the scope of the claims herein.

[0031]

[0039] Certain terms are used in this specification, but they are used only in a general and descriptive sense and not for any restrictive purpose.

[0032]

[0040] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features that can be readily separated from or combined with features of any of several other embodiments without departing from the scope or spirit of this disclosure.

[0033]

[0041] Any of the recited methods may be performed in the order of the recited events or in any other order that is logically possible. That is, unless otherwise specified, it is never intended that any method or aspect described herein be construed as requiring that its steps be performed in a particular order. Thus, where a method claim does not specifically state in the claim or the specification that the steps should be limited to a particular order, no order should be inferred in any respect. This applies to any possible implicit basis for interpretation, including matters of logic regarding the arrangement of steps or the operation flow, the plain meaning derived from the grammatical construction or punctuation, or the number or type of aspects described herein.

[0034]

[0042] All publications referred to herein are incorporated herein by reference for the purpose of disclosing and describing the relevant methods and / or materials cited therein. The publications described herein are provided only for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present disclosure has no right to antedate such publications by virtue of prior disclosure. Further, the publication dates provided herein may be different from the actual publication dates and may require independent verification.

[0035]

[0043] Aspects of the present disclosure may be described and claimed in terms of specific statutory classes such as system statutory classes, but this is for convenience only, and one of ordinary skill in the art will understand that each aspect of the present disclosure may be described and claimed in terms of any statutory class.

[0036]

[0044] It should also be understood that the terms used herein are intended to describe only specific aspects and are not intended to limit them. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the field to which the disclosed compositions and methods belong. Terms such as those defined in commonly used dictionaries should be interpreted as having the meaning consistent with their meaning in the context of this specification and the related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0037]

[0045] Unless otherwise specified, the aspects of this disclosure utilize techniques within the scope of the art of those skilled in the art, such as molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, and vascular biology. Such techniques are adequately described in the literature.

[0038]

[0046] Before describing the various aspects of this disclosure, the following definitions are provided and should be used unless otherwise specified. Additional terms may be defined elsewhere in this disclosure.

[0039]

[0047] A.Definition As used herein, “comprising” should be interpreted as specifying the presence of the described feature, integer, step, or component mentioned, but not as excluding the presence or addition of one or more features, integers, steps, or components or groups thereof. Furthermore, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” may be used interchangeably in their open and non-restrictive senses. In addition, the term “comprising” is intended to include examples and aspects that are encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples that are encompassed by the term “consisting of.”

[0040]

[0048] As used herein, the terms “and / or” include any combination of one or more of the related enumerated items. Expressions such as “at least one of” modify the entire list of elements, but not the individual elements of the list, when they precede a list of elements.

[0041]

[0049] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple references unless the context clearly indicates otherwise. Thus, for example, references to two or more such compounds, substituents, or cancers, including but not limited to a compound, substituent, or cancer, such as a compound, a substituent group, or a cancer.

[0042]

[0050] References to chemical compounds, proteins, and antibodies under the name "a / an" are not limited to single molecules of chemical compounds, proteins, and antibodies, but rather refer to one or more molecules of each category. Furthermore, these one or more molecules may or may not be identical, as long as they belong to the categories of chemical compounds, proteins, and antibodies. Therefore, for example, "an" antibody is interpreted as containing one or more antibody molecules, and these antibody molecules may or may not be identical (e.g., different isotypes and / or different antigen-binding sites that may be found in polyclonal antibodies).

[0043]

[0051] It should be noted that ratios, concentrations, quantities, and other numerical data may be expressed in range form as herein. It will be further understood that the endpoint of each range is important both in relation to and independently of the other endpoint. It should also be understood that there are several values ​​disclosed herein, and each value is disclosed herein not only as the value itself, but also as "about" that particular value. For example, if the value "10" is disclosed, "about 10" is also disclosed. Ranges may be expressed herein as "about" one particular value and / or "about" another particular value. Similarly, it will be understood that when a value is expressed as an approximation using the antecedent "about", the particular value forms further aspects. For example, if the value "about 10" is disclosed, "10" is also disclosed.

[0044]

[0052] Where a range is expressed, further aspects include from one specific value and / or to another specific value. Where a range of values ​​is provided, unless the context clearly indicates otherwise, each intervening value up to one-tenth of the lower limit between the upper and lower limits of that range, and any other stated or intervening values ​​within that stated range, are understood to be included in this disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller range and are included in this disclosure subject to any specifically excluded limits within the stated range. If a stated range includes one or both limits, the range excluding one or both of those limits is also included in this disclosure. For example, if a stated range includes one or both limits, the range excluding one or both of those limits is also included in this disclosure; for example, the phrase "x to y" includes the range from "x" to "y" and the range greater than "x" and less than "y". The range can be expressed as an upper limit, for example, "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." Similarly, 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." Furthermore, the phrase "about 'x' to 'y'" (where "x" and "y" are numerical values) includes "about 'x' to about 'y'."

[0045]

[0053] Such range formats are used for convenience and brevity, and should therefore be interpreted flexibly to include not only the numbers explicitly listed as the limits of the range, but also all individual numbers or subranges contained within that range, as if each number and subrange were explicitly listed. For example, the numerical range "approximately 0.1% to 5%" should be interpreted to include not only the explicitly listed values ​​of approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., approximately 1%, approximately 2%, approximately 3%, and approximately 4%) and subranges (e.g., approximately 0.5% to approximately 1.1%; approximately 5% to approximately 2.4%; approximately 0.5% to approximately 3.2%; and approximately 0.5% to approximately 4.4%, as well as other possible subranges).

[0046]

[0054] As used herein, “about,” “approximately,” and “substantially,” when used in relation to numerical variables, can generally refer to the larger of the variable value within experimental error (e.g., within the 95% confidence interval of the mean) or within + / - 10% of the indicated value, and all variable values. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” may mean that the quantity or value in question may be an exact value or a value that provides an equivalent result or effect to those enumerated in the claims or taught herein. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics are not, and do not necessarily need to be, exact, but may be approximate and / or larger or smaller, as desired, taking into account tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art to obtain an equivalent result or effect. In some circumstances, a value that provides an equivalent result or effect cannot be reasonably determined. In general, quantities, sizes, formulations, parameters, or other quantities or characteristics are "about," "approximate," or "at or about," whether or not it is explicitly stated otherwise. When "about," "approximate," or "at or about" is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specified.

[0047]

[0055] As used herein, the terms “optional” or “optionally” mean that the following events or circumstances may or may not occur, and that the descriptions thereof include both cases in which such events or circumstances occur and cases in which they do not occur.

[0048]

[0056] As used herein, “Cereblon” and “CRBN” may be used interchangeably and refer to the protein encoded by the human CRBN gene, which has a cytogenetic position of 3p26.2 and a molecular position of base pairs 3,148,489 to 3,179,716 on chromosome 3 (UCSC Genome Browser on Human Dec.2013 (GRCh38 / hg38) Assembly). The human gene structure contains 11 exons. CRBN is the substrate-recognizing component of the DCX(DDB1-CUL4-X-box)E3 protein ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The DCX(DDB1-CUL4-X-box)E3 protein ligase complex consists of at least 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; isoform 2 has 441 amino acids and a molecular weight of 50,475 Da.

[0049]

[0057] As used herein, "CC-220" refers to the compound having the IUPAC name (CAS number 1323403-33-3; (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindorin-2-yl)piperidine-2,6-dione) and the structure given by the following formula: [ka]

[0050]

[0058] As used herein, "CC-885" refers to the compound having the IUPAC name of CAS number 1010100-07-8; N-(3-chloro-4-methylphenyl)-N'-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindole-5-yl]methyl]urea and the structure given by the following formula: [ka]

[0051]

[0059] As used herein, "CC-90009" refers to a compound having the IUPAC name CAS number 1860875-51-9; 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide and the structure given by the following formula:

Chem.

[0052]

[0060] As used herein, “administering” may refer to administration by oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, arteriole, dermal, ventricular, bone, ocular, intracranial, abdominal, lesion, nasal cavity, cardiac, intraarticular, cavity, medullary, vitreous, cerebral and lateral ventricles, tympanic cavity, cochlea, rectum, or vaginal; administration by inhalation; administration by catheter, stent; or administration via other devices that actively or passively (e.g., by diffusion) administer the composition into an implanted reservoir or perivascular space and adventitia. For example, medical devices such as stents may contain a composition or formulation placed on their surface, which can then be dissolved or otherwise distributed into the surrounding tissues and cells. The term "parenteral" may include subcutaneous injection or subcutaneous infusion techniques, intravenous injection or intravenous infusion techniques, intramuscular injection or intramuscular infusion techniques, intra-articular injection or intra-articular infusion techniques, synovial injection or synovial infusion techniques, intrasternal injection or intrasternal infusion techniques, intrathecal injection or intrathecal infusion techniques, intrahepatic injection or intrahepatic infusion techniques, intrafocal injection or intrafocal infusion techniques, and intracranial injection or intracranial infusion techniques. Administration may be continuous or intermittent. In various embodiments, the preparation may be administered therapeutically, i.e., to treat an existing disease or condition. In even more various embodiments, the preparation may be administered prophylactically, i.e., to prevent a disease or condition.

[0053]

[0061] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, etc. that may be biologically active or, otherwise, may induce pharmacological, immunogenic, biological, and / or physiological effects on a target to which it is administered by local and / or systemic action. A therapeutic agent may be a primary activator, or in other words, a component of a composition to which all or part of the effects of the composition are attributed. A therapeutic agent may be a secondary therapeutic agent, or in other words, a component of a composition to which additional parts and / or other effects of the composition are attributed. Accordingly, the term encompasses compounds or chemical substances conventionally considered as drugs, vaccines, and biologics, including molecules such as proteins, peptides, hormones, nucleic acids, and gene constructs. Examples of therapeutic agents are listed in well-known literature, such as the Merck Index (14th edition), Physicians' Desk Reference (64th edition), and Pharmacological Basis of Therapeutics (12th edition), and include, without limitation, pharmaceuticals; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure or alleviate diseases or illnesses; substances that affect the structure or function of the body; or prodrugs that become biologically active or further active after being placed in a physiological environment.For example, the term "therapeutic agent" includes, without limitation, adjuvants; anti-infective agents, e.g., antibiotics and antivirals; analgesics and combinations of analgesics; appetite suppressants; anti-inflammatory agents; anticonvulsants; topical and general anesthetics; hypnotics; sedatives; antipsychotics; nerve blockers; antidepressants; anxiolytics; antagonists; neuroleptics; anticholinergics and cholinergics; antimuscarinic agents and muscarinic agents; anti-adrenergics; antiarrhythmics; antihypertensives; hormones and nutrients; anti-arthritis agents; anti-asthmatics agents; anticonvulsants; antihistamines; antiemetics; anticancer agents; antipruritics; antipyretics; antispasmodics; cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrhythmics); antihypertensives; diuretics; vasodilators; central nervous system stimulants. This includes compounds or compositions for use in any major therapeutic area, including potent drugs; preparations for coughs and colds; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides and their fragments (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-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin), and other biologically active macromolecules, such as proteins and enzymes. The drugs may be biologically active agents used in medical applications, including veterinary medicine, and agriculture, including plants, for example, and other fields. The term therapeutic agent includes, but is not limited to, pharmaceuticals; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure or alleviate diseases or illnesses; or substances that affect the structure or function of the body; or prodrugs that become biologically active or further active after being placed in a given physiological environment.

[0054]

[0062] As used herein, “kit” means a collection of at least two components that make up the kit. Together, the components constitute a functional unit for a given purpose. Individual component parts may be packaged together or separately. For example, a kit that includes instructions for using the kit may or may not physically include the instructions together with the other individual component parts. Alternatively, the instructions may be supplied as a separate component part, either in paper or electronic form, or as a recorded presentation, which may be supplied on a computer-readable memory device or downloaded from an internet website.

[0055]

[0063] As used herein, “Instructions” means a document describing the materials or methods relating to the kit. These materials may include background information, a list of components and their availability information (such as purchasing information), a simple or detailed protocol for using the kit, troubleshooting, references, technical support, and any other relevant documentation in any combination. Instructions may be supplied with the kit or as a separate component, either in paper or electronic form, or as a recorded presentation, which may be supplied on a computer-readable memory device or downloaded from an internet website. Instructions may include one or more documents and include future updates.

[0056]

[0064] As used herein, “bonded” may refer to covalent or non-covalent interactions between two or more molecules. Non-covalent interactions may include ionic bonds, electrostatic interactions, van der Waals forces, dipole-dipole interactions, dipole-inductive-dipole interactions, London dispersion forces, hydrogen bonds, halogen bonds, electromagnetic interactions, π-π interactions, cation-π interactions, anion-π interactions, polar π interactions, and hydrophobic effects.

[0057]

[0065] As used herein, the term “subject” can be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Therefore, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. The term is not intended to indicate a specific age or sex; therefore, it is intended to encompass adult and young subjects, whether male or female. In one embodiment, the subject is a mammal. “Patient” means a subject suffering from a disease or disorder. The term “patient” includes human and veterinary subjects.

[0058]

[0066] As used herein, the terms “treating” and “treatment” can generally refer to obtaining a desired pharmacological and / or physiological effect. An effect may be prophylactic in that it prevents or partially prevents a disease, its symptoms or pathology, such as uncontrolled cellular disorders, such as cancers such as acute leukemia or medulloblastoma, but it is not necessarily required to be so. An effect may be therapeutic in that it partially or completely cures a disease, pathology, symptoms, or adverse effects resulting from a disease, disorder or pathology. As used herein, the term “treatment” may include any treatment of a subject, in particular uncontrolled cellular disorders in humans, such as cancers such as acute leukemia or medulloblastoma, and may include one or more of the following: (a) preventing the development of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with it; (b) inhibiting the disease, i.e., stopping its development; and (c) mitigating the disease, i.e., alleviating or improving the disease and / or its symptoms or pathology. As used herein, the term “treatment” may refer to a therapeutic measure alone, a preventive measure alone, or both a therapeutic and a preventive measure. Those in need of treatment (subjects requiring treatment) may include those who already have a disability and / or those who should be prevented from developing a disability. As used herein, the term “treating” may include inhibiting a disease, disability, or condition, e.g., preventing its progression, and alleviating a disease, disability, or condition, e.g., causing regression of the disease, disability, and / or condition. Treating a disease, disability, or condition may include improving at least one symptom of a particular disease, disability, or condition, even if the underlying pathophysiology is not affected, e.g., treating pain in a subject by administering an analgesic, even if such analgesic does not treat the cause of the pain.

[0059]

[0067] As used herein, “dose,” “unit dose,” or “administered amount” may refer to a physically distinct unit suitable for use on a subject, each unit containing a predetermined amount of the disclosed compound and / or its pharmaceutical composition calculated to produce one or more desired responses in relation to its administration.

[0060]

[0068] As used herein, “therapeutic” may mean treating, curing, and / or improving a disease, disorder, condition, or side effect, or slowing the progression of a disease, disorder, condition, or side effect.

[0061]

[0069] As used herein, “effective dose” may mean an amount of a compound or pharmaceutical composition disclosed herein that is sufficient to produce a beneficial or desired biological, emotional, medical, or clinical response in a cell, tissue, system, animal, or human. An effective dose may be administered in one or more doses, applications, or dosages. The term may also include, within its range, amounts that are effective in enhancing or restoring substantially normal physiological function.

[0062]

[0070] As used herein, the term “therapeutic dose” refers to a quantity sufficient to achieve the desired therapeutic outcome or to have an effect on an undesirable symptom, but generally insufficient to cause adverse side effects. The specific therapeutic dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the time of administration; the route of administration; the rate of excretion of the specific compound used; the duration of treatment; and drugs used in combination with or concurrently with specific compounds and similar factors used within the knowledge and expertise of the healthcare professional, including drugs that may be well-known in the medical field. When treating a particular disease or condition, in some cases the desired response may be to inhibit the progression of the disease or condition. This may only involve a temporary slowing of disease progression. In other cases, however, it may be desirable to permanently halt disease progression. This can be monitored by commonly used diagnostic methods known to those skilled in the art for any particular disease. The desired response to the treatment of a disease or condition may also be to delay the onset of the disease or condition, or even to prevent its onset.

[0063]

[0071] For example, it is well within the realm of the art to start with a dose of a compound at a level lower than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. If desired, an effective daily dose may be divided into multiple doses for administration. As a result, a single-dose composition may contain such an amount or a fraction thereof to constitute a daily dose. Dosages may be adjusted by the individual physician in the event of any contraindications. It is generally preferable to use the maximum dose of the pharmacological agents of this disclosure (alone or in combination with other therapeutic agents), i.e., to use the safe highest dose based on reasonable medical judgment. However, it will be understood by those skilled in the art that patients may request a lower or more acceptable dose for medical, psychological, or substantially any other reason.

[0064]

[0072] The response to a therapeutically effective dose of the disclosed compound and / or pharmaceutical composition may be measured, for example, by determining the physiological effect of the treatment or drug therapy, e.g., the reduction or absence of disease symptoms after administration of the treatment or pharmacological agent. Other assays are known to those skilled in the art and may be used to measure the level of response. The therapeutic dose may vary, for example, by increasing or decreasing the amount of the disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, or by changing the timing of administration. Dosages may vary and may be administered once or more times a day over a day or several days. Guidelines for appropriate dosages of a given class of pharmaceuticals can be found in the literature.

[0065]

[0073] As used herein, the term “preventive dose” refers to the amount that is effective in preventing the onset or commencement of a disease or condition.

[0066]

[0074] As used herein, the terms “prevent” or “preventing” mean, in particular, to prevent, avoid, eliminate, deter, stop, or delay something from happening through prior action. Where “reduce,” “inhibit,” or “prevent” are used herein, it is understood that the use of the other two words is also expressly disclosed unless otherwise specifically designated.

[0067]

[0075] The term "pharmaceutically acceptable" refers to a material that is not biologically or otherwise undesirable; that is, it does not cause undesirable levels of biological effects or interact in a harmful manner.

[0068]

[0076] As used herein, the term “pharmaceutically acceptable salt” means a salt of an active ingredient prepared with an acid or base that, when administered in a therapeutically effective dose, is tolerable by the biological system or by the subject, or tolerable by the biological system and tolerable by the subject. If a compound of the disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either undiluted or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts of sodium, potassium, calcium, ammonium, organic amino acids, magnesium salts, lithium salts, strontium salts, or similar substances. If a compound of the disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either undiluted or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids, such as alginates, and salts of organic acids, such as glucuronic acid or galacturonic acid, are also included.

[0069]

[0077] The term “pharmaceutically acceptable ester” refers to an ester of a compound of the disclosure that is hydrolyzable in vivo and includes those that readily decompose in the human body, leaving the parent compound or a salt thereof. Examples of pharmaceutically acceptable non-toxic esters of the disclosure include C1-C6 alkyl esters and C5-C7 cycloalkyl esters, with C1-C4 alkyl esters being preferred. Esters of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be prepared by adding a hydroxyl group to a compound containing a hydroxyl group by reaction with an acid and an alkylcarboxylic acid, such as acetic acid, or by reaction with an acid and an arylcarboxylic acid, such as benzoic acid. In the case of a compound containing a carboxylic acid group, a pharmaceutically acceptable ester can be prepared from the compound containing the carboxylic acid group by reaction with a base such as triethylamine and an alkyl halide, for example, methyl iodide, benzyl iodide, cyclopentyl iodide, or alkyl triflate. They can also be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0070]

[0078] The term “pharmaceutically acceptable amide” refers to the non-toxic amides of this disclosure derived from ammonia, primary C1-C6 alkylamines, and secondary C1-C6 dialkylamines. In the case of secondary amines, the amine may be in the form of a 5 or 6-membered heterocyclic ring containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides, and C1-C2 dialkyl secondary amides are preferred. Amides of the disclosed compounds may be prepared according to conventional methods. Pharmaceutically acceptable amides may be prepared from compounds containing a primary or secondary amine group by reacting the amino group-containing compound with an alkyl anhydride, aryl anhydride, acyl halogenated or alloyl halogenated compound. In the case of compounds containing a carboxylic acid group, pharmaceutically acceptable amides are prepared from the carboxylic acid group-containing compound by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyldiimidazole, and alkylamines, dialkylamines, for example, methylamine, diethylamine, and piperidine. These can also be prepared by reacting the compound with an acid, such as sulfuric acid, and an alkylcarboxylic acid, such as acetic acid, or with an acid and an arylcarboxylic acid, such as benzoic acid, under dehydrating conditions, such as by adding a molecular sieve. The composition may contain the compounds of this disclosure in the form of a pharmaceutically acceptable prodrug.

[0071]

[0079] The term “pharmaceutically acceptable prodrug” or “prodrug” refers to a prodrug of a compound of the Disclosure that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. The prodrugs of the Disclosure can be rapidly converted in vivo to a parent compound having the structure of the disclosed compound, for example, by hydrolysis in the blood. A complete description is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V.14 of the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0072]

[0080] As used herein, the term “derivative” means a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein), whose structure is sufficiently similar to that disclosed herein, and which, based on that similarity, would be expected by those skilled in the art to exhibit the same or similar activity and utility as the claimed compound, or, as a precursor, to induce the same or similar activity and utility as the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

[0073]

[0081] Where used herein, the nomenclature of compounds, including organic compounds, may be assigned using the common name, the IUPAC, IUBMB, or CAS nomenclature recommendations. If one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to specify stereochemical priority, E / Z specifications, etc. Those skilled in the art can easily verify the structure of a compound once a name is assigned by systematic reduction of the compound structure using the nomenclature rules, or by using commercially available software such as CHEMDRAW® (Cambridgesoft Corporation, USA).

[0074]

[0082] A reference to "a" chemical compound is not limited to a single molecule of a chemical compound, but rather refers to one or more molecules of a chemical compound. Furthermore, the one or more molecules may or may not be identical, as long as they belong to the category of chemical compound. Therefore, for example, "a" chemical compound is interpreted as containing one or more molecules of a chemical substance, and the molecules may or may not be identical (e.g., different isotopic ratios, enantiomers, etc.).

[0075]

[0083] It should be noted that ratios, concentrations, quantities, and other numerical data may be expressed in range form as herein. It will be further understood that the endpoint of each range is important both in relation to and independently of the other endpoint. It should also be understood that there are several values ​​disclosed herein, and each value is disclosed herein not only as the value itself, but also as "about" that particular value. For example, if the value "10" is disclosed, "about 10" is also disclosed. Ranges may be expressed herein as "about" one particular value and / or "about" another particular value. Similarly, it will be understood that when a value is expressed as an approximation using the antecedent "about", the particular value forms further aspects. For example, if the value "about 10" is disclosed, "10" is also disclosed.

[0076]

[0084] Where a range is expressed, further embodiments include a range from one specific value and / or to another specific value. For example, if a stated range includes one or both of the limits, the range excluding one or both of the limits that they include is also included in this disclosure, for example, the phrase “x to y” includes the range from “x” to “y” and the range greater than “x” and less than “y”. A range may be expressed as an upper limit, for example, “about x, y, z or less,” and should be interpreted as including the specific ranges of “about x,” “about y,” and “about z,” as well as the ranges “less than x,” “less than y,” and “less than z.” Similarly, the phrase “about x, y, z or more” should be interpreted as including the specific ranges of “about x,” “about y,” and “about z,” as well as the ranges “greater than x,” “greater than y,” and “greater than z.” Furthermore, the phrase “about “x” to “y”” (where “x” and “y” are numerical values) includes “about “x” to about “y.”

[0077]

[0085] Such range formats are used for convenience and brevity, and should therefore be interpreted flexibly to include not only the numbers explicitly listed as the limits of the range, but also all individual numbers or subranges contained within that range, as if each number and subrange were explicitly listed. For example, the numerical range "approximately 0.1% to 5%" should be interpreted to include not only the explicitly listed values ​​of approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., approximately 1%, approximately 2%, approximately 3%, and approximately 4%) and subranges (e.g., approximately 0.5% to approximately 1.1%; approximately 5% to approximately 2.4%; approximately 0.5% to approximately 3.2%; and approximately 0.5% to approximately 4.4%, as well as other possible subranges).

[0078]

[0086] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the quantity or value may be an exact value or a value that provides equivalent results or effects to those enumerated in the claims or taught herein. That is, quantities, sizes, formulations, parameters, and other quantities and characteristics are not, and do not necessarily need to be, exact, but may be approximate and / or larger or smaller, as desired, taking into account tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art to obtain equivalent results or effects. In some circumstances, a value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” generally mean nominal values ​​with a variation of ±10%, unless otherwise specified or inferred. In general, quantities, sizes, formulations, parameters, or other quantities or characteristics are "about," "approximate," or "at or about," whether or not it is explicitly stated otherwise. When "about," "approximate," or "at or about" is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specified.

[0079]

[0087] As used herein, the term “bring to contact” means bringing the disclosed compound or pharmaceutical composition into close proximity to a cell, target protein, or other biological entity so that the disclosed compound or pharmaceutical composition may directly affect the activity of the cell, target protein, or other biological entity, i.e., by interacting with the cell, target protein, or other biological entity itself, or so that the disclosed compound or pharmaceutical composition may indirectly affect the activity of the target protein or other biological entity, i.e., by interacting with another molecule, cofactor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself depends.

[0080]

[0088] As used herein, the term “effective amount” means an amount sufficient to achieve a desired modification of the physical properties of a composition or material. For example, the “effective amount” of a disclosed compound or pharmaceutical composition means an amount sufficient to achieve a desired degree of regulation of a target, e.g., regulation of cereblon protein, or a desired improvement or enhancement of a clinical condition, e.g., remission of cancer. The amount of a disclosed compound or pharmaceutical composition required as an effective amount, e.g., in milligrams, or a specific level in terms of concentration, e.g., in micromoles, depends on various factors, e.g., the route of administration or route of contact with the target, the severity of the clinical condition, the desired degree of regulation, and so on.

[0081]

[0089] As used herein, the terms “optional” or “optionally” mean that the following events or circumstances may or may not occur, and that the descriptions thereof include both cases in which such events or circumstances occur and cases in which they do not occur.

[0082]

[0090] As used herein, the term “substituted” is understood to include any acceptable substituent of an organic compound. In broad embodiments, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those listed below: an acceptable substituent may be one or more identical or different for a given organic compound. For the purposes of this disclosure, a heteroatom such as nitrogen may have hydrogen substituents and / or any acceptable substituents of the organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any way by the acceptable substituents of an organic compound. Furthermore, the terms “substitution” or “substituted with” include the implicit condition that such substitution is subject to the atom being substituted and the acceptable valence of the substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. In certain embodiments, unless otherwise explicitly indicated, it is intended that individual substituents may be further substituted (i.e., further substituted or unsubstituted).

[0083]

[0091] When defining various terms, "A 1 "A 2 "A 3 " and "A 4 The symbol ' is used herein as a general symbol to represent various specific substituents. These symbols may represent any substituent, not limited to those disclosed herein, and may be defined in some cases as a specific substituent, or in other cases as several other substituents.

[0084]

[0092] As used herein, the term “alkyl” refers to a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups can also be substituted or unsubstituted. For example, an alkyl group may be substituted with one or more groups, without limitation, including 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 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl group can also refer to alkyl groups up to C1-C24, such as 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, etc.

[0085]

[0093] Throughout this specification, “alkyl” is used generally to refer to both unsubstituted and substituted alkyl groups. However, substituted alkyl groups are also referred to specifically in this specification by identifying specific substituents on the alkyl group. For example, the term “haloalkyl” or “haloalkyl” specifically refers to an alkyl group substituted with one or more halides, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group substituted with a single halide, e.g., fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group independently substituted with two or more halides, i.e., each halide substituent does not have to be the same halide as another halide substituent, nor do multiple instances of the halide substituents have to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxyl groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another, it does not mean that the term "alkyl" does not also refer to the specific term such as "hydroxyalkyl."

[0086]

[0094] This practice is also applied to other groups described herein. That is, terms such as “cycloalkyl” refer to both unsubstituted and substituted cycloalkyl moieties, but the substituted moieties may be further specifically identified herein. For example, certain substituted cycloalkyls may be called, for example, “alkylcycloalkyl.” Similarly, substituted alkoxys may be specifically called, for example, “halogenated alkoxy,” and certain substituted alkenyls may be, for example, “alkenyl alcohols.” Here again, practices using general terms such as “cycloalkyl” and specific terms such as “alkylcycloalkyl” do not mean that the general terms do not include the specific terms.

[0087]

[0095] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and others. The term "heterocycloalkyl" is a type of cycloalkyl as defined above, and falls within the scope of the meaning of the term "cycloalkyl" if at least one of the carbon atoms in the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but is not limited to. Cycloalkyls and heterocycloalkyls may be substituted or unsubstituted. Cycloalkyls and heterocycloalkyls may be substituted by one or more groups, without limitation, including alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0088]

[0096] The terms “alkoxy” and “alkoxyl” are used herein to refer to alkyl or cycloalkyl groups linked via ether bonds. That is, the “alkoxy” group is -OA 1 It can be defined as, in the formula, A 1 is an alkyl or cycloalkyl group as defined above. "Alkoxy" also includes polymers of alkoxy groups as just described. That is, alkoxy is a polyether, e.g., -OA 1 -OA 2 , or -OA 1 -(OA 2 ) a -OA 3 This is possible, and in the formula, "a" is an integer between 1 and 200, and A 1 , A 2 and A 3 These are alkyl groups and / or cycloalkyl groups.

[0089]

[0097] As used herein, the terms "amine" or "amino" refer to the formula -NA 1A 2 It is expressed by, in the formula, A 1 and A 2 This can be, independently, hydrogen or an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group or heteroaryl group, as described herein. A specific example of amino is -NH2.

[0090]

[0098] As used herein, the term "alkylamino" is represented by the formulas -NH(-alkyl) and -N(-alkyl)2, where alkyl is as defined herein. Typical examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, and N-ethyl-N-propylamino group.

[0091]

[0099] As used herein, the term "ether" refers to formula A 1 OA 2 It is expressed by, in the formula, A 1 and A 2 This can independently be an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group, or heteroaryl group as described herein. The term "polyether" as used herein refers to a group of the formula -(A 1 OA 2 O) a - is expressed by, in the formula, A 1 and A 2can independently be an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group, or heteroaryl group as described herein, where "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0092]

[0100] As used herein, the term "hydroxyl" or "hydroxy" is represented by the formula -OH.

[0093]

[0101] As used herein, the term "thiol" is represented by the formula -SH.

[0094]

[0102] The term "azide" or "azido" as used herein is represented by formula -N3.

[0095]

[0103] As used herein, the term "nitro" is represented by the formula -NO2.

[0096]

[0104] As used herein, the terms "nitrile" or "cyano" are represented by the formula -CN.

[0097]

[0105] As used herein, the terms “halo,” “halogen,” or “halide” may be used interchangeably and refer to F, Cl, Br, or I.

[0098]

[0106] As used herein, the terms “pseudohalides,” “pseudohalogens,” or “pseudohalo” may be used interchangeably and refer to functional groups that behave substantially similarly to halides. Such functional groups include, for example, cyano groups, thiocyanate groups, azide groups, trifluoromethyl groups, trifluoromethoxy groups, perfluoroalkyl groups, and perfluoroalkoxy groups.

[0099]

[0107] As used herein, the term “heteroalkyl” refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0100]

[0108] As used herein, the term “heterocycloalkyl” refers to aliphatic partially unsaturated or fully saturated 3- to 14-membered ring systems, including monocyclic rings of 3 to 8 atoms, as well as bicyclic and tricyclic systems. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms may be oxidized, and the nitrogen heteroatom may 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.

[0101]

[0109] As used herein, the term "carbonyl" is represented by the formula -C(O)-. Throughout this specification, "C(O)" or C=O is an abbreviation for the carbonyl group.

[0102]

[0110] As used herein, the term “aromatic group” refers to a cyclic structure having a cyclic cloud of delocalized π electrons above and below the plane of the molecule, the π cloud containing (4n+2)π electrons. A further explanation of aromaticity can be found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477–497, which is incorporated herein by reference. The term “aromatic group” includes both aryl and heteroaryl groups.

[0103]

[0111] As used herein, the term “aryl” refers to any group containing any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, and anthracene. The aryl group may be substituted or unsubstituted. The aryl group may be substituted with one or more groups, as described herein, 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. The term “biaryl” refers to a specific type of aryl group and is included in the definition of “aryl.” Furthermore, the aryl group may be a monocyclic structure, a fused-ring structure, or a multi-ring structure linked via one or more bridging groups, such as carbon-carbon bonds. For example, a biaryl to two aryl groups linked together via a fused-ring structure, as in naphthalene, or linked via one or more carbon-carbon bonds, as in biphenyl.

[0104]

[0112] As used herein, the term “heteroaryl” refers to an aromatic group having 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, and N-oxides, sulfur oxides, and dioxides are acceptable heteroatom substitutions. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may be substituted with one or more groups, without limitation, including alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol groups, as described herein. Heteroaryl groups may be monocyclic or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinil, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridadinyl, pyrazinyl, benzofuranil, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyridinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyradinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyradinyl.

[0105]

[0113] As used herein, the term “heterocycle” may be used without distinction and refers to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is not carbon. Therefore, the term includes, without limitation, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, e.g., 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole, thiadiazole, e.g., 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, e.g., 1, These include 2,3-triazoles, 1,3,4-triazoles, tetrazoles, e.g., 1,2,3,4-tetrazoles and 1,2,4,5-tetrazoles, pyridazines, pyrazines, triazines, e.g., 1,2,4-triazines and 1,3,5-triazines, tetrazines, e.g., 1,2,4,5-tetrazine, pyrrolidines, piperidines, piperazines, morpholine, azetidines, tetrahydropyrans, tetrahydrofurans, and dioxanes. Furthermore, the term heterocyclyl group can refer to heterocyclyls from C2 to C18 or lower, such as 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, etc. For example, a C2 heterocyclyl includes, without limitation, groups having two carbon atoms and at least one heteroatom, including aziridinyl, diazetidinyl, dihydrodiazetyl, oxyranil, thyranil, etc. Alternatively, a C5 heterocyclyl includes, without limitation, groups having five carbon atoms and at least one heteroatom, including piperidinyl, tetrahydropyranil, tetrahydrothiopyranil, diazepanil, pyridinyl, etc.It is understood that heterocyclyl groups can be bonded via either heteroatoms within the ring, if chemically possible, or via one of the carbon atoms containing the heterocyclyl ring.

[0106]

[0114] "R 1 "R 2 "R 3 ", ... "R n When used herein, (wherein n is an integer) can independently have one or more of the bases listed above. For example, R 1 If the group is a linear alkyl group, one of the hydrogen atoms of the alkyl group may be substituted by a hydroxyl group, an alkoxy group, another alkyl group, a halide, etc. Depending on the group selected, the first group can be incorporated into the second group, or alternatively, the first group can be pendanted (i.e., bonded) to the second group. For example, in the phrase "alkyl group containing an amino group," the amino group may be incorporated into the alkyl group's skeleton, or the amino group may be bonded to the alkyl group's skeleton. The properties of the selected group determine whether the first group is embedded in or bonded to the second group.

[0107]

[0115] As described herein, the compounds of this disclosure may contain “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a given moiety are replaced by a preferred substituent, whether preceded by the term “optionally.” Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each substituted position of the group, and the substituents may be the same or different at all positions if multiple positions in any given structure can be replaced by multiple substituents selected from a particular group. The substituent combinations envisioned by this disclosure preferably result in the formation of stable or chemically feasible compounds. In certain embodiments, unless expressly indicated otherwise, it is also intended that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0108]

[0116] Where used herein and in the final claims, a chemical species residue refers to a portion that is the obtained product of a chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the portion is actually obtained from the chemical species. Thus, an ethylene glycol residue in polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether the polyester was prepared using ethylene glycol. Similarly, a sebacic acid residue in polyester refers to one or more -CO(CH2)8CO- portions in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0109]

[0117] The term “organic residue” defines a carbon-containing residue, i.e., a residue containing at least one carbon atom, and includes, without limitation, the carbon-containing groups, carbon-containing residues, or carbon-containing radicals as defined above. Organic residues may contain a variety of heteroatoms or may be bonded to another molecule via heteroatoms containing oxygen, nitrogen, sulfur, phosphorus, etc. Examples of organic residues include, without limitation, alkyl or substituted alkyl groups, alkoxy or substituted alkoxy groups, mono or disubstituted amino groups, amide groups, etc. Organic residues may preferably contain 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In further embodiments, organic residues may contain 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0110]

[0118] A very close synonym for the term “residue” is the term “radical,” which, as used herein and in the final claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the following structure: [ka] (Whether or not the compound is prepared using thiazolidinediones). In some embodiments, the radical (e.g., alkyl) may be further modified by attaching one or more "substituted radicals" (i.e., substituted alkyls). The number of atoms in a given radical is not important to this disclosure unless otherwise indicated elsewhere herein.

[0111]

[0119] As used herein, the term “stable” means a compound that, in its production, detection, and in certain embodiments, remains substantially unchanged when subjected to conditions that enable its recovery, purification, and use for one or more purposes disclosed herein.

[0112]

[0120] The compounds described herein may contain one or more double bonds and thus may potentially give rise to cis / trans (E / Z) isomers and other conformational isomers. Unless otherwise stated, this disclosure includes all such possible isomers and mixtures of such isomers.

[0113]

[0121] Unless otherwise stated, formulas in which chemical bonds are shown only as solid lines and not as wedge-shaped or dashed lines intend each possible isomer, e.g., each enantioma and diastereoma, as well as mixtures of isomers, e.g., racemic or scalemic mixtures. The compounds described herein may contain one or more chiral centers and thus potentially give rise to diastereomas and optical isomers. Unless otherwise stated, this disclosure includes all such possible diastereomas, as well as their racemic mixtures, their substantially pure decomposed enantiomas, all possible geometric isomers, and their pharmaceutically acceptable salts. It also includes mixtures of stereoisomers and specific stereoisomers that have been isolated. In the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0114]

[0122] Many organic compounds exist in optically active forms that have the ability to rotate the plane of linearly polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute conformation of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of linearly polarized light by the compound, with (-) or meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images that cannot be superimposed on each other. Certain stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomatous mixtures. A 50:50 mixture of enantiomas is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomatous forms. If desired, chiral carbons may be indicated by an asterisk (*). When a disclosed formula shows a bond to a chiral carbon as a straight line, it is understood that both the (R) and (S) conformations of the chiral carbon, and therefore both enantiomas and mixtures thereof, are included in the formula. If it is desired to specify the absolute conformation around a chiral carbon, as used in the art, one of the bonds to the chiral carbon may be shown as a wedge (bond to an atom in a plane) and the other as a series of short parallel lines or a wedge (bond to an atom below the plane). The Cahn-Inglod-Prelog system can be used to specify the (R) or (S) conformation for a chiral carbon.

[0115]

[0123] The compounds described herein contain atoms in both their natural and unnatural isotopic abundances. The disclosed compounds may be identical isotopic-labeled or isotopic-substituted compounds to those described, but in that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Examples include Cl. The compound further comprises its prodrug and a pharmaceutically acceptable salt of the compound or prodrug containing the aforementioned isotopes, and / or other isotopes of other atoms are within the scope of this disclosure. Specific isotope-labeled compounds of this disclosure, for example, 3 H and 14 Tritiation, i.e., incorporating radioactive isotopes such as 13C, is useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 13C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium, i.e., 2 Substitution with heavier isotopes, such as 1H, may be preferable in certain situations because it can lead to certain therapeutic benefits resulting from increased metabolic stability, such as an increased in vivo half-life or a reduced required dose. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the following procedure, which involves replacing readily available isotope-labeling reagents with non-isotope-labeling reagents.

[0116]

[0124] The compounds described herein may exist as solvates. In some cases, the solvent used to prepare the solvates is an aqueous solution, and the solvates are often referred to as hydrates. The compounds may exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this regard, one, two, three, or any number of solvent or water molecules may combine with the compounds according to this disclosure to form solvates and hydrates. Unless otherwise stated, this disclosure includes all such possible solvates.

[0117]

[0125] The term "cocrystal" refers to the physical association of two or more molecules that have stability due to non-covalent interactions. One or more components of this molecular complex provide a stable framework within the crystal lattice. In certain examples, a guest molecule is incorporated into the crystal lattice as an anhydride or solvate. See, for example, "Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?" Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0118]

[0126] It is also understood that certain compounds described herein may exist in equilibrium as tautomers. For example, ketones having an α-hydrogen may exist in equilibrium between keto and enol forms. [ka] Similarly, amides having an N-hydrogen can exist in equilibrium between the amide form and the imido acid form. Unless otherwise stated, this disclosure includes any such possible tautomers.

[0119]

[0127] Chemical substances are known to form solids that exist in different ordered states called polymorphs or modifications. Different modifications of polymorphic substances can differ significantly in terms of their physical properties. The compounds according to this disclosure can exist in different polymorphs and can be modified in certain ways to be metastable. Unless otherwise stated, this disclosure includes all such possible polymorphs.

[0120]

[0128] In some embodiments, the structure of a compound may be represented by the following formula: [ka] This is understood to be equivalent to the following equation: [ka] In the formula, n is typically an integer. That is, R n It has five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) and R n(e) This is understood to mean that "independent substituents" means that each R substituent can be defined independently. For example, in one example, R n(a) If it is a halogen, in that example, R n(b) It is not necessarily halogen.

[0121]

[0129] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e., one atmosphere).

[0122]

[0130] Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those skilled in the art. For example, the starting materials and reagents used in the preparation of the disclosed compounds and compositions are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or from 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). It is prepared by a method known to those skilled in the art, following the procedure described in Inc., 1989).

[0123]

[0131] Unless otherwise specified, no method described herein is ever intended to be construed as requiring its steps to be performed in a particular order. Therefore, if a claim for a method does not actually enumerate the order in which its steps are performed, or unless otherwise specifically stated in the claims or description that the steps should be limited to a particular order, no order is ever intended to be inferred. This applies to any possible implicit grounds for interpretation, including logical matters relating to the arrangement of steps or operational flows, plain meaning derived from grammatical structure or punctuation, and the number or type of embodiments described herein.

[0124]

[0132] The components used to prepare the compositions of this disclosure, and the compositions themselves used in the methods disclosed herein, are disclosed. While these and other materials are disclosed herein, and combinations, parts, interactions, groups, etc., of these materials are disclosed, it is understood that each is specifically contemplated and described herein, whereas specific references to various individual and collective combinations and permutations of these compounds are not explicitly disclosed. For example, if a particular compound is disclosed and described, and several modifications that may be made to several molecules containing that compound are described, then, unless specifically indicated otherwise, all possible combinations and permutations of the compound and said modifications are specifically contemplated. Therefore, if classes of molecules A, B, and C are disclosed, along with classes of molecules D, E, and F, and examples of combined molecules A-D, then, even if not individually enumerated, it is understood that combinations of meaning, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F, are disclosed, each individually and collectively contemplated. Similarly, any parts or combinations of these are also disclosed. Therefore, it can be considered that, for example, subgroups A-E, B-F, and C-E are disclosed. This concept applies, without limitation, to all embodiments of this application, including steps of a method for preparing and using the compositions of this disclosure. Accordingly, where there are various additional steps that may be taken, it is understood that each of these additional steps may be taken by any particular embodiment or combination of embodiments of the method of this disclosure.

[0125]

[0133] It is understood that the compositions disclosed herein have a specific function. This specification discloses specific structural requirements for performing the disclosed function, and it is understood that there are various structures that can perform the same function related to the disclosed structure, and these structures typically achieve the same results.

[0126]

[0134] Abbreviations used throughout this specification: ADME, absorption, distribution, metabolism, excretion; AL, acute leukemia; AlogP, lipophilic; CK1α, casein kinase 1α; CL, clearance; CRBN, cereblon; F, bioavailability; GSPT1, transition from G1 to S phase 1; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; IMiD, immunomodulator; IKZF, Ikaros family zinc finger; IV, intravenous; LCMS, liquid chromatography-mass spectrometry; MB, medulloblastoma; MG, molecular glue; MW, molecular weight; PPB, plasma protein binding; PK, pharmacokinetics; PROTAC, proteolysis-inducing chimeric molecule; PSA, polar surface area; SBDD, structure-based drug design; SAR, structure-activity relationship; TMT, tandem mass tag; and TPD, targeted proteolysis.

[0127]

[0135] Substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analogs as modulators of cereblon protein having therapeutic or clinical utility are described herein. Methods for synthesizing the substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analogs are also described herein. Methods for administering the substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analogs to subjects requiring them are also described herein. In some embodiments, subjects may have impaired uncontrolled cell proliferation, such as cancer. Other compositions, compounds, methods, features and advantages of this disclosure will become apparent to those skilled in the art by examining the following drawings, detailed description and examples. All such additional compositions, compounds, methods, features, and advantages are included in this description and are intended to be within the scope of this disclosure.

[0128]

[0136] B. Biological situation Targeted proteolysis (TPD) is a novel chemical biology technique that has the potential to have a significant impact on basic biology and drug discovery research by revealing opportunities for drugging undruggable targets (see references 1-2). The TPD paradigm includes two main approaches to molecular design that generate small molecules with similar proteasome-dependent mechanisms of action: proteolysis-inducing chimeric molecules (PROTAC; see references 3-4) and molecular glues (MG; see references 5-8). MGs are small molecules that can bind to E3 ligases, altering their surface and specificity, leading to the recruitment, ubiquitination, and subsequent degradation of substrates not normally targeted by the ligase (neo-substrates). Recognition of neo-substrates is governed by protein-ligase surface interactions (structural degron motifs) and does not require a ligand-binding pocket. This offers a revolutionary opportunity to degrade previously drug-ineffective targets such as fusion oncoproteins and transcription factors (see references 9-10). Immunomodulatory drugs (IMiDs), thalidomide, and its close analogues pomalidomide and lenalidomide are the “original” molecular glues that provide mechanistic and clinical validation for this approach (see references 7 and 11).

[0129]

[0137] Interestingly, despite their high molecular structural similarity, IMiDs exhibit diverse proteolytic profiles. While both lenalidomide and pomalidomide degrade the transcription factor IKZF1 / 3, only lenalidomide induces the degradation of CSNK1A1 (CK1α), illustrating how small changes in molecular structure can significantly alter specificity to neosubstrates (Figure 1; see Reference 12). Furthermore, diversification around the IMiD scaffold has been shown to affect neosubstrate degradation (exemplified by CC-220, which is 10 times more potent than lenalidomide in cells; see Reference 13) or the efficacy and dynamics of specificity, leading to the discovery of novel neosubstrates, as demonstrated by the GSPT1 (G1-to-S phase transition 1) degradation agent CC-885 developed by Celgene (Figure 1; see Reference 14). These chemical modifications result in significant alterations in cellular responses, creating opportunities for new clinical interpretations.

[0130]

[0138] For IMiDs and closely related analogues, an increasing number of neosubstrates containing a common C2H2 zinc finger-recognizing degron motif have been discovered (IKZF2 / 4, SALL4, RNF166, ZFP91, ZNF692, ZNF276, ZNF653, and ZNF827; see references 11 and 15). Each IMiD has been shown to exhibit a different pattern of substrate specificity, supporting the idea that neosubstrate diversity can be regulated by ligand structural changes and is not limited to conventionally known targets. It has also been suggested that achieving selective proteolysis is a challenge, and that understanding the structural basis of how ligand modifications alter neosubstrate interactions at the cereblon (CRBN) interface is crucial (see reference 16). Several recently reported studies have shown how simple structural modifications can lead to the unexpected conversion of PROTACs to GSPT1 molecular glue degraders (see references 17-18).

[0131]

[0139] Abnormal activation, dysregulation, and / or mutations of C2H2 zinc finger transcription factors are common in high-risk cancers such as pediatric acute leukemia (AL) and medulloblastoma (MB), and targeted therapies are limited. Representative examples include the ZNF384 fusion oncoprotein observed in ambiguous acute leukemias, 19 IKZF1 mutations in acute lymphoblastic leukemia (ALL; see reference 20), disregulated MECOM in high-risk acute myeloid leukemia (AML), and enhancer-hijack-dependent activation of GFI1, GFI1B, and PRDM6 in high-risk group 3 and group 4 MB subgroups (see references 21-24).

[0132]

[0140] Small molecule degrading agents, often referred to as molecular glues, offer an intriguing prospect of targeting oncogeneic proteins that are currently untreatable by drug discovery, such as transcription factors and chimeric fusion oncogeneic proteins. This disclosure relates to a method and use of a small molecule degrading agent that modulates CRBN proteins and exhibits high antiproliferative activity.

[0133]

[0141] C. Compound In one embodiment, the disclosure provides a novel approach to target previously drug-untreatable oncoplastic proteins, such as GSPT1, with respect to potent modulators of CRBN proteins. In a further embodiment, the disclosed compounds are potent and selective GSPT1 degraders exhibiting up to 30-fold selectivity for IKZF1 degradation, which has high oral bioavailability in mice. While not wishing to be bound by any particular theory, the disclosed compounds are thought to possess chemical features for CRBN involvement while maximizing the three-dimensionality of the chemical diversity exhibited on the CRBN substrate-binding surface.

[0134]

[0142] More specifically, in one embodiment, the present disclosure relates to a compound having a structure represented by the following formula: [ka] (In the formula, n is an integer selected from 0, 1, and 2, and A 1and A 2 Each of these is independently selected from -(C=O)- and -CH2-, where A 1 and A 2 At least one of them is -(C=O)-, and R 1 (a) 5-10 membered aryl or heteroaryl compounds optionally substituted with groups selected from halogens, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, and (b) halogens The present invention relates to 5-10 membered cycloalkyls (selected from ,-SF5,-CN,-N3,-NH2,-OH,-CN,-SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, optionally substituted with a group selected from these) or pharmaceutically acceptable salts thereof. The various structures disclosed herein include substituents as defined throughout this specification, including those disclosed in the claims.

[0135]

[0143] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0144] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0145] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0146] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0147] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0148] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0149] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0150] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0151] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0152] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0153] In a further aspect, the present disclosure relates to a compound having a structure represented by the following formula: [Chemical formula]

[0154] In a further aspect, Ar 1 is a 5-member heteroaryl optionally substituted by a group selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0136]

[0155] In a further aspect, Ar 1 is (a) a 5-member heteroaryl having one heteroatom and substituents R 11 , R 12 and R 13 (wherein each of R 11 , R 12 and R 13 is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl); and (b) a 5-member heteroaryl having two heteroatoms and substituents R 11 , R 12 and R 13 (wherein R 11 , R 12 and R 13Each of them is selected independently from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl).

[0137]

[0156] In a further aspect, Cy 1 is a 5- to 10-member cycloalkyl optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl. In still a further aspect, Cy 1 is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl).

[0138]

[0157] In a further aspect, the present disclosure relates to a compound having a structure represented by the following formula:

Chemical formula

Chemical formula

[0158] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0159] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0160] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0161] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0162] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0163] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0164] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0165] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0166] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0167] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0168] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] or [ka]

[0169] In a further embodiment, the present disclosure relates to a compound having a structure represented by the following formula: [ka] (In the formula, n is an integer selected from 0, 1, and 2, and A 1 and A 2 Each of these is independently selected from -(C=O)- and -CH2-, where A 1 and A 2 At least one of them is -(C=O)-, and R 11 , R 12 , R 13 , R 14 and R 15 Each of these relates to hydrogen, halogens, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl (or a pharmaceutically acceptable salt thereof).

[0139]

[0170] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0171] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0172] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0173] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0174] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0175] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0176] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0177] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0178] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0179] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0180] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0181] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0182] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0183] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0184] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0185] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] [ka] or [ka]

[0186] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0187] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] [ka] or [ka]

[0188] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka]

[0189] In a further embodiment, this disclosure relates to a compound having a structure represented by the following formula: [ka] [ka] or [ka]

[0190] In a further embodiment, the disclosed compound has a structure given by: [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] or a subgroup thereof.

[0140]

[0191] In a further embodiment, the disclosed compound has a structure given by: [ka] or [ka] or a subgroup thereof.

[0141]

[0192] In a further embodiment, the disclosed compound has a structure given by: [ka] or a subgroup thereof.

[0142]

[0193] In a further embodiment, the disclosed compound has a structure given by: [ka] [ka] [ka] or [ka] or a subgroup thereof.

[0143]

[0194] In various embodiments, the disclosed compounds are intended herein to further include their biosteric equivalents. The term “biosteric equivalent” refers to a compound or group having substantially the same molecular shape and volume, substantially the same electron distribution, and exhibiting similar physical and biological properties. Examples of such equivalents include (i) fluorine versus hydrogen, (ii) oxo versus thia, (iii) hydroxyl versus amide, (iv) carbonyl versus oxime, and (v) carboxylate versus tetrazole. Examples of such biological equivalence substitutions can be found in the literature, and such examples are as follows: (i) Burger A, Relation of chemical structure and biological activity; in Medicinal Chemistry Third ed., Burger A, ed.; Wiley-Interscience; New York, 1970, 64-80; (ii) Burger, A.; “Isosterism and bioisosterism in drug design”; Prog. Drug Res. 1991, 37, 287-371; (iii) Burger A, “Isosterism and bioanalogy in drug design”, Med. Chem. Res. 1994, 4, 89-92; (iv) Clark RD, Ferguson AM, Cramer RD, “Bioisosterism and molecular diversity”, Perspect. Drug Discovery Des. 1998, 9 / 10 / 11, 213-224; (v) Koyanagi T, Haga T, “Bioisosterism in agrochemicals”,ACS Symp.Ser.1995,584,15-24;(vi)Kubinyi H,”Molecular similarities.Part 1.Chemical structure and biological activity”,Pharm.Unserer Zeit 1998,27,92-106;(vii)Lipinski C A.;”Bioisosterism in drug design”;Annu.Rep.Med.Chem.1986, 21, 283-91; (viii) Patani GA, LaVoie EJ, “Bioisosterism: A rational approach in drug design”, Chem. Rev. (Washington, DC) 1996, 96, 3147-3176; (ix) Soskic V, Joksimovic J, “Bioisosteric approach in the design of new dopaminergic / serotonergic Thornber CW, “Isosterism and molecular modification in drug design”, Chem. Soc. Rev. 1979, 8, 563-80. .

[0144]

[0195] In further embodiments, a bioisoster is an atom, ion, or molecule whose peripheral electron layers can be considered substantially identical. The term bioisoster is usually used to mean a part of a whole molecule, rather than the whole molecule itself. Biological equivalence substitution involves substituting one bioisoster with another, with the expectation that the biological activity of the first bioisoster will be maintained or slightly modified. Thus, the bioisoster in this case is an atom or group of atoms having similar size, shape, and electron density. Preferred bioisosters of esters, amides, or carboxylic acids are compounds containing two sites for hydrogen bond acceptance. In one embodiment, the bioisoster of an ester, amide, or carboxylic acid is a five-membered monocyclic heteroaryl ring, e.g., optionally substituted 1H-imidazolyl, optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or optionally substituted [1,2,4]oxadiazolyl.

[0145]

[0196] In various embodiments, the disclosed compounds include their isotopically labeled or isotopically substituted variants, i.e., identical compounds as described, but in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Examples include Cl. The compound further comprises its prodrug and pharmaceutically acceptable salts of the compound or the prodrug containing the aforementioned isotopes, and / or other isotopes of other atoms are within the scope of this disclosure. Specific isotope-labeled compounds of this disclosure, for example, 3 H and 14 Tritiation, i.e., incorporating radioactive isotopes such as 13C, is useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 13C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium, i.e., 2 Substitution with heavier isotopes, such as 1H, may be preferable in certain situations because it can lead to certain therapeutic benefits resulting from increased metabolic stability, such as an increased in vivo half-life or a reduced required dose. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the following procedure, which involves replacing readily available isotope-labeling reagents with non-isotope-labeling reagents.

[0146]

[0197] In various embodiments, the disclosed compounds may have at least one chiral center, which may exist in racemic form, in pure enantioma and / or diastereoma form, or in mixture form of these enantioma and / or diastereoma. Stereoisomers may be present in any proportion in the mixture. In some embodiments, where this is possible, the disclosed compounds may exist in tautomer form.

[0147]

[0198] Therefore, using methods known in themselves, disclosed compounds having one or more chiral centers and arising as racemates can be separated into their optical isomers, i.e., enantiomas or diastereomas. Separation can be performed by column separation using a chiral phase, by recrystallization from an optically active solvent, by using an optically active acid or base, or by derivatization with an optically active reagent, such as an optically active alcohol, followed by cleavage of the residue.

[0148]

[0199] In various embodiments, the disclosed compounds may be in the form of cocrystals. The term “cocrystal” refers to the physical association of two or more molecules that have stability due to non-covalent interactions. One or more components of this molecular complex provide a stable framework within the crystal lattice. In certain examples, the guest molecule is incorporated into the crystal lattice as an anhydride or solvate. See, for example, “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 cocrystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0149]

[0200] The term "pharmaceutically acceptable cocrystal" refers to a cocrystal that is compatible with other components of a formulation and is not harmful to its recipient.

[0150]

[0201] In further embodiments, the disclosed compounds may be isolated as solvates, particularly as hydrates of the disclosed compounds, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In connection therewith, one, two, three or any number of solvates or water molecules may be combined with the compounds according to the Disclosure to form solvates and hydrates.

[0151]

[0202] The disclosed compounds may 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 alkali metal salts, e.g., base addition salts including sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed by suitable organic ligands, e.g., quaternary ammonium salts which can similarly be prepared by reacting a drug compound with a suitable pharmaceutically acceptable base. Salts may be prepared in situ during or after the final isolation and purification of the disclosed compounds by reacting a free basic functional group of the disclosed compound, e.g., a secondary or tertiary amine, with a suitable inorganic or organic acid, or by reacting a free acidic functional group of the disclosed compound, e.g., a carboxylic acid, with a suitable inorganic or organic base.

[0152]

[0203] Acidic addition salts can be prepared in situ during the final isolation and purification of the disclosed compound, or separately by reacting a portion containing one or more nitrogen groups with a suitable acid. In various embodiments, acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, as well as organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. In further embodiments, the salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidic phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, This includes butyrate, camphorate, camphor sulfonate, 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)).Furthermore, the basic nitrogen-containing group can be quaternized by active substances such as lower alkyl halides, for example methyl chloride, ethyl chloride, propyl chloride and butyl chloride, methyl bromide, ethyl bromide, propyl bromide and butyl bromide, as well as methyl iodide, ethyl iodide, propyl iodide and butyl iodide; dialkyl sulfates, for example dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long-chain halides, for example decyl chloride, lauryl chloride, myristyl chloride and stearyl chloride, decyl bromide, lauryl bromide, myristyl bromide and stearyl bromide, as well as decyl iodide, lauryl iodide, myristyl iodide and stearyl iodide; and aralkyl halides, for example benzyl bromide and phenethyl bromide.

[0153]

[0204] Basic addition salts can be prepared in situ during the final isolation and purification of the disclosed compounds, or separately by reacting the carboxylic acid moiety with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, or with ammonia, or with an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals and alkaline earth metals, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but are not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines useful for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. In a further embodiment, bases that can be used to prepare pharmaceutically acceptable salts include ammonia, L-arginine, benetamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydravamin, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0154]

[0205] D. Method for preparing compounds.

[0155] In one embodiment, this disclosure relates to a method for producing compounds useful as antibacterial agents that may be useful in the treatment of bacterial infections. In one embodiment, this disclosure relates to the disclosed synthetic operation. In a further embodiment, the disclosed compounds include products of the synthetic methods described herein.

[0156]

[0206] In further embodiments, the disclosed compounds include compounds produced by the synthesis methods described herein. In further embodiments, the disclosure includes a pharmaceutical composition comprising a therapeutically effective amount of the product of the disclosed method and a pharmaceutically acceptable carrier. In further embodiments, the disclosure includes a method for producing a pharmaceutical product, comprising the step of combining at least one product of the disclosed method with a pharmaceutically acceptable carrier or diluent.

[0157]

[0207] The compounds of this disclosure can be prepared by using the reactions shown in the disclosed schemes, in addition to the literature illustrated in the experimental section or other standard operations known in the literature obvious to those skilled in the art. For clarity, where multiple substituents are permitted under the definitions disclosed herein, examples with fewer substituents may be shown. The following examples are provided so that this disclosure may be understood more fully, and are merely illustrative and should not be construed as limitations.

[0158]

[0208] Each disclosed method is intended to further include additional steps, operations, and / or components. Any one or more steps, operations, and / or components may be omitted from this disclosure as appropriate. It is understood that the disclosed compounds can be provided using the disclosed methods. It is also understood that the products of the disclosed methods may be used in the disclosed compositions, kits, and uses.

[0159]

[0209] Synthesis Route 1 In one embodiment, intermediates useful for preparing the aryl-substituted aminomethylspectinomycin analogs of this disclosure can generally be prepared by the synthesis scheme shown below. All positions are defined herein.

[0160] Scheme 1A [ka]

[0210] The compounds are represented in their general forms, having substituents as described elsewhere in this specification. More specific examples are given below.

[0161] Scheme 1B [ka]

[0211] The substituted N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analogs of the present disclosure, for example, compound 1.3 of reaction scheme 1B above, and related compounds are prepared by reacting 5-amino-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, compound 1.1, with a suitable sulfonyl chloride, compound 1.2, in a suitable solvent, for example, pyridine, and carrying out the reaction for a suitable time, for example, 8 to 24 hours, at a suitable temperature, for example, about 70°C to about 100°C, under an inert atmosphere, for example, under nitrogen. After the reaction, the reaction mixture is concentrated to dryness (or oil), and the resulting solid (or oil) can be reconstituted (or diluted) in a suitable solvent, for example, DMSO. Further purification can be carried out using the Waters purification / analytical LC / UV / ELSD system, as detailed in the examples, with parallel evaporation using Genevac HT-24. Other purification methods known to those skilled in the art, such as recrystallization, can be used as alternatives. Alternative or modified conditions can be used in the above reaction, as can be understood by those skilled in the art.

[0162]

[0212] Each disclosed method is intended to include additional steps, operations, and / or components. Any one or more steps, operations, and / or components may be omitted from this disclosure as appropriate. It is understood that the disclosed compounds can be provided using the disclosed methods. It is also understood that the products of the disclosed methods may be used in the disclosed uses.

[0163]

[0213] E. Pharmaceutical Compositions In various embodiments, this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically acceptable carrier” means one or more pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, and adjuvants. The disclosed pharmaceutical compositions may be conveniently provided in unit dosage forms and may be prepared by any method known in the fields of compounding and pharmaceutical science.

[0164]

[0214] In further embodiments, the disclosed pharmaceutical composition comprises, as an active ingredient, at least one disclosed compound, at least one product of the disclosed method, or a therapeutically effective amount of a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agents, and optionally one or more adjuvants. The disclosed pharmaceutical composition includes those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, but the most preferred route in any given case depends on the particular host, as well as the nature and severity of the disease to which the active ingredient is administered. In further embodiments, the disclosed pharmaceutical composition may be formulated to enable oral, nasal, inhalation, parenteral, paracancerally, mucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intraventricular, intracranial, and intratumoral administration.

[0165]

[0215] As used herein, “parenteral administration” includes administration by bolus injection or bolus infusion, as well as administration by intravenous injection and infusion, intramuscular injection and infusion, intra-arterial injection and infusion, intrathecal injection and infusion, intracapsular injection and infusion, intraorbital injection and infusion, intracardiac injection and infusion, intradermal injection and infusion, intraperitoneal injection and infusion, transtracheal injection and infusion, subcutaneous injection and infusion, subepidermal injection and infusion, intra-articular injection and infusion, subcapsular subarachnoid injection and subcapsular subarachnoid injection and infusion, intraspinal injection and infusion, epidural injection and infusion, and intrasternal injection and infusion.

[0166]

[0216] In various embodiments, the disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of the disclosed compound, a product of the disclosed method of preparation, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, or its stereochemical isomer as an active ingredient. In further embodiments, the disclosed compound, a product of the disclosed method of preparation, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, or its stereochemical isomer, or any subgroup or combination thereof, may be formulated into various pharmaceutical forms for administration.

[0167]

[0217] A pharmaceutically acceptable salt may be prepared from a pharmaceutically acceptable non-toxic base or acid. For therapeutic use, the salt of the disclosed compound is one in which the counterion is pharmaceutically acceptable. However, in the preparation or purification of a pharmaceutically acceptable compound, for example, salts of pharmaceutically unacceptable acids and bases may also be used. Any salt, whether pharmaceutically acceptable or not, is contemplated in this disclosure. A pharmaceutically acceptable acid-addition salt and a base-addition salt means including therapeutically active non-toxic acid-addition salt forms and base-addition salt forms that can form the disclosed compound.

[0168]

[0218] In various embodiments, pharmaceutically acceptable salts can be prepared using disclosed compounds containing an acidic group or acidic moiety, such as a carboxylic acid group. For example, such disclosed compounds may involve an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to a 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, for example, by treating the corresponding acid compound with an aqueous solution containing a desired pharmaceutically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, the base addition salt can also be prepared by mixing a lower alkanol (alkanolic) solution of the acid compound with a desired alkali metal alkoxide, and then evaporating the resulting solution to dryness as before.

[0169]

[0219] Bases that can be used to prepare pharmaceutically acceptable base addition salts of basic compounds are bases that can form salts containing pharmaceutically 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 further embodiments, derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic and substituted amines, such as naturally occurring and synthetic substituted amines. In various embodiments, such pharmaceutically acceptable organic nontoxic bases include, but are not limited to, ammonia salts, methylamine salts, ethylamine salts, propylamine salts, isopropylamine salts, any of the four butylamine isomers, betaine salts, caffeine salts, choline salts, dimethylamine salts, diethylamine salts, diethanolamine salts, dipropylamine salts, diisopropylamine salts, di-n-butylamine salts, N,N'-dibenzylethylenediamine salts, pyrrolidine salts, piperidine salts, morpholine salts, trimethylamine salts, triethylamine salts, tripropylamine salts, and This includes lomethamine salts, 2-diethylaminoethanol salts, 2-dimethylaminoethanol salts, ethanolamine salts, quinuclidine salts, pyridine salts, quinoline salts, and isoquinoline salts; benzathine salts, N-methyl-D-glucamine salts, ethylenediamine salts, N-ethylmorpholine salts, N-ethylpiperidine salts, glucamine salts, glucosamine salts, methylglucamine salts, morpholine salts, piperazine salts, piperidine salts, polyamine resin salts, procaine salts, purine salts, theobromine salts, hydravamin salts, and salts with amino acids such as histidine, arginine, and lysine. The aforementioned salt forms can be converted back to free acid forms by treatment with acid.

[0170]

[0220] In various embodiments, pharmaceutically acceptable salts can be prepared using disclosed compounds containing a protonable group or moiety, such as an amino group. For example, such a disclosed compound may involve an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be preferable in practice to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to a free base compound by treatment with a basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, for example, by treating the corresponding basic compound with an aqueous solution containing a desired pharmaceutically acceptable anion, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, the acid addition salt can also be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0171]

[0221] Acids that can be used to prepare pharmaceutically acceptable acid addition salts of basic compounds are those that can form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary but non-limiting inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Exemplary but non-limiting organic acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc. In further embodiments, the acid addition salts contain anions formed from hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0172]

[0222] In practice, the compounds of this disclosure, or their pharmaceutically acceptable salts thereof, may be combined as active ingredients in close mixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a wide variety of forms depending on the desired form of the preparation for administration, e.g., orally or parenterally (including intravenously). Thus, the pharmaceutical compositions of this disclosure may be provided as individual units suitable for oral administration, e.g., capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions may be provided as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil liquid emulsions. In addition to the general dosage forms described above, the compounds of this disclosure and / or their pharmaceutically acceptable salts may also be administered by controlled release means and / or delivery devices. The compositions may be prepared by any of the methods of compounding. Generally, such methods include the step of associating the active ingredient with a carrier constituting one or more required components. Generally, the compositions are prepared by uniformly and closely mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both. Next, the product can be conveniently molded into the desired shape.

[0173]

[0223] For ease of administration and uniformity of dosage, it is particularly effective to formulate the above-mentioned pharmaceutical compositions into unit dosage forms. As used herein, the term “unit dosage form” refers to a physically distinct unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in combination with the necessary pharmaceutical carrier. That is, “unit dosage form” is interpreted as a single dose in which all active and inactive ingredients are combined in a suitable system, allowing the patient, or the person administering the drug to the patient, to open a single container or package containing the entire dose, without the need to mix any of the ingredients from two or more containers or packages. Typical examples of unit dosage forms include tablets for oral administration (including notched or coated tablets), capsules or pills; single-dose vials for injectable solutions or suspensions; suppositories for rectal administration; powder packets; wafers; and isolated populations thereof. This list of unit dosage forms is not intended to be limitful, but merely to represent typical examples.

[0174]

[0224] The pharmaceutical compositions disclosed herein comprise a compound of the disclosure (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various embodiments, the disclosed pharmaceutical compositions may include a pharmaceutically acceptable carrier and the disclosed compound or a pharmaceutically acceptable salt thereof. In further embodiments, the disclosed compound or a pharmaceutically acceptable salt thereof may be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds. The compositions include those suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous), but the most preferred route in any given case depends on the specific host, as well as the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions may be conveniently provided in unit dosage forms and may be prepared by any method well known in the art of compounding.

[0175]

[0225] Techniques and compositions for producing useful dosage forms for the materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, 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) 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;JGHardy,SSDavis,Clive G.Wilson,Eds.);Modern Pharmaceutics Drugs and the Pharmaceutical Sciences,Vol 40(Gilbert S.Banker, Christopher T.Rhodes,Eds.).

[0226] The compounds described herein are typically administered in mixture with suitable pharmaceutical diluents, excipients, expanders, or carriers (hereinafter referred to herein as pharmaceutically acceptable carriers or carriers) that are suitably selected with respect to the intended dosage form and consistent with conventional pharmaceutical practice. The deliverable compounds are in forms suitable for oral, rectal, topical, intravenous injection, or parenteral administration. Carriers may be solid or liquid, and the type of carrier is selected based on the type of dosage used. The compounds may be administered in doses containing a known amount of the compound.

[0176]

[0227] Due to their ease of administration, oral administration may be a preferred dosage form, and tablets and capsules are the most effective oral dose units, in which case solid pharmaceutical carriers are clearly used. However, other dosage forms may be preferred depending on the clinical population (e.g., age and severity of clinical condition), the solubility characteristics of the specific disclosed compound used, etc. Therefore, the disclosed compounds may be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Any convenient pharmaceutical medium can be used when preparing compositions for oral dosage forms. For example, oral liquid preparations such as suspensions, elixirs, and solutions can be formed using water, glycols, oils, alcohols, flavorings, preservatives, colorants, etc., while oral solid preparations such as powders, capsules, and tablets can be formed using carriers such as starch, sugars, and microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants. Due to their ease of administration, tablets and capsules are preferred oral dose units, and thus solid pharmaceutical carriers are used. Depending on the circumstances, the tablets may be coated using standard aqueous or non-aqueous techniques.

[0177]

[0228] The pharmaceutical composition disclosed in oral dosage form may contain one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars (e.g., raw sugar or lactose), lecithin, pectin, starch (e.g., corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tyrose, tarkan, lycopodium, silica gel (e.g., colloidal), cellulose, cellulose derivatives (e.g., cellulose hydroxyl groups partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols). Cellulose (e.g., methyloxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate), fatty acids, and magnesium, calcium, or aluminum salts of fatty acids having 12 to 22 carbon atoms, especially saturated (e.g., stearate), emulsifiers, oils and fats, especially vegetable oils (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, in all cases, hydrated); saturated fatty acids C 12 H 24 O2~C 18 H 36Glycerol esters and polyglycerol esters of O2, and mixtures thereof (where the glycerol hydroxyl group can be esterified completely or partially) (e.g., mono-, di-, and triglycerides); pharmaceutically acceptable monohydric or polyhydric alcohols, and polyglycols, e.g., polyethylene glycol and its derivatives, esters of aliphatic saturated or unsaturated fatty acids (2-22 carbon atoms, particularly 10-18 carbon atoms) and monohydric aliphatic alcohols (1-20 carbon atoms), or polyhydric alcohols that may optionally be etherified, e.g., glycols, glycerols Examples include diethylene glycol, pentacrythritol, sorbitol, mannitol, esters of citric acid and primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glyceroformal, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12 alcohols, dimethylacetamide, lactamide, lactate, ethyl carbonate, silicone (especially medium viscosity polydimethylsiloxane), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, and magnesium carbonate.

[0178]

[0229] Other auxiliary substances useful for preparing oral dosage forms include disintegrants (so-called disintegrants), such as cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, or microcrystalline cellulose. Oral dosage forms may also be prepared using conventional coating materials. For example, those that may be considered include polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters; copolymers of acrylic acid esters and methacrylic acid esters having a relatively low ammonium group content (e.g., Eudragit® RS); copolymers of acrylic acid esters and methacrylic acid esters with trimethylammonium methacrylate (e.g., Eudragit® RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methylcellulose phthalate or acetate succinate; cellulose phthalate acetate, starch phthalate acetate and polyvinyl phthalate acetate, carboxymethylcellulose; These include cellulose phthalate, methylcellulose succinate, phthalate succinate and methylcellulose phthalate half-esters; zein; ethylcellulose and ethylcellulose succinate; shellac, gluten; ethyl carboxyethylcellulose; ethacrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethyl ethylcellulose glycerol monooctanoate; cellulose acetate succinate; and polyarginine.

[0179]

[0230] Plasticizers that may be considered coating substances in the disclosed oral dosage forms include citrate and tartaric acid esters (acetyl-triethyl citrate, acetyl-tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, triacetate, acetylated monoglycerides, castor oil); phthalate esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethyl phthalyl glycolate, butyl phthalyl ethyl glycolate. butyl glycolates; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate); benzophenone; diethyl- and dibril sebacate, dibutyl succinate, dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, dibutylate, dipropionate; tributyl phosphate, tributylin; polyethylene glycol sorbitan monooleate (polysorbate, e.g., Polysorbar 50); sorbitan monooleate.

[0180]

[0231] Furthermore, suitable binders, lubricants, disintegrants, colorants, flavorings, flow inducers, and fluxes may be included as carriers. The pharmaceutical carrier used may be, for example, a solid, a liquid, or a gas. Examples of solid carriers include, but are not limited to, lactose, clay, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0181]

[0232] In various embodiments, the binder may include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms may include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. In further embodiments, the disintegrant may include, for example, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0182]

[0233] In various embodiments, oral dosage forms, such as solid dosage forms, may include disclosed compounds bound to the polymer as targetable drug carriers or prodrugs. Suitable biodegradable polymers useful for achieving controlled drug release include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels, preferably covalently crosslinked hydrogels.

[0183]

[0234] Tablets may contain the active ingredient in combination with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulators and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.

[0184]

[0235] Tablets containing the disclosed compounds may be prepared by compression or molding, possibly together with one or more auxiliary components or adjuvants. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine and optionally mixing it with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets may be produced by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine.

[0185]

[0236] In various embodiments, solid oral dosage forms, such as tablets, may be coated with enteric coatings to prevent them from easily disintegrating in the stomach. In various embodiments, enteric coating agents include, but are not limited to, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid 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 based on testing to achieve an enteric coated dosage form designed from the outset to have a preferred combination of dissolution time, coating thickness, and diametrical crush strength (see, for example, SCPorter et al., “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J.Pharm.Pharmacol.22:42p(1970)). In further embodiments, the enteric coating agent may include hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate.

[0186]

[0237] In various embodiments, the oral dosage form may be a solid dispersion containing a water-soluble or water-insoluble carrier. Examples of water-soluble or water-insoluble carriers include, but are not limited to, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, phosphatidylcholine, polyoxyethylene hydrogenated castor oil, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose or hydroxypropyl methylcellulose, ethylcellulose, or stearic acid.

[0187]

[0238] In various embodiments, the oral dosage form may be a liquid dosage form containing the substance to be ingested, or it may be administered as a mouthwash or gargle. For example, the liquid dosage form may include an aqueous suspension containing the active ingredient mixed with an excipient suitable for the production of an aqueous suspension. Furthermore, the oily suspension may be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin. The oily suspension may also contain a variety of excipients. The pharmaceutical compositions of this disclosure may also be in the form of an oil-in-water emulsion, which may also contain excipients such as sweeteners and flavorings.

[0188]

[0239] For the preparation of solutions or suspensions, it is possible to use, for example, water, especially 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 (e.g., peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, bovine hoof oil), paraffin, dimethyl sulfoxide, triglycerides, etc.

[0189]

[0240] In the case of liquid dosage forms such as potable solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic monohydric and polyhydric alcohols having 2 to 4 carbon atoms, e.g., ethanol, n-propanol, glycerol; polyethylene glycol having a molecular weight of 200 to 600 (e.g., 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol; organic amides, e.g., ammonia or amides of aliphatic C1 to C6 carboxylic acids with primary, secondary or tertiary C1 to C4 amines or C1 to C4 hydroxyamines, e.g., urea, urethane, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide; lower aliphatic amines and diamines having 2 to 6 carbon atoms, e.g., ethylenediamine, hydroxyethyltheophylline, tromethamine (e.g., 0.1 to 20% aqueous solution); aliphatic amino acids.

[0190]

[0241] When preparing the disclosed liquid dosage forms which may contain solubilizers and emulsifiers, the following non-limiting examples may be used, for example: polyvinylpyrrolidone, sorbitan fatty acid esters, e.g., sorbitan trioleate, phosphatides, e.g., lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate, and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, fatty alcohols, polyethylene oxide condensation products of alkylphenols or fatty acids, or 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). In this regard, polyoxyethylated means that the substance contains polyoxyethylene chains, the degree of polymerization of which is generally 2 to 40, particularly 10 to 20. This type of polyoxyethylated substance can be obtained, for example, by the reaction of a hydroxyl group-containing compound (e.g., an unsaturated compound such as a mono- or diglyceride, or one containing an oleic acid radical) with ethylene oxide (e.g., 40 moles of ethylene oxide per mole of glyceride). Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. H.P. Fiedler, “Lexikon der Hillsstoffe fur Pharmazie, Kostnetik und angrenzende Gebiete” 1971, pages 191–195.

[0191]

[0242] In various embodiments, the liquid dosage form may further include preservatives, stabilizers, buffering agents, flavor modifiers, sweeteners, colorants, antioxidants, and complexing agents. For example, complexing agents that may be considered include chelating agents, such as ethylenediamine retracetic acid, nitrilotriacetic acid, diethylenetriaminepentaacetic acid, and their salts.

[0192]

[0243] In some cases, it may be necessary to stabilize the liquid dosage form containing a physiologically acceptable base or buffer to a pH range of approximately 6–9. A neutral or weakly basic pH value (up to pH 8) is preferable whenever possible.

[0193]

[0244] To enhance the solubility and / or stability of the disclosed compounds in the disclosed liquid dosage forms, parenteral injection forms, or intravenous injection forms, it may be effective to use α-, β-, or γ-cyclodextrins or their derivatives, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Additionally, cosolvents such as alcohols may improve the solubility and / or stability of the compounds according to this disclosure in pharmaceutical compositions.

[0194]

[0245] In various embodiments, the disclosed liquid dosage form, parenteral injection form, or intravenous injection form may further include liposome delivery systems, such as small monolamellar vesicles, large monolamellar vesicles, and multilamellar vesicles. The liposomes may be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.

[0195]

[0246] The pharmaceutical compositions of this disclosure are suitable for injection, for example, parenteral administration, such as intravenous, intramuscular, or subcutaneous administration. Pharmaceutical compositions for injection may be prepared as a solution or suspension of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions may be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful growth of microorganisms.

[0196]

[0247] Pharmaceutical compositions of this disclosure suitable for parenteral administration may include sterile aqueous solutions or sterile oily solutions, sterile suspensions or sterile dispersions. Furthermore, the compositions may be in the form of sterile powders for the immediate preparation of such sterile injectable solutions or sterile dispersions. In some embodiments, the final injectable form must be sterile and effectively fluid for use in a syringe. The pharmaceutical compositions should be stable under manufacturing and storage conditions and, therefore preferably, should be protected from microbial contamination such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, or suitable mixtures thereof.

[0197]

[0248] For example, an injectable solution can be prepared in which the carrier contains physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. An injectable suspension may also be prepared, in which case a suitable liquid carrier, suspending agent, etc., may be used. In some embodiments, the disclosed parenteral formulation may contain about 0.01 to 0.1 M, for example, about 0.05 M of phosphate buffer. In further embodiments, the disclosed parenteral formulation may contain about 0.9% physiological saline.

[0198]

[0249] In various embodiments, the disclosed parenteral pharmaceutical compositions may include pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and organic esters for injection, such as ethyl oleate. Aqueous carriers include, but are not limited to, water, alcoholic solutions / aqueous solutions, emulsions, or suspensions, including physiological saline and buffering media. Parenteral vehicles may include mannitol, normal serum albumin, sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, lactated ringer's solution, and fixative oils. Intravenous vehicles may include fluid replacement solutions and nutritional replacement solutions, electrolyte replacement solutions, such as those based on ringer's dextrose. Preservatives and other additives, such as antimicrobial agents, antioxidants, collating agents, and inert gases, may also be present. In further embodiments, the disclosed parenteral pharmaceutical compositions may include small amounts of additives, such as substances that enhance isotonicity and chemical stability, such as buffers and preservatives. For pharmaceutical compositions for injection, solid preparations intended to be converted into liquid preparations immediately before use are also contemplated. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the subject or patient.

[0199]

[0250] In addition to the pharmaceutical compositions described above, the disclosed compounds may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Therefore, for example, the compounds may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil), or with an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0200]

[0251] The pharmaceutical compositions of this disclosure may be in forms suitable for topical administration. As used herein, the term “topical application” means administration to a biological surface, which includes, for example, skin areas (e.g., hands, forearms, elbows, legs, face, nails, anal and genital areas) or mucous membranes. By selecting suitable carriers and, optionally, other components that may be included in the composition, as detailed below herein, the compositions of this disclosure may be formulated into any form typically used for topical application. Topical pharmaceutical compositions may be in the form of creams, ointments, pastes, gels, lotions, milks, suspensions, aerosols, sprays, foams, powders, pads, and patches. Furthermore, the compositions may be in forms suitable for use in transdermal devices. These formulations may be prepared by conventional processing methods using the compounds of this disclosure or pharmaceutically acceptable salts thereof. As an example, a cream or ointment may be prepared by mixing about 5% to about 10% by weight of the compound with a hydrophilic material and water to produce a cream or ointment of the desired consistency.

[0201]

[0252] In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable humectant, optionally combined with a small amount of a suitable additive of any properties, the additive not introducing significant adverse effects on the skin. The additive may facilitate administration to the skin and / or may help in preparing the desired composition. These compositions may be administered in various ways, for example, as transdermal patches, spot-on agents, or ointments.

[0202]

[0253] Ointments are typically semi-solid preparations based on petrolatum or petroleum derivatives. The specific ointment base used provides optimal delivery of the activator selected for a given formulation and preferably also provides other desired properties (e.g., skin softening). Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing. As described in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases can be classified into four classes: oily bases, emulsifying bases, emulsion bases, and water-soluble bases. Oily ointment bases include, for example, vegetable oils, fats derived from animals, and semi-solid hydrocarbons derived from petroleum. Emulsifying ointment bases, also known as absorbent ointment bases, contain little to no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. The emulsion ointment base is either a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion, and may contain, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycol of various molecular weights.

[0203]

[0254] A lotion is a preparation applied to the skin surface without friction. Typically, a lotion is a liquid or semi-liquid preparation in which solid particles containing an surfactant are present in a water or alcohol base. Lotions are typically preferred for treating large body areas because their highly fluid composition is easy to apply. Lotions are typically solid suspensions and often contain oil-in-water liquid emulsions. Generally, insoluble components in lotions need to be finely dispersed. Lotions typically contain suspending agents to produce a better dispersion, as well as compounds useful for localizing and retaining surfactants, such as methylcellulose or sodium carboxymethylcellulose, in contact with the skin.

[0204]

[0255] A cream is either an oil-in-water or water-in-oil viscous liquid or semi-solid emulsion. The cream base is typically water-washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also called the “internal” phase, generally consists of petrolatum and / or fatty alcohols, such as cetyl alcohol or stearyl alcohol. The aqueous phase, though not necessarily, typically exceeds the volume of the oil phase and generally contains a wetting agent. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. For further information, see Remington: The Science and Practice of Pharmacy above.

[0205]

[0256] A paste is a semi-solid dosage form in which a bioactive agent is suspended in a suitable base. Depending on the properties of the base, pastes are classified into fatty pastes or those made from single-phase aqueous gels. Bases in fatty pastes are generally petrolatum, hydrophilic petrolatum, etc. Pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose, etc., as a base. For more detailed information, you may refer further to Remington: The Science and Practice of Pharmacy.

[0206]

[0257] Gel formulations are semi-solid suspension systems. Single-phase gels typically contain organic polymers substantially uniformly distributed throughout a carrier liquid, which is usually aqueous, but also preferably contain alcohols and occasionally oils. Preferred organic polymers, i.e., gelling agents, are crosslinked acrylic acid polymers, e.g., carbomer polymers commercially available under the trademark Carbopol®, e.g., the carboxypolyalkylene family. Other preferred types of polymers in this regard include hydrophilic polymers, e.g., polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; modified celluloses, e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums, e.g., tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, dispersants, e.g., alcohol or glycerin, can be added, or the gelling agent can be dispersed by grinding, mechanical mixing or stirring, or a combination thereof.

[0207]

[0258] Sprays generally provide activators in aqueous and / or alcoholic solutions that can be atomized onto the skin for delivery. Such sprays include formulations designed to concentrate the activator solution at the administration site after delivery; for example, the spray solution may consist primarily of an alcohol or other similar volatile liquid in which the activator can dissolve. Upon delivery to the skin, the carrier evaporates, leaving the concentrated activator at the administration site.

[0208]

[0259] The foaming compositions are typically formulated in single-phase or multi-phase liquid form and, optionally, contained in a suitable container with a propellant that facilitates the discharge of the composition from the container and, consequently, converts the composition into a foam upon application. Other foaming techniques include, for example, "bag-in-a-can" formulation techniques. Compositions formulated in this manner typically contain low-boiling hydrocarbons, such as isopropane. Application and stirring of such compositions at body temperature, as in pressurized aerosol foaming systems, vaporizes the isopropane and generates a foam. The foam may be aqueous or aqueous alkanol, but is typically formulated to have a high alcohol content that evaporates rapidly upon application to the user's skin, pushing the active ingredient through the upper skin layers to the treatment site.

[0209]

[0260] A skin patch typically comprises a backing to which a reservoir containing an activator is attached. The reservoir may be, for example, a pad in which the activator or composition is dispersed or immersed, or a liquid reservoir. The patch typically further comprises a front permeable adhesive that adheres and secures the device to the treatment area. Self-adhesive silicone rubber can be used as an alternative. In either case, a protective permeable layer may be used to protect the adhesive surface of the patch before use. The skin patch may further comprise a removable cover that helps protect it during storage.

[0210]

[0261] Examples of patch configurations that may be utilized by this disclosure include single-layer or multi-layer intrapharmaceutical adhesive systems characterized by directly incorporating the drug within a skin-contact adhesive. In such transdermal patch designs, the adhesive not only helps to adhere the patch to the skin but also serves as a formulation foundation containing the drug and all excipients beneath a single backing film. In multi-layer intrapharmaceutical adhesive patches, the membrane is positioned between two separate intrapharmaceutical adhesive layers, or multiple intrapharmaceutical adhesive layers are incorporated beneath a single backing film.

[0211]

[0262] Examples of pharmaceutically acceptable carriers suitable for pharmaceutical compositions for topical application include, depending on the final form of the composition, carrier materials well known for use in the cosmetic and medical fields as bases for emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols, etc. Accordingly, typical examples of suitable carriers according to this disclosure include, but are not limited to, 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 similar materials commonly used in cosmetic and pharmaceutical compositions. Other suitable carriers according to this disclosure include, but are not limited to, alcohols, e.g., monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, and propylene glycol; ethers, e.g., diethyl ether or dipropyl ether; polyethylene glycol and methoxypolyoxyethylene (carbowax having a molecular weight in the range of 200 to 20,000); polyoxyethylene glycerol, polyoxyethylene sorbitol, stearoyl diacetin, and the like.

[0212]

[0263] The topical compositions of this disclosure may, if desired, be provided in packs or dispenser devices, such as FDA-approved kits, capable of containing one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, include a tube. The packs or dispenser devices may be accompanied by instructions for administration. The packs or dispenser devices may also be accompanied by a notice in the form prescribed by a government agency that regulates the manufacture, use or sale of a drug, which reflects the agency's approval of the composition in a form for human or veterinary administration. Such a notice may, for example, include a label approved by the U.S. Food and Drug Administration for a prescription drug or an approved product insert. Compositions containing the topical compositions of this disclosure, formulated in a pharmaceutically acceptable carrier, may also be prepared, placed in a suitable container, and labeled for the treatment of the indicated medical condition.

[0213]

[0264] Another patch system configuration that may be used by this disclosure is a reservoir transdermal system design characterized by comprising a semipermeable membrane and a liquid compartment containing a drug solution or suspension separated from the release liner by an adhesive. The adhesive component of this patch system may be incorporated as a continuous layer between the membrane and the release liner, or concentrically around the membrane. Yet another patch system configuration that may be used by this disclosure is a matrix system design characterized by comprising a semi-solid matrix containing a drug solution or suspension in direct contact with the release liner. The components responsible for skin adhesion are incorporated into an overlay and form a concentric configuration around the semi-solid matrix.

[0214]

[0265] The pharmaceutical compositions of this disclosure may be in a form suitable for rectal administration, wherein the carrier is solid. The mixture preferably forms a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be conveniently formed by first mixing the composition with a softened or molten carrier, followed by cooling and molding in a mold.

[0215]

[0266] Pharmaceutical compositions containing the compounds of this disclosure and / or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0216]

[0267] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Generally, articles for distribution include a container that holds the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, and foil blister packs. Containers may also include tamper-evident features to prevent unintentional access to the contents of the package. Furthermore, containers typically have labels indicating the contents of the container and any appropriate warnings or instructions.

[0217]

[0268] The disclosed pharmaceutical compositions may, if desired, be provided in packs or dispenser devices capable of containing one or more unit dosage forms containing the active ingredient. The packs may include, for example, metal foil or plastic foil, such as blister packs. The packs or dispenser devices may be accompanied by instructions for administration. The packs or dispensers may also be accompanied by a notice relating to a form of container prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals, the notice reflecting the agency's approval of the form of the drug for human or veterinary administration. Such a notice may, for example, be a label approved by the U.S. Food and Drug Administration for a prescription drug or approved product insert. Pharmaceutical compositions containing the disclosed compounds formulated in a suitable pharmaceutical carrier may also be prepared, placed in appropriate containers, and labeled for the treatment of the indicated medical conditions.

[0218]

[0269] The precise dosage and frequency of administration depend, as is well known to those skilled in the art, on a particular disclosed compound, a product of the disclosed method of preparation, a pharmaceutically acceptable salt, solvate or polymorph thereof, its hydrate, its solvate, its polymorph, or its stereochemical isomer; the particular medical condition being treated and the severity of the medical condition being treated; various factors specific to the medical history of the person receiving the dosage, such as age; the weight, sex, degree of disability, and overall physical condition of the particular person, as well as any other drug treatments the individual may be receiving. Furthermore, it is clear that the effective daily dose may be reduced or increased depending on the response of the treated person and / or the assessment of the physician prescribing the compounds of this disclosure.

[0219]

[0270] Depending on the mode of administration, the pharmaceutical composition comprises 0.05 to 99% by weight, preferably 0.1 to 70% by weight, and more preferably 0.1 to 50% by weight of an active ingredient and 1 to 99.95% by weight, preferably 30 to 99.9% by weight, and more preferably 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all proportions based on the total weight of the composition.

[0220]

[0271] In therapeutic conditions requiring regulation of cereblon protein, appropriate dose levels are generally about 0.01–1000 mg / kg patient body weight / day and can be administered as a single or multiple dose. In various embodiments, dose levels are about 0.1–500 mg / kg / day, about 0.1–250 mg / kg / day, or about 0.5–100 mg / kg / day. Preferred dose levels may be about 0.01–1000 mg / kg / day, about 0.01–500 mg / kg / day, about 0.01–250 mg / kg / day, about 0.05–100 mg / kg / day, or about 0.1–50 mg / kg / day. Within this range, doses may be 0.05–0.5, 0.5–5.0, or 5.0–50 mg / kg / day. For oral administration, the composition is 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 symptomatic adjustment of the dosage for the patient being treated. The compound may be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. This administration regimen may be adjusted to provide an optimal therapeutic response.

[0221]

[0272] In therapeutic conditions requiring modulation of GSPT1 activity, appropriate dose levels are generally about 0.01–1000 mg / kg patient body weight / day and can be administered as a single or multiple dose. In various embodiments, dose levels are about 0.1–500 mg / kg / day, about 0.1–250 mg / kg / day, or about 0.5–100 mg / kg / day. Preferred dose levels may be about 0.01–1000 mg / kg / day, about 0.01–500 mg / kg / day, about 0.01–250 mg / kg / day, about 0.05–100 mg / kg / day, or about 0.1–50 mg / kg / day. Within this range, doses may be 0.05–0.5, 0.5–5.0, or 5.0–50 mg / kg / day. For oral administration, the composition is 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 symptomatic adjustment of the dosage for the patient being treated. The compound may be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. This administration regimen may be adjusted to provide an optimal therapeutic response.

[0222]

[0273] In therapeutic conditions requiring inhibition of cell proliferation, appropriate dose levels are generally about 0.01–1000 mg / kg patient body weight / day and can be administered as a single or multiple dose. In various embodiments, dose levels are about 0.1–500 mg / kg / day, about 0.1–250 mg / kg / day, or about 0.5–100 mg / kg / day. Preferred dose levels may be about 0.01–1000 mg / kg / day, about 0.01–500 mg / kg / day, about 0.01–250 mg / kg / day, about 0.05–100 mg / kg / day, or about 0.1–50 mg / kg / day. Within this range, doses may be 0.05–0.5, 0.5–5.0, or 5.0–50 mg / kg / day. For oral administration, the composition is 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 symptomatic adjustment of the dosage for the patient being treated. The compound may be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. This administration regimen may be adjusted to provide an optimal therapeutic response.

[0223]

[0274] The unit doses described above and below may be administered multiple times a day, for example, two, three, four, five, or six times a day. In various embodiments, such unit doses may be administered once or twice a day, such that the total dose for a 70 kg adult is in the range of 0.001 to about 15 mg per kg of the subject's body weight per dose. In further embodiments, the dose is 0.01 to about 1.5 mg per kg of the subject's body weight per dose, and such therapy may be extended for several weeks or months, and possibly for several years. However, it will be understood that the specific dose level for any particular patient depends on a variety of factors, including, as is well understood by those skilled in the art: the activity of the particular compound used; the age, weight, overall health, sex, and diet of the individual being treated; the time of administration, and the route of administration; the rate of excretion; other drugs previously administered; and the severity of the particular disease being treated.

[0224]

[0275] Typical dosages may be one 1 mg to approximately 100 mg tablet or 1 mg to approximately 300 mg taken once or multiple times daily, or one time-release capsule or tablet taken once daily containing a proportionally higher amount of the active ingredient. Time-release effects may be achieved by capsule materials that dissolve at various pH values, by capsules that release slowly by osmosis, or by any other known means of controlled release.

[0225]

[0276] As will be apparent to those skilled in the art, it may be necessary in some cases to use dosages outside these ranges. Furthermore, it should be noted that clinicians or therapists know how and when to initiate, interrupt, adjust, or discontinue treatment in conjunction with the individual patient's response.

[0226]

[0277] This disclosure further relates to a method for producing a pharmaceutical product for modulating the cereblon protein in a mammal (e.g., human) (e.g., one or more disorders related to the function or dysfunction of cereblon, e.g., the treatment of cancer), the method comprising the step of combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one embodiment, this disclosure further relates to a method for producing a pharmaceutical product comprising the step of combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, the pharmaceutical product being useful for modulating the cereblon protein.

[0227]

[0278] This disclosure further relates to a method for producing a pharmaceutical product for modulating GSPT1 in a mammal (e.g., human) (e.g., one or more disorders related to the function or dysfunction of cereblon, e.g., the treatment of cancer), comprising the step of combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one embodiment, this disclosure further relates to a method for producing a pharmaceutical product, comprising the step of combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, the pharmaceutical product being useful for modulating the GSPT1 protein.

[0228]

[0279] This disclosure further relates to a method for producing a pharmaceutical product for inhibiting cell proliferation in a mammal (e.g., human) (e.g., one or more disorders related to the function or dysfunction of cereblon, e.g., the treatment of cancer), comprising the step of combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Thus, in one embodiment, this disclosure further relates to a method for producing a pharmaceutical product, comprising the step of combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, the pharmaceutical product being useful for inhibiting cell proliferation.

[0229]

[0280] The disclosed pharmaceutical composition may further comprise other therapeutic compounds typically used to treat the above-mentioned pathological or clinical conditions.

[0230]

[0281] It is understood that the disclosed compositions may be prepared from the disclosed compounds. It is also understood that the disclosed compositions may be used in the disclosed methods of use.

[0231]

[0282] As previously stated, this disclosure relates to a pharmaceutical composition comprising a disclosed compound, a product of a disclosed method of preparation, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and a pharmaceutically acceptable carrier. Furthermore, this disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that the pharmaceutically acceptable carrier is closely mixed with a pharmaceutically acceptable amount of the compound according to this disclosure.

[0232]

[0283] As previously stated, this disclosure also relates to pharmaceutical compositions comprising the disclosed compound, the product of the disclosed method of preparation, pharmaceutically acceptable salts, its hydrate, its solvate, its polymorph, and one or more other drugs in the treatment, prevention, control, improvement, or reduction of the risk thereof of a disease or condition in which the disclosed compound or other drugs may be useful, and to the use of such compositions for the manufacture of pharmaceuticals. This disclosure also relates to combinations of the disclosed compound, the product of the disclosed method of preparation, pharmaceutically acceptable salts, its hydrate, its solvate, its polymorph, and additional therapeutic agents, such as cell proliferation inhibitors or anticancer agents. This disclosure also relates to such combinations for use as pharmaceuticals. The disclosure also relates to (a) the disclosed compound, the product of the disclosed method of preparation, pharmaceutically acceptable salts, hydrates thereof, solvates thereof, and polymorphs thereof, and (b) additional therapeutic agents as combination preparations for simultaneous, separate or sequential use in the treatment or prevention of a mammalian pathology, including human, whose treatment or prevention is affected or enhanced by the modulating effects of the disclosed compound and the additional therapeutic agent. The various drugs of such combinations or products may be combined in a single preparation with a pharmaceutically acceptable carrier or diluent, or they may each be present in separate preparations with a pharmaceutically acceptable carrier or diluent.

[0233]

[0284] F. Method using compounds

[0234] In various embodiments, the present disclosure provides a therapeutic method comprising the step of administering a therapeutically effective amount of the compound or pharmaceutical composition disclosed herein to a subject in need thereof.

[0235]

[0285] In a further embodiment, the present disclosure provides a method for treating a disorder of uncontrolled cell proliferation in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0236]

[0286] In a further embodiment, the disclosure provides a method for modulating cereblon activity in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0237]

[0287] In a further embodiment, the present disclosure provides a method for modulating cereblon activity in at least one cell, comprising the step of contacting at least one cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed pharmaceutical composition.

[0238]

[0288] In a further embodiment, a disorder of uncontrolled cell proliferation is cancer, for example, cancer is selected from brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary cancer, lymphoid cancer, stomach cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof. In a further aspect, cancer is a hematological cancer selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burket's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

[0239]

[0289] In a further embodiment, a disclosed method for treating disorders of uncontrolled cell proliferation in mammals involves at least one agent known to treat cancer, e.g., uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altoretamine, me Totrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextresed, idarubicin, paclitaxel, docetaxel, ixabepyrone, mitramycin, topotecan, irinotecan, deoxygenated Sycoformycin, Mitomycin-C, L-asparaginase, Interferon, Etoposide, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone Propionate, Testolactone, Megestrol Acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianicene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone Acetate, Leup Lorid, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrin, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Oxaliplatin, Gefinitib, Capecitabine, Erlotinib, Azacitidine, Temozolomide, Gemcitabine,The procedure further includes administering therapeutically effective doses of vasostatin and / or combinations thereof.

[0240]

[0290] In a further embodiment, a disclosed method for modulating cereblon activity in at least one cell involves regulating at least one cell with at least one drug known to treat cancer, e.g., uracil mustard, chlormetine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altoretamine, methotrexate 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thiogunine, Fludarabine Phosphate, Pentostatin, Bortezomib, Vinblastine, Vincristine, Vinorelbine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemextreced, Idarubicin, Paclitaxel, Docetaxel, Ixabepyrone, Mitramycin, Topotecan, Irinotecan, Deoxycoformin Syn, Mitomycin-C, L-asparaginase, Interferon, Etoposide, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone Propionate, Testolactone, Megestrol Acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianicene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogestin Acetate The further step involves contacting an effective amount of terone, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0241]

[0291] In a further embodiment, a disclosed method for modulating cereblon activity in a mammal includes the step of administering to a mammal at least one agent known to treat cancer, e.g., uracil mustard, chlormetine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thiogunine, Fludarabine Phosphate, Pentostatin, Bortezomib, Vinblastine, Vincristine, Vinorelbine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemextreced, Idarubicin, Paclitaxel, Docetaxel, Ixabepyrone, Mitramycin, Topotecan, Irinotecan, Deoxycoformycin, Mitomycin-C, L-asparaginase, interferon, etoposide, teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, The procedure further includes administering therapeutically effective doses of leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrin, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0242]

[0292] G. Kitt In a further embodiment, the present disclosure relates to a kit comprising at least one compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 144; or at least one pharmaceutical composition as described in any one of claims 145 to 154; and one or more of the following: (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 GSPT1 activity; (d) at least one agent known to decrease GSPT1 activity; (e) at least one agent known to increase cell proliferation; (f) at least one agent known to decrease cell proliferation; (g) at least one agent known to treat disorders related to cereblon activity; (h) at least one agent known to treat disorders related to GSPT1 activity; (i) at least one agent known to treat disorders of uncontrolled cell proliferation; and / or (j) instructions for treating disorders of uncontrolled cell proliferation.

[0243]

[0293] The disclosed compounds, and / or pharmaceutical compositions comprising the disclosed compounds, may be conveniently provided as a kit, thereby providing two or more components, carriers, diluents, etc., which may be active or inactive components, along with instructions for the preparation of actual dosage forms by the patient or the person administering the drug to the patient. Such a kit may contain all the necessary materials and components contained therein, or may include instructions for using or preparing materials or components that the patient or the person administering the drug to the patient must obtain independently. In a further embodiment, the kit may include any components that assist in administering a unit dose to the patient, e.g., vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Furthermore, the kit may include instructions for the preparation and administration of the composition. The kit may be manufactured as a single-use unit dose for one patient, as a multi-use kit for a specific patient (at a constant dose, or with varying potency of individual compounds as treatment progresses), or the kit may include multi-use doses suitable for administration to multiple patients ("bulk packaging"). The kit components can be assembled into cartons, blister packs, bottles, tubes, etc.

[0244]

[0294] In a further embodiment, the disclosed kit may be packaged in a daily dosing regimen (e.g., packaged in a card, packaged in a dosing card, packaged in a blister or blow-molded plastic). Such packaging promotes the product and enhances patient compliance with the drug regimen. Such packaging can also reduce patient confusion. The disclosure also features such a kit further including instructions for use.

[0245]

[0295] In a further embodiment, the Disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more components of the pharmaceutical composition of the Disclosure. Such containers may be associated with a notice in a form prescribed by a government agency that regulates the manufacture, use or sale of a pharmaceutical or biological product, the notice reflecting the agency's approval for manufacture, use or sale for human administration.

[0246]

[0296] In various embodiments, the disclosed kit may also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, drug reseller, physician, compounding shop, or pharmacist could provide a kit comprising the disclosed compounds and / or products and other components for delivery to a patient.

[0247]

[0297] The disclosed kit is intended to be used in connection with the disclosed method of preparation, the disclosed method of use or treatment, and / or the disclosed composition.

[0248]

[0298] H.'s research tools The disclosed compounds and pharmaceutical compositions have activity as modulators of cereblon protein. In further embodiments, the disclosed compounds and pharmaceutical compositions have activity as modulators of GSPT1 expression and / or activity. In even further embodiments, the disclosed compounds and pharmaceutical compositions have activity as inhibitors of cell proliferation. Therefore, the disclosed compounds are also useful as research tools. Accordingly, one aspect of the present disclosure relates to a method for using the compounds of the present disclosure as research tools, comprising the step of performing a biological assay using the compounds of the present disclosure. New chemical compounds can also be evaluated using the compounds of the present disclosure. Accordingly, another aspect of the present disclosure relates to a method for evaluating a test compound in a biological assay, comprising the steps of (a) performing a biological assay using the test compound to provide a first assay value; (b) performing a biological assay using the compound of the present disclosure to provide a second assay value, wherein step (a) is performed before, after, or concurrently with step (b); and (c) comparing the first assay value obtained from step (a) with the second assay value obtained from step (b). Exemplary biological assays include cereblon assays or GSPT1 assays that may be performed in vitro or in cell culture systems disclosed herein, or alternatively, cell proliferation assays using cell lines and cell proliferation assays disclosed herein. Another aspect of the disclosure relates to a method for testing a biological system, e.g., a model animal for a clinical condition, or a biological sample containing cereblon protein, comprising the steps of (a) contacting the biological system or biological sample with a compound of the disclosure; and (b) determining the effect caused by the compound on the biological system or biological sample.In various embodiments, the disclosed compounds are useful as chemical probes for GSPT1 / 2 testing in vitro and in vivo.

[0249]

[0299] I. References References are cited throughout this specification using parenthetical reference numbers, corresponding to one or more of the numbered references below. For example, the references to references 1 and 2 immediately below this specification are indicated in this disclosure as (References 1 and 2).

[0250]

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[0341] @@@

[0252]

[0342] J. Modes The following list of exemplary embodiments supplements and is supplemented by the disclosures provided herein.

[0253]

[0343] Embodiment 1. Compounds having a structure represented by the following formula: [ka] (In the formula, n is an integer selected from 0, 1, and 2, and A 1 and A 2 Each of these is independently selected from -(C=O)- and -CH2-, where A 1 and A 2 At least one of them is -(C=O)-, and R1 is a 5-10 membered aryl or heteroalkyl group optionally substituted with a group selected from (a) halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl. (b) selected from halogens, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, and 5-10 membered cycloalkyls optionally substituted with a group selected from these, or a pharmaceutically acceptable salt thereof.

[0254]

[0344] Embodiment 2. Compounds having the following structure: [ka] (In the formula, R 20aR is selected from bromo, methyl, -CF3, and -OCF3. 20b , R 20c , R 20d and R 20e Each of these is independently selected from hydrogen, halogen, and methyl (or a pharmaceutically acceptable salt thereof), and a compound having a structure represented by the following formula: [ka] Two compounds, excluding or their pharmaceutically acceptable salts.

[0255]

[0345] Embodiment 3. Excluded compounds, compounds of Embodiment 2.

[0256]

[0346] Appearance 4.R 20a Two compounds, one of which is bromo.

[0257]

[0347] Appearance 5.R 20a A compound of 4 in which is methyl.

[0258]

[0348] Appearance 6.R 20a However, two compounds are selected from -CF3 and -OCF3.

[0259]

[0349] Appearance 7.R 20b , R 20c , R 20d and R 20e A compound according to any one of embodiments 2 to 6, wherein each of the atoms is hydrogen.

[0260]

[0350] Appearance 8.R 20b , R 20c , R 1d and R 1e A compound according to any one of embodiments 2 to 6, wherein at least one of the elements is a halogen.

[0261]

[0351] Appearance 9.R 20b , R 20c , R 20d and R 20eA compound according to any one of embodiments 2 to 6, wherein at least one of the members is methyl.

[0262]

[0352] Embodiment 10. A compound having a structure represented by the following formula, one of the compounds from Embodiments 2 to 9: [ka] [ka] or [ka] or a subgroup thereof.

[0263]

[0353] Embodiment 11.n is one compound from any of Embodiments 1 to 10, selected from 0 and 1.

[0264]

[0354] Embodiment 12. A compound from any one of Embodiments 1 to 10, wherein n is 0.

[0265]

[0355] Embodiment 13. A compound from any one of Embodiments 1 to 10, wherein n is 1.

[0266]

[0356] Appearance 14.A 1 is -(C=O)- and A 2 A compound in any one of embodiments 1 to 13, wherein the parent group is -CH2-.

[0267]

[0357] Appearance 15.A 1 is -CH2-, and A 2 A compound in any of embodiments 1 to 13, wherein the parent molecule is -(C=O)-.

[0268]

[0358] Appearance 16.A 1 and A 2 A compound in any of embodiments 1 to 13, wherein each of the elements is -(C=O)-.

[0269]

[0359] Appearance 17.R1 is Ar 1 And Ar 1 A compound, any one of embodiments 1 to 16, which is a 5- to 10-membered aryl or heteroaryl, optionally substituted with a group selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0270]

[0360] Appearance 18.Ar 1 However, substituent R 11 , R 12 , R 13 and R 14 It is a pyridinyl having R 11 , R 12 , R 13 and R 14 A compound of embodiment 17, wherein each of is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0271]

[0361] Appearance 19.R 11 , R 12 , R 13 and R 14Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, - Compounds of Embodiment 18, independently selected from OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0272]

[0362] Appearance 20.R 11 , R 12 , R 13 and R 14 A compound of embodiment 19, wherein each of is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0273]

[0363] Appearance 21.R 11 , R 12 , R 13 and R 14The compound of embodiment 19, wherein each of is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0274]

[0364] Appearance 22.R 11 , R 12 , R 13 and R 14 The compound of embodiment 19, wherein each of is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0275]

[0365] Appearance 23.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that at least one R 11 , R 12 , R 13 and R 14 A compound of embodiment 18, wherein the hydrogen is not hydrogen.

[0276]

[0366] Appearance 24.R 11 , R 12 , R 13 and R 14each of hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF 3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Independently selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 , R 13 and R 14 A compound of embodiment 23, wherein the hydrogen is not hydrogen.

[0277]

[0367] Appearance 25.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 , R 13 and R 14 A compound of embodiment 23, wherein the hydrogen is not hydrogen.

[0278]

[0368] Appearance 26.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 , R 13 and R 14 A compound of embodiment 23, wherein the hydrogen is not hydrogen.

[0279]

[0369] Appearance 27.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, provided that at least one R 11 , R 12 , R 13 and R 14 A compound of embodiment 23, wherein the hydrogen is not hydrogen.

[0280]

[0370] Appearance 28.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 , R 13 and R 14 A compound of embodiment 18, wherein only one of the elements is not hydrogen.

[0281]

[0371] Appearance 29.R 11 , R 12 , R 13 and R14 Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 , R 13 and R 14 A compound according to embodiment 28, wherein only one of the elements is not hydrogen.

[0282]

[0372] Appearance 30.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 and R 14 A compound according to embodiment 28, wherein only one of the elements is not hydrogen.

[0283]

[0373] Appearance 31.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 and R 14 A compound according to embodiment 28, wherein only one of the elements is not hydrogen.

[0284]

[0374] Appearance 32.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 , R 13 and R 14 A compound according to embodiment 28, wherein only one of the elements is not hydrogen.

[0285]

[0375] Appearance 33.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 , R 13 and R 14 A compound of embodiment 18, wherein only two of the elements are not hydrogen.

[0286]

[0376] Appearance 34.R 11 , R 12 , R 13and R 14 Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 , R 13 and R 14 A compound of embodiment 33, wherein only two of the elements are not hydrogen.

[0287]

[0377] Appearance 35.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 and R 14 A compound of embodiment 33, wherein only two of the elements are not hydrogen.

[0288]

[0378] Appearance 36.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 and R 14 A compound of embodiment 33, wherein only two of the elements are not hydrogen.

[0289]

[0379] Appearance 37.R 11 , R 12 , R 13 and R 14 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 , R 13 and R 14 A compound of embodiment 33, wherein only two of the elements are not hydrogen.

[0290]

[0380] Appearance 38.R 11 , R 12 , R 13 and R 14 A compound according to embodiment 18, wherein each of the atoms is hydrogen.

[0291]

[0381] Appearance 39.Ar 1 However, substituent R 11 , R 12 and R 13 It is a pyrimidinyl having R 11 , R 12 and R 13A compound of embodiment 17, wherein each of is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0292]

[0382] Appearance 40.R 11 , R 12 and R 13 Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, - Compounds of Embodiment 39, independently selected from OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0293]

[0383] Appearance 41.R 11 , R 12 and R 13A compound of embodiment 40, wherein each of is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0294]

[0384] Appearance 42.R 11 , R 12 and R 13 A compound of embodiment 40, wherein each of is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0295]

[0385] Appearance 43.R 11 , R 12 and R 13 A compound of embodiment 40, wherein each of is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0296]

[0386] Appearance 44.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 39, wherein the hydrogen is not hydrogen.

[0297]

[0387] Appearance 45.R11 , R 12 and R 13 each of hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF 3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Independently selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 44, wherein the hydrogen is not hydrogen.

[0298]

[0388] Appearance 46.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 44, wherein the hydrogen is not hydrogen.

[0299]

[0389] Appearance 47.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 44, wherein the hydrogen is not hydrogen.

[0300]

[0390] Appearance 48.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 44, wherein the hydrogen is not hydrogen.

[0301]

[0391] Appearance 49.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 and R 13 A compound according to embodiment 39, wherein only one of the elements is not hydrogen.

[0302]

[0392] Appearance 50.R 11 , R 12 and R 13Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound according to embodiment 49, wherein only one of the elements is not hydrogen.

[0303]

[0393] Appearance 51.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 , R 14 A compound of embodiment 49, wherein only one of R15 is not hydrogen.

[0304]

[0394] Appearance 52.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound according to embodiment 49, wherein only one of the elements is not hydrogen.

[0305]

[0395] Appearance 53.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound according to embodiment 49, wherein only one of the elements is not hydrogen.

[0306]

[0396] Appearance 54.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 and R 13 A compound according to embodiment 39, wherein only one of the elements is not hydrogen.

[0307]

[0397] Appearance 55.R 11 , R 12 and R 13Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 54 in which two of the elements are not hydrogen.

[0308]

[0398] Appearance 56.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound of embodiment 54 in which two of the elements are not hydrogen.

[0309]

[0399] Appearance 57.R 11 , R12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound of embodiment 54 in which two of the elements are not hydrogen.

[0310]

[0400] Appearance 58.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 54 in which two of the elements are not hydrogen.

[0311]

[0401] Appearance 59.R 11 , R 12 and R 13 A compound according to embodiment 39, wherein each of the atoms is hydrogen.

[0312]

[0402] Appearance 60.Ar 1 The compound of embodiment 17, which is a five-membered heteroaryl optionally substituted with a group selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0313]

[0403] Appearance 61.Ar 1 However, (a) one heteroatom and substituent R 11 , R 12 and R 13 A 5-membered heteroaryl (wherein R) has 11 , R 12 and R 13Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl); as well as (b) two heteroatoms and substituent R 11 , R 12 and R 13 A 5-membered heteroaryl (wherein R) has 11 , R 12 and R 13 A compound of embodiment 60, each of which is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0314]

[0404] Appearance 62.Ar 1 The compound according to embodiment 61, wherein the compound is a five-membered heteroaryl having one heteroatom, and the heteroatom is selected from -O- and -S-.

[0315]

[0405] Appearance 63.Ar 1 The compound according to embodiment 61, wherein the compound is a five-membered heteroaryl having two heteroatoms, and the two heteroatoms comprise a first heteroatom and a second heteroatom.

[0316]

[0406] Embodiment 64. The first heteroatom is -N=, and the second heteroatom is -NR 12 A compound according to embodiment 63, selected from -, -O-, and -S-.

[0317]

[0407] Embodiment 65. The first heteroatom is -N= and the second heteroatom is -NR 12 -The compound of embodiment 63.

[0318]

[0408] Appearance 66.R 11 , R 12 and R 13 each of hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2 A compound from any one of embodiments 61 to 65, independently selected from -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0319]

[0409] Appearance 67.R 11 , R 12 and R 13 Compounds of Embodiment 66, wherein each of is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0320]

[0410] Appearance 68.R 11 , R 12 and R 13A compound of embodiment 66, wherein each of is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0321]

[0411] Appearance 69.R 11 , R 12 and R 13 A compound according to embodiment 66, wherein each of is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0322]

[0412] Appearance 70.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that at least one R 11 , R 12 and R 13 A compound that is not hydrogen, any one of embodiments 61 to 65.

[0323]

[0413] Appearance 71.R 11 , R 12 and R 13each of hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF 3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Independently selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 70, wherein the compound is not hydrogen.

[0324]

[0414] Appearance 72.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 70, wherein the compound is not hydrogen.

[0325]

[0415] Appearance 73.R 11, R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 70, wherein the compound is not hydrogen.

[0326]

[0416] Appearance 74.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, provided that at least one R 11 , R 12 and R 13 A compound of embodiment 70, wherein the compound is not hydrogen.

[0327]

[0417] Appearance 75.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 and R 13 A compound according to any one of embodiments 61 to 65, wherein only one of the compounds is not hydrogen.

[0328]

[0418] Appearance 76.R 11 , R 12 and R 13Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 75, wherein only one of the elements is not hydrogen.

[0329]

[0419] Appearance 77.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 , R 13 , R 14 A compound of embodiment 75, wherein only one of R15 is not hydrogen.

[0330]

[0420] Appearance 78.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound of embodiment 75, wherein only one of the elements is not hydrogen.

[0331]

[0421] Appearance 79.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 75, wherein only one of the elements is not hydrogen.

[0332]

[0422] Appearance 80.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 and R 13 A compound according to any one of embodiments 61 to 65, wherein only one of the compounds is not hydrogen.

[0333]

[0423] Appearance 81.R 11 , R 12 and R 13Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br -OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 78, in which two of the elements are not hydrogen.

[0334]

[0424] Appearance 82.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound of embodiment 78, in which two of the elements are not hydrogen.

[0335]

[0425] Appearance 83.R 11 , R12 and R 13 Each of these is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, provided that R 11 , R 12 and R 13 A compound of embodiment 78, in which two of the elements are not hydrogen.

[0336]

[0426] Appearance 84.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, however, R 11 , R 12 and R 13 A compound of embodiment 78, in which two of the elements are not hydrogen.

[0337]

[0427] Appearance 85.R 11 , R 12 and R 13 A compound according to any one of embodiments 61 to 65, wherein each of the atoms is hydrogen.

[0338]

[0428] Appearance 86.Ar 1 However, one compound from any of embodiments 61 to 85 having a structure represented by the following formula: [ka] or [ka]

[0339]

[0429] Appearance 87.Ar 1 However, one compound from any of embodiments 61 to 85 having a structure represented by the following formula: [ka] or [ka]

[0340]

[0430] Appearance 88.Ar 1 However, it is a 5-membered heteroaryl having two heteroatoms, a first heteroatom and a second heteroatom, where the first heteroatom is -N= and the second heteroatom is selected from -O- and -S-, Ar 1 However, R 11 and R 12 It is replaced by R 11 and R 12 Compounds of embodiment 60, each of which is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl;

[0431] Appearance 89.R 11 and R 12 Each of these is hydrogen, -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, - Compounds of embodiment 88, independently selected from OCHBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0341]

[0432] Appearance 90.R 11 and R 12 A compound of embodiment 88, wherein each of is independently selected from hydrogen, -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0342]

[0433] Appearance 91.R 11 and R 12 A compound of embodiment 88, wherein each of is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0343]

[0434] Appearance 92.R 11 and R 12 A compound of embodiment 88, wherein each of is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0344]

[0435] Appearance 93.R 11 and R 12 A compound according to any one of embodiments 88 to 92, wherein at least one of the elements is hydrogen.

[0345]

[0436] Appearance 94.R 11 and R 12 A compound according to any one of embodiments 88 to 92, wherein each of the atoms is hydrogen.

[0346]

[0437] Appearance 95.Ar 1 However, one compound from any of embodiments 88 to 94 having a structure represented by the following formula: [ka] or [ka]

[0438] Embodiment 96. A compound from any one of Embodiments 1 to 13, wherein R1 is Cy1, and Cy1 is a 5-10 membered cycloalkyl group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0347]

[0439] Embodiment 97. The compound of Embodiment 96, wherein Cy1 is selected from cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0348]

[0440] Embodiment 98. The compound of Embodiment 97, wherein Cy1 is selected from cyclopentyl, cyclohexyl, and cycloheptyl.

[0349]

[0441] Embodiment 99. The compound of Embodiment 97, wherein Cy1 is cyclohexyl.

[0350]

[0442] Aspect 100. A compound from any one of Aspects 96 to 99, wherein Cy1 is monosubstituted with a group selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0351]

[0443] Embodiment 101.Cy1 is -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2C F3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHB A compound of embodiment 100, monosubstituted with a group selected from r2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0352]

[0444] Embodiment 102. The compound of Embodiment 100, wherein Cy1 is monosubstituted with a group selected from -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0353]

[0445] Embodiment 103. The compound of Embodiment 100, wherein Cy1 is monosubstituted with a group selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0354]

[0446] Embodiment 104. The compound of Embodiment 100, wherein Cy1 is monosubstituted with a group selected from -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0355]

[0447] Aspect 105. Any one of the compounds from aspects 96 to 99, wherein Cy1 is disubstituted with two groups independently selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl.

[0356]

[0448] Embodiment 106.Cy1 is -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3 , -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, Compounds of Embodiment 105, disubstituted with two groups independently selected from -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0357]

[0449] Embodiment 107. The compound of Embodiment 105, wherein Cy1 is disubstituted with two groups independently selected from -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0358]

[0450] Embodiment 108. The compound of Embodiment 105, wherein Cy1 is disubstituted with two groups independently selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0359]

[0451] Embodiment 109. The compound of Embodiment 105, wherein Cy1 is disubstituted with two groups independently selected from -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0360]

[0452] Embodiment 110. A compound from any one of Embodiments 96 to 99, wherein Cy1 is unsubstituted.

[0361]

[0453] Embodiment 111. One compound from any one of Embodiments 1 to 16 having a structure represented by the following formula: [ka] (In the formula, n is an integer selected from 0, 1, and 2, and A 1 and A 2 Each of these is independently selected from -(C=O)- and -CH2-, where A 1 and A 2 At least one of them is -(C=O)-, and R 11 , R 12 , R13 , R 14 Each of R15 is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl) or a pharmaceutically acceptable salt thereof.

[0362]

[0454] Appearance 112.R 11 , R 12 , R 13 , R 14 Each of R15 is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, -SCF3, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, provided that R 11 , R 12 , R 13 , R 14 A compound of embodiment 111, wherein at least one of R15 is not hydrogen.

[0363]

[0455] Appearance 113.R 11 , R 12 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl, provided that at least one R 11 , R 12 and R 13 It is not hydrogen, but R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0364]

[0456] Appearance 114.R11 and R 12 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl, R 13 , R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0365]

[0457] Appearance 115.R 11 and R 13 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl, R 12 , R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0366]

[0458] Appearance 116.R 11 and R 14 Each of these is independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl, R 12 , R 13 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0367]

[0459] Appearance 117.R 11However, R is selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 aminoalkyl, C1~C3 alkylamino, C1~C3 hydroxyalkyl, -O-(C1~C3 haloalkyl), C1~C3 alkyl, and phenyl. 12 , R 13 , R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0368]

[0460] Appearance 118.R 11 is -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Compounds of Embodiment 117, selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0369]

[0461] Appearance 119.R 11The compound of embodiment 117, selected from -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0370]

[0462] Appearance 120.R 11 The compound of embodiment 117, selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0371]

[0463] Appearance 121.R 11 A compound of embodiment 117, selected from -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0372]

[0464] Appearance 122.R 12 However, R is selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 aminoalkyl, C1~C3 alkylamino, C1~C3 hydroxyalkyl, C1~C3 alkyl, and phenyl. 12 , R 13 , R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0373]

[0465] Appearance 123.R 11is -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Compounds of Embodiment 122, selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0374]

[0466] Appearance 124.R 12 The compound of embodiment 122, selected from -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0375]

[0467] Appearance 125.R 12 The compound of embodiment 122, selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0376]

[0468] Appearance 126.R 12The compound of embodiment 122, selected from -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0377]

[0469] Appearance 127.R 13 However, R is selected from halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 aminoalkyl, C1~C3 alkylamino, C1~C3 hydroxyalkyl, C1~C3 alkyl, and phenyl. 12 , R 13 , R 14 A compound according to embodiment 111, wherein each of R15 is hydrogen.

[0378]

[0470] Appearance 128.R 13 is -Cl, -Br, -SF5, -CN, -N3, -CN, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, - CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2Br, -CH2CHBr2, -CH2CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OC Compounds of Embodiment 127, selected from HBr2, -OCBr3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2Br, -OCH2CHBr2, -OCH2CBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0379]

[0471] Appearance 129.R 13The compound of embodiment 127, selected from -Cl, -Br, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2Br, -OCHBr2, -OCBr3, -OCH3, -OCH2CH3, -CH2OH, -(CH2)2OH, -NHCH3, -NHCH2CH3, -N(CH3)2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0380]

[0472] Appearance 130.R 13 A compound of embodiment 127, selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0381]

[0473] Appearance 131.R 13 A compound of embodiment 127, selected from -Cl, -OCF3, methyl, ethyl, and tert-butyl.

[0382]

[0474] Embodiment 132. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 12 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0383]

[0475] Embodiment 133. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 13 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0384]

[0476] Embodiment 134. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 14 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0385]

[0477] Embodiment 135. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0386]

[0478] Embodiment 136. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 12 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0387]

[0479] Embodiment 137. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 13 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0388]

[0480] Embodiment 138. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 12 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0389]

[0481] Embodiment 139. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 13 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0390]

[0482] Embodiment 140. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 14 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0391]

[0483] Embodiment 141. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0392]

[0484] Embodiment 142. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 12 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0393]

[0485] Embodiment 143. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 13 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0394]

[0486] Embodiment 144. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 12 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0395]

[0487] Embodiment 145. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 13 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0396]

[0488] Embodiment 146. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 and R 14 Each of these is a compound independently selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0397]

[0489] Embodiment 147. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 11 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0398]

[0490] Embodiment 148. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 12 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0399]

[0491] Embodiment 149. A compound of Embodiment 111 having a structure represented by the following formula: [ka] R 13 The compounds selected from hydrogen, halogen, -SF5, -CN, -N3, -NH2, -OH, -CN, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C1-C3 alkyl, and phenyl.

[0400]

[0492] Embodiment 150. One compound exists as follows: [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] or a subgroup thereof.

[0401]

[0493] Embodiment 151. A compound that exists as follows: [ka] or [ka] or a subgroup thereof.

[0402]

[0494] Embodiment 152. One compound exists as follows: [ka] or a subgroup thereof.

[0403]

[0495] Embodiment 153. A compound that exists as follows: [ka] [ka] [ka] or [ka] or a subgroup thereof.

[0404]

[0496] A pharmaceutical composition comprising a therapeutically effective amount of any compound according to Embodiments 154.1 to 153 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

[0405]

[0497] Embodiment 155. The pharmaceutical composition of Embodiment 154, further comprising at least one agent known to treat cancer.

[0406]

[0498] Embodiment 156. A pharmaceutical composition of Embodiment 155, wherein at least one agent known to treat cancer is a hormone therapy agent; an alkylating agent, an antimetabolite, an antineoplastic antibiotic agent, a mitotic inhibitor agent, an mTor inhibitor agent, another chemotherapeutic agent, or a combination thereof.

[0407]

[0499] Embodiment 157. A pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is a hormonal therapy agent selected from one or more of the group consisting of leuprolide, tamoxifen, raloxifene, megestrol, fulvestrant, triptorelin, medroxyprogesterone, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histrelin, fluoxymesterone, estramustine, flutamide, toremifene, degarelix, nilutamide, abarelix, and testolactone, or a pharmaceutically acceptable salt thereof.

[0408]

[0500] Embodiment 158. The pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is an antineoplastic antibiotic selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and barrubicin, or a pharmaceutically acceptable salt thereof.

[0409]

[0501] Embodiment 159. A pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is an antimetabolite selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nerarabine, cladribine, clopharabine, cytarabine, decitabine, pralatrexate, phloxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0410]

[0502] Embodiment 160. The pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is an alkylating agent selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechloretamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.

[0411]

[0503] Embodiment 161. The pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is a mitotic inhibitor selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepirone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0412]

[0504] Embodiment 162. The pharmaceutical composition of Embodiment 156, wherein at least one agent known to treat cancer is an mTor inhibitor selected from one or more of the group consisting of everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt thereof.

[0413]

[0505] Apparatus 163. At least one drug known to treat cancer is uracil mustard, chlormetine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6- Thioguanine, fludarabine phosphate, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextreced, idarubicin, paclitaxel, docetaxel, ixabepyrone, mitramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, intero - Feron, etoposide, teniposide 17-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flu A pharmaceutical composition according to embodiment 156, selected from tamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrin, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0414]

[0506] Embodiment 164. A method for treating a disorder of uncontrolled cell proliferation in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof from any one of Embodiments 1 to 153, or at least one pharmaceutical composition from any one of Embodiments 154 to 163.

[0415]

[0507] Embodiment 165. The method of Embodiment 164, wherein the mammal is a human.

[0416]

[0508] Embodiment 166. The method of Embodiment 164, wherein a mammal has been diagnosed with needing treatment for a disorder of uncontrolled cell proliferation prior to the administration step.

[0417]

[0509] Embodiment 167. The method of Embodiment 164, further comprising the step of identifying mammals in need of treatment for disorders of uncontrolled cell proliferation.

[0418]

[0510] Embodiment 168. The method of Embodiment 164, wherein impaired uncontrolled cell proliferation is associated with cereblon (CRBN) dysfunction.

[0419]

[0511] Embodiment 169. The method of Embodiment 168, wherein the disorder of uncontrolled cell proliferation is cancer.

[0420]

[0512] Apparatus 170. The method of Apparatus 169, wherein the cancer is childhood cancer.

[0421]

[0513] Apparatus 171. The method of Apparatus 169, wherein the cancer is childhood acute leukemia (AL) or medulloblastoma (MB) cancer.

[0422]

[0514] Apparatus 172. The method of Apparatus 169, wherein the cancer is selected from brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphoid cancer, stomach cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof.

[0423]

[0515] Embodiment 173. The method of Embodiment 172, wherein the cancer is selected from lung cancer, ovarian cancer, and brain cancer.

[0424]

[0516] Embodiment 174. The method of Embodiment 173, wherein the lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof.

[0425]

[0517] Apparatus 175. The method of Apparatus 173, wherein the renal cancer is kidney clear cell carcinoma.

[0426]

[0518] Apparatus 176. The method of Apparatus 173, wherein the brain cancer is selected from glioblastoma, medulloblastoma, glioma and combinations thereof.

[0427]

[0519] Apparatus 177. The method of Apparatus 173, wherein the bladder cancer is urothelial carcinoma of the bladder.

[0428]

[0520] Apparatus 178. The method of Apparatus 173, wherein the liver cancer is hepatocellular carcinoma.

[0429]

[0521] Embodiment 179. The method of Embodiment 173, wherein the hematological cancer is selected from chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burket's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

[0430]

[0522] Embodiment 180. Any one of embodiments 164 to 179, further comprising the step of administering a therapeutically effective dose of at least one drug known to treat cancer.

[0431]

[0523] Embodiment 181. At least one drug is uracil mustard, chlormetine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, phosphate Fludarabine, pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextreced, idarubicin, paclitaxel, docetaxel, ixabepirone, mitramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferon, Etoposide, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone Propionate, Testolactone, Megestrol Acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianicene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone Acetate, Leuprolide, Fluta A method according to embodiment 180, selected from mid, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrin, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0432]

[0524] Embodiment 182. The method of Embodiment 180, wherein at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

[0433]

[0525] Embodiment 183. The method of Embodiment 182, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacitidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination thereof.

[0434]

[0526] Embodiment 184. The method of Embodiment 182, wherein the HDAC inhibitor is vorinostat, entinostat, panbinostat, trichostatin A, mosetinostat, belinostat, dacinostat, givinostat, tubastatin A, prasinostat, droxinostat, quisinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tasejinarin, rocilinostat, apicidine, or a combination thereof.

[0435]

[0527] Embodiment 185. The method of Embodiment 182, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0436]

[0528] Embodiment 186. The method of Embodiment 182, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination thereof.

[0437]

[0529] Embodiment 187. The method of Embodiment 182, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antineoplastic antibiotic, a mitotic inhibitor, an mTor inhibitor, or another chemotherapeutic agent.

[0438]

[0530] Embodiment 188. The method of Embodiment 187, wherein the antineoplastic antibiotic is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and barrubicin, or from pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof.

[0439]

[0531] Embodiment 189. The method of Embodiment 187, wherein the antimetabolite is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nerarabine, cladribine, clopharabine, cytarabine, decitabine, pralatrexate, phloxuridine, methotrexate, and thioguanine, or from pharmaceutically acceptable salts, hydrates, solvates, or polyforms thereof.

[0440]

[0532] Embodiment 190. The method of Embodiment 187, wherein the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechloretamine, temozolomide, thiotepa, bendamustine, and streptozocin, or from pharmaceutically acceptable salts, hydrates, solvates, or polyforms thereof.

[0441]

[0533] Embodiment 191. The method of Embodiment 187, wherein the mitotic inhibitor is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepyrone, vinorelbine, vinblastine, and teniposide, or from pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof.

[0442]

[0534] Embodiment 192. The method of Embodiment 187, wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof.

[0443]

[0535] Embodiment 193. The method of Embodiment 187, wherein the other chemotherapeutic agent is anthracycline, cytarabine, purine analogue, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination thereof.

[0444]

[0536] Embodiment 194. The method of Embodiment 193, wherein the anthracycline is daunorubicin, idarubicin, or a combination thereof.

[0445]

[0537] Embodiment 195. The method of Embodiment 193, wherein the purine analog is cladribine, fludarabine, clopharabine, or a combination thereof.

[0446]

[0538] Embodiment 196. Any one of Embodiments 180 to 195, wherein at least one compound, at least one pharmaceutical composition, and at least one drug are administered sequentially.

[0447]

[0539] Embodiment 197. Any one of Embodiments 180 to 195, wherein at least one compound, at least one pharmaceutical composition, and at least one drug are administered simultaneously.

[0448]

[0540] Embodiment 198. Any one of Embodiments 180 to 195, wherein at least one compound, at least one pharmaceutical composition, and at least one drug are co-formulated.

[0449]

[0541] Embodiment 199. Any one of Embodiments 180 to 195, wherein at least one compound, at least one pharmaceutical composition, and at least one drug are packaged together.

[0450]

[0542] Embodiment 200. A method for modulating cereblon activity in a mammal, comprising the step of administering to a mammal a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof from any one of Embodiments 1 to 153, or at least one pharmaceutical composition from any one of Embodiments 154 to 163.

[0451]

[0543] Embodiment 201. The method of Embodiment 200, wherein the mammal is a human.

[0452]

[0544] Embodiment 202. The method of Embodiment 200, wherein a mammal is diagnosed as requiring modification of cereblon activity prior to the administration step.

[0453]

[0545] Embodiment 203. The method of Embodiment 200, further comprising the step of identifying mammals that require regulation of cereblon activity.

[0546] Embodiment 204. A method for regulating cereblon activity in at least one cell, comprising the step of contacting at least one cell with an effective amount of at least one compound or a pharmaceutically acceptable salt thereof from any one of Embodiments 1 to 153, or at least one pharmaceutical composition from any one of Embodiments 154 to 163.

[0454]

[0547] Apparatus 205. The method of Apparatus 204, wherein the cells are mammalian.

[0455]

[0548] Embodiment 206. The method of Embodiment 204, wherein the cells are human.

[0456]

[0549] Embodiment 207. The method of Embodiment 204, wherein the cells are isolated from the mammal before the contact step.

[0457]

[0550] Embodiment 208. The method of Embodiment 204, wherein the contact step is performed by administration to a mammal.

[0458]

[0551] Embodiment 209. The method of Embodiment 208, wherein a mammal is diagnosed as requiring modification of cereblon activity prior to the administration step.

[0459]

[0552] Embodiment 210. The method of Embodiment 208, wherein a mammal is diagnosed with needing treatment for a disorder related to cereblon activity prior to the administration step.

[0460]

[0553] Embodiment 211. The method of Embodiment 164, Embodiment 200, or Embodiment 204, wherein the compound inhibits cell proliferation with an IC50 of less than about 20 μM, and / or the compound exhibits cerebron binding with an IC50 of less than about 10 μM, as determined in a cell viability assay using MV4-11 cells as described herein.

[0461]

[0554] Embodiment 212. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 15 μM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 7.5 μM.

[0462]

[0555] Embodiment 213. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 10 μM, and / or the compound exhibits cereblon binding with an IC50 of less than approximately 5 μM.

[0463]

[0556] Embodiment 214. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 10 μM, and / or the compound exhibits cereblon binding with an IC50 of less than approximately 1 μM.

[0464]

[0557] Embodiment 215. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 5 μM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 500 nM.

[0465]

[0558] Embodiment 216. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 1 μM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 100 nM.

[0466]

[0559] Embodiment 217. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 100 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 100 nM.

[0467]

[0560] Embodiment 218. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 10 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 50 nM.

[0468]

[0561] Embodiment 219. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 1 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 50 nM.

[0469]

[0562] Embodiment 220. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 0.1 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 50 nM.

[0470]

[0563] Embodiment 221. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 0.01 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 50 nM.

[0471]

[0564] Embodiment 222. The method of Embodiment 211, wherein the compound inhibits cell proliferation with an IC50 of less than approximately 0.01 nM, and / or the compound exhibits cerebron binding with an IC50 of less than approximately 25 nM.

[0472]

[0565] A kit comprising at least one compound or a pharmaceutically acceptable salt thereof from any of embodiments 223.1 to 153; or at least one pharmaceutical composition from any one of embodiments 154 to 163; and one or more of the following: (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 GSPT1 activity; (d) at least one agent known to decrease GSPT1 activity; (e) at least one agent known to increase cell proliferation; (f) at least one agent known to decrease cell proliferation; (g) at least one agent known to treat disorders related to cereblon activity; (h) at least one agent known to treat disorders related to GSPT1 activity; (i) at least one agent known to treat disorders of uncontrolled cell proliferation; and / or (j) instructions for treating disorders of uncontrolled cell proliferation.

[0473]

[0566] Embodiment 224. A kit according to Embodiment 223, wherein at least one compound or at least one product is co-formulated with at least one drug.

[0474]

[0567] Embodiment 225. A kit according to Embodiment 223, wherein at least one compound or at least one product and at least one drug are packaged together.

[0475]

[0568] Embodiment 226. A kit from any one of Embodiments 223 to 225, further comprising instructions for providing a compound in connection with surgery.

[0476]

[0569] Embodiment 227. The kit of Embodiment 226, wherein the instructions specify that the surgery is performed before the step of administering at least one compound.

[0477]

[0570] Embodiment 228. The kit of Embodiment 226, wherein the instructions specify that the surgery is performed after a step of administering at least one compound.

[0478]

[0571] Embodiment 229. The kit according to Embodiment 226, wherein the instructions specify that the step of administering at least one compound is to perform a neoadjuvant tumor resection.

[0479]

[0572] Embodiment 230. The kit according to Embodiment 226, wherein the instructions specify that the surgery is performed approximately simultaneously with the step of administering at least one compound.

[0480]

[0573] Embodiment 231. Any one of Embodiments 223 to 230, further comprising instructions for providing at least one compound or pharmaceutical composition in relation to radiotherapy.

[0481]

[0574] Embodiment 232. The kit of Embodiment 231, wherein the instructions specify that radiotherapy is performed before the step of administering at least one compound.

[0482]

[0575] Embodiment 233. The kit of Embodiment 231, wherein the instructions specify that radiotherapy is performed after the step of administering at least one compound.

[0483]

[0576] Embodiment 234. The kit of Embodiment 231, wherein the instructions specify that radiotherapy is performed approximately simultaneously with the step of administering at least one compound.

[0484]

[0577] Embodiment 235. A kit comprising any one of Embodiments 223 to 234, further comprising a plurality of dosage forms, the plurality comprising one or more doses, each dose comprising at least one compound or pharmaceutical composition and at least one therapeutically effective amount of drug.

[0485]

[0578] Embodiment 236. A kit according to Embodiment 235, wherein each dose of at least one compound or pharmaceutical composition is co-formulated with at least one drug.

[0486]

[0579] Embodiment 237. A kit according to Embodiment 235, wherein each dose of at least one compound or pharmaceutical composition and at least one drug are co-packaged.

[0487]

[0580] Embodiment 238. A kit according to Embodiment 235, wherein the dosage form is formulated for oral and / or intravenous administration.

[0488]

[0581] Embodiment 239. The kit according to Embodiment 235, wherein the dosage form is formulated for oral administration.

[0489]

[0582] Embodiment 240. The kit according to Embodiment 235, wherein the dosage form is formulated for intravenous administration.

[0490]

[0583] Embodiment 241. A kit according to Embodiment 235, wherein at least one compound or pharmaceutical composition dosage form is formulated for oral administration, and at least one drug dosage form is formulated for intravenous administration.

[0491]

[0584] Embodiment 242. A kit according to Embodiment 235, wherein at least one compound or pharmaceutical composition dosage form is formulated for intravenous administration, and at least one drug dosage form is formulated for oral administration.

[0492]

[0585] A kit comprising at least one compound from any of embodiments 243.1 to 153 or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition from any one of embodiments 154 to 163, and one or more of the following: (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 cell proliferation, (d) at least one agent known to decrease cell proliferation, (e) at least one agent known to treat disorders related to cereblon activity, (f) at least one agent known to treat disorders of uncontrolled cell proliferation, and / or (g) instructions for treating disorders of uncontrolled cell proliferation.

[0493]

[0586] Embodiment 244. A kit according to Embodiment 243, wherein at least one compound or at least one product is co-formulated with at least one drug.

[0494]

[0587] Embodiment 245. A kit according to Embodiment 243, wherein at least one compound or at least one product and at least one drug are packaged together.

[0495]

[0588] Embodiment 246. A kit from any one of Embodiments 243 to 245, further comprising instructions for providing a compound in connection with surgery.

[0496]

[0589] Embodiment 247. The kit of Embodiment 246, wherein the instructions specify that the surgery is performed before the step of administering at least one compound.

[0497]

[0590] Embodiment 248. The kit of Embodiment 246, wherein the instructions specify that the surgery is performed after a step of administering at least one compound.

[0498]

[0591] Embodiment 249. The kit according to Embodiment 246, wherein the instructions specify that the step of administering at least one compound is to perform a neoadjuvant tumor resection.

[0499]

[0592] Embodiment 250. The kit according to Embodiment 246, wherein the instructions specify that the surgery is performed approximately simultaneously with the step of administering at least one compound.

[0500]

[0593] Embodiment 251. Any one of Embodiments 243 to 250, further comprising instructions for providing at least one compound or pharmaceutical composition in relation to radiotherapy.

[0501]

[0594] Embodiment 252. The kit of Embodiment 251, wherein the instructions specify that radiotherapy is performed before the step of administering at least one compound.

[0502]

[0595] Embodiment 253. The kit of Embodiment 251, wherein the instructions specify that radiotherapy is performed after the step of administering at least one compound.

[0503]

[0596] Embodiment 254. The kit of Embodiment 251, wherein the instructions specify that radiotherapy is performed approximately simultaneously with the step of administering at least one compound.

[0504]

[0597] Embodiment 255. A kit comprising any one of Embodiments 243 to 254, further comprising a plurality of dosage forms, the plurality comprising one or more doses, each dose comprising at least one compound or pharmaceutical composition and at least one therapeutically effective amount of drug.

[0505]

[0598] Embodiment 256. A kit according to Embodiment 255, wherein each dose of at least one compound or pharmaceutical composition is co-formulated with at least one drug.

[0506]

[0599] Embodiment 257. A kit according to Embodiment 255, wherein each dose of at least one compound or pharmaceutical composition and at least one drug are co-packaged.

[0507]

[0600] Embodiment 258. A kit according to Embodiment 255, wherein the dosage form is formulated for oral and / or intravenous administration.

[0508]

[0601] Embodiment 259. The kit according to Embodiment 255, wherein the dosage form is formulated for oral administration.

[0509]

[0602] Embodiment 260. The kit according to Embodiment 255, wherein the dosage form is formulated for intravenous administration.

[0510]

[0603] Embodiment 261. A kit according to Embodiment 255, wherein at least one compound or pharmaceutical composition dosage form is formulated for oral administration, and at least one drug dosage form is formulated for intravenous administration.

[0511]

[0604] Embodiment 262. A kit according to Embodiment 255, wherein at least one compound or pharmaceutical composition dosage form is formulated for intravenous administration, and at least one drug dosage form is formulated for oral administration.

[0512]

[0605] A kit comprising at least one compound from any of embodiments 263.1 to 153 or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition from any one of embodiments 154 to 163, and one or more of the following: (a) at least one agent known to increase GSPT1 activity, (b) at least one agent known to decrease GSPT activity, (c) at least one agent known to increase cell proliferation, (d) at least one agent known to decrease cell proliferation, (e) at least one agent known to treat disorders related to GSPT1 activity, (f) at least one agent known to treat disorders of uncontrolled cell proliferation, and / or (g) instructions for treating disorders of uncontrolled cell proliferation.

[0513]

[0606] Embodiment 264. A kit according to Embodiment 263, wherein at least one compound or at least one product is co-formulated with at least one drug.

[0514]

[0607] Embodiment 265. A kit according to Embodiment 263, wherein at least one compound or at least one product and at least one drug are packaged together.

[0515]

[0608] Embodiment 266. A kit from any one of Embodiments 263 to 265, further comprising instructions for providing a compound in connection with surgery.

[0516]

[0609] Embodiment 267. The kit of Embodiment 266, wherein the instructions specify that the surgery is performed before the step of administering at least one compound.

[0517]

[0610] Embodiment 268. The kit of Embodiment 266, wherein the instructions specify that the surgery is performed after a step of administering at least one compound.

[0518]

[0611] Embodiment 269. The kit according to Embodiment 266, wherein the instructions specify that the step of administering at least one compound is to perform a neoadjuvant debulking procedure for a tumor.

[0519]

[0612] Embodiment 270. The kit of Embodiment 266, wherein the instructions specify that the surgery is performed approximately simultaneously with the step of administering at least one compound.

[0520]

[0613] Embodiment 271. Any one of Embodiments 263 to 270, further comprising instructions for providing at least one compound or pharmaceutical composition in relation to radiotherapy.

[0521]

[0614] Embodiment 272. The kit of Embodiment 271, wherein the instructions specify that radiotherapy is performed before the step of administering at least one compound.

[0522]

[0615] Embodiment 273. The kit of Embodiment 271, wherein the instructions specify that radiotherapy is performed after the step of administering at least one compound.

[0523]

[0616] Embodiment 274. The kit of Embodiment 271, wherein the instructions specify that radiotherapy is performed approximately simultaneously with the step of administering at least one compound.

[0524]

[0617] Embodiment 275. A kit comprising any one of Embodiments 263 to 274, further comprising a plurality of dosage forms, the plurality comprising one or more doses, each dose comprising at least one compound or pharmaceutical composition and at least one therapeutically effective amount of drug.

[0525]

[0618] Embodiment 276. A kit according to Embodiment 275, wherein each dose of at least one compound or pharmaceutical composition is co-formulated with at least one drug.

[0526]

[0619] Embodiment 277. A kit according to Embodiment 275, wherein each dose of at least one compound or pharmaceutical composition and at least one drug are co-packaged.

[0527]

[0620] Embodiment 278. A kit according to Embodiment 275, wherein the dosage form is formulated for oral and / or intravenous administration.

[0528]

[0621] Embodiment 279. A kit according to Embodiment 275, wherein the dosage form is formulated for oral administration.

[0529]

[0622] Embodiment 280. The kit according to Embodiment 275, wherein the dosage form is formulated for intravenous administration.

[0530]

[0623] Embodiment 281. A kit according to Embodiment 275, wherein at least one compound or pharmaceutical composition dosage form is formulated for oral administration, and at least one drug dosage form is formulated for intravenous administration.

[0531]

[0624] Embodiment 282. A kit according to Embodiment 275, wherein at least one compound or pharmaceutical composition dosage form is formulated for intravenous administration, and at least one drug dosage form is formulated for oral administration.

[0532]

[0625] Applicable aspect 283. Use of at least one compound from any of Applicable aspects 1 to 153 or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition from any of Applicable aspects 154 to 163; or a combination thereof, in the manufacture of a pharmaceutical for treating disorders associated with cereblon dysfunction in mammals.

[0533]

[0626] Apparatus 284. Use in the manufacture of a pharmaceutical product for treating a disorder of uncontrolled cell proliferation in mammals: at least one compound from any of Apparatus 1 to 153 or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition from any of Apparatus 154 to 163; or a combination thereof.

[0534]

[0627] Embodiment 285. Compounds having a structure represented by the following formula: [ka] (In the formula, R 1a R is selected from bromo, methyl, -CF3, and -OCF3. 1b , R 1c , R 1d and R 1e Each of these is independently selected from hydrogen, halogen, and methyl (or a pharmaceutically acceptable salt thereof).

[0535]

[0628] Appearance 286.R 1a A compound according to embodiment 286, wherein the compound is bromo.

[0536]

[0629] Appearance 287.R 1a A compound according to embodiment 286, wherein the compound is methyl.

[0537]

[0630] Appearance 288.R 1a A compound of embodiment 286, selected from -CF3 and -OCF3.

[0538]

[0631] Appearance 289.R 1b , R 1c , R 1d and R 1e A compound according to embodiment 286, wherein each of the atoms is hydrogen.

[0539]

[0632] Appearance 290.R 1b , R 1c , R 1d and R 1e A compound according to embodiment 286, wherein at least one of the elements is a halogen.

[0540]

[0633] Appearance 291.R 1b , R 1c , R 1d and R 1e A compound according to embodiment 286, wherein at least one of the members is methyl.

[0541]

[0634] Embodiment 292. The compound of Embodiment 286 having a structure represented by the following formula: [ka] or [ka] or a subgroup thereof.

[0542]

[0635] Embodiment 293. Compounds having a structure represented by the following formula: [ka] or a pharmaceutically acceptable salt thereof.

[0543]

[0636] Appearance 294. A pharmaceutical composition comprising a therapeutically effective amount of any compound from Appearances 286 to 293 or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

[0544]

[0637] Embodiment 295. The pharmaceutical composition of Embodiment 294, further comprising at least one agent known to treat cancer.

[0545]

[0638] Embodiment 296. A pharmaceutical composition of Embodiment 295, wherein at least one agent known to treat cancer is a hormone therapy agent; an alkylating agent, an antimetabolite, an antineoplastic antibiotic, a mitotic inhibitor, an mTor inhibitor, another chemotherapeutic agent, or a combination thereof.

[0546]

[0639] Embodiment 297. The pharmaceutical composition of Embodiment 296, wherein at least one agent known to treat cancer is a hormonal therapy agent selected from one or more of the group consisting of leuprolide, tamoxifen, raloxifene, megestrol, fulvestrant, triptorelin, medroxyprogesterone, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histrelin, fluoxymesterone, estramustine, flutamide, toremifene, degarelix, nilutamide, abarelix, and testolactone, or a pharmaceutically acceptable salt thereof.

[0547]

[0640] Embodiment 298. The pharmaceutical composition of Embodiment 296, wherein at least one agent known to treat cancer is an antineoplastic antibiotic selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and barrubicin, or a pharmaceutically acceptable salt thereof.

[0548]

[0641] Embodiment 299. A pharmaceutical composition of Embodiment 296, wherein at least one agent known to treat cancer is an antimetabolite selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nerarabine, cladribine, clopharabine, cytarabine, decitabine, pralatrexate, phloxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0549]

[0642] Embodiment 300. A pharmaceutical composition according to Embodiment 296, wherein at least one agent known to treat cancer is an alkylating agent selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechloretamine, temozolomide, thiotepa, bendamustine, and streptozosin, or a pharmaceutically acceptable salt thereof.

[0550]

[0643] Embodiment 301. A pharmaceutical composition according to Embodiment 296, wherein at least one agent known to treat cancer is a mitotic inhibitor selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepirone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0551]

[0644] Embodiment 302. The pharmaceutical composition of Embodiment 296, wherein at least one agent known to treat cancer is an mTor inhibitor selected from one or mor...

Claims

1. A compound having the structure represented by the following formula, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, n is an integer selected from 0, 1, and 2. R １ is optionally substituted by a group selected from (a) halogen, -SF ５ , -CN, -N ３ , -NH ２ , -OH, -CN, -SCF ３ , C １ to C ３ alkoxy, C １ to C ３ haloalkyl, C １ to C ３ aminoalkyl, C １ to C ３ alkylamino, C １ to C ３ hydroxyalkyl, -O-(C １ to C ３ haloalkyl), C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, and 5- to 10-membered aryl or heteroaryl optionally substituted by a group selected from phenyl, and (b) Halogen, -SF ５ -CN, -N ３ , -NH ２ , -OH, -CN, -SCF ３ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Alkylamino, C １ ~C ３ Hydroxyalkyl, -O-(C １ ~C ３ Haloalkyl), C ３ ~C ８ Cycloalkyl, C １ ~C ６ (Selected from 5- to 10-membered cycloalkyl groups, which may be substituted with groups selected from alkyl and phenyl.)

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer selected from 0 and 1.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. 【Chemistry 2】 (In the formula, n is an integer selected from 0, 1, and 2. R １１ , R １２ , R １３ , R １４ and R １５ Each of these is hydrogen, halogen, -SF ５ -CN, -N ３ , -NH ２ , -OH, -CN, -SCF ３ , C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Alkylamino, C １ ~C ３ Hydroxyalkyl, -O-(C １ ~C ３ Haloalkyl), C ３ ~C ８ Cycloalkyl, C １ ~C ６ (Independently selected from alkyl and phenyl.)

4. R １１ , R １２ , R １３ , R １４ and R １５ The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is not hydrogen.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. 【Transformation 3】 (In the formula, R １ａ , bromo, methyl, -CF ３ , and -OCF ３ Selected from, R １ｂ , R １ｄ and R １ｅ Each of these is independently selected from hydrogen, halogen, and methyl. R １ｃ (This is independently selected from hydrogen, halogen, methyl, and phenyl.)

6. R １ａ However, -CF ３ and -OCF ３ A compound according to claim 5 or a pharmaceutically acceptable salt thereof, selected from the above.

7. R １ｂ , R １ｃ , R １ｄ and R １ｅ The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. Table 1

9. A compound according to claim 7 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. 【Chemistry 4】

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising at least one agent known to treat cancer.

12. A pharmaceutical composition for treating disorders of uncontrolled cell proliferation in mammals by administration to mammals, A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

13. The pharmaceutical composition according to claim 12, wherein the mammal is a mammal that has been diagnosed prior to the administration as requiring treatment for the disorder of uncontrolled cell proliferation.

14. The pharmaceutical composition according to claim 12, wherein the impairment of uncontrolled cell proliferation is related to cereblon (CRBN) dysfunction.

15. The pharmaceutical composition according to claim 12, wherein the impairment of uncontrolled cell proliferation is cancer.

16. The pharmaceutical composition according to claim 15, wherein the cancer is selected from brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, urogenital cancer, lymphoid cancer, stomach cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, liver cancer, and combinations thereof.

17. The lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof. The aforementioned renal cancer is a clear cell carcinoma of the kidney. The brain cancer is selected from glioblastoma, medulloblastoma, glioma, and combinations thereof. The aforementioned bladder cancer is urothelial carcinoma of the bladder, The aforementioned liver cancer is hepatocellular carcinoma. The aforementioned blood cancers include: pediatric acute leukemia (AL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burket's lymphoma, and Hodgkin's lymphoma. The pharmaceutical composition according to claim 16, selected from lymphoma, non-Hodgkin lymphoma, and combinations thereof.

18. The pharmaceutical composition according to claim 12, for administration in combination with at least one therapeutically effective amount of an agent known to treat cancer.

19. The aforementioned at least one drug is uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabinol Pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextreced, idarubicin, paclitaxel, docetaxel, ixabepirone, mitramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferon, etoposide Teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremi The pharmaceutical composition according to claim 18, selected from fen, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrin, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

20. The pharmaceutical composition according to claim 18, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

21. The DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacitidine, zebralin, epigallocatechin-3-gallate, procaine, or a combination thereof. The aforementioned HDAC inhibitors are vorinostat, entinostat, panvinostat, trichostatin A, mosetinostat, bellinostat, dasinostat, zivinostat, tubastatin A, prasinostat, droxinostat, xinostat, romidepsin, valproic acid, AR-42 (OSU-HDAC42), tasejinarin, rosirinostat, apicidine, or a combination thereof. The glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or a combination thereof. The aforementioned mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or a combination thereof. The pharmaceutical composition according to claim 20, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antineoplastic antibiotic, a mitotic inhibitor, an mToR inhibitor, or another chemotherapeutic agent.

22. The aforementioned antineoplastic antibiotic is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and barrubicin, or from pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. The aforementioned antimetabolite is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clopharabine, cytarabine, decitabine, pralatrexate, phloxuridine, methotrexate, and thioguanine, or from pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. The alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechloretamine, temozolomide, thiotepa, bendamustine, and streptozocin, or from pharmaceutically acceptable salts, hydrates, solvates, or polyforms thereof. The mitotic inhibitor is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepyrone, vinorelbine, vinblastine, and teniposide, or from pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. The aforementioned mTor inhibitor is everolimus, sirolimus, temsirolimus, or a combination thereof. The pharmaceutical composition according to claim 21, wherein the other chemotherapeutic agent is anthracycline, cytarabine, purine analog, sorafenib, gemtuzumab ozogamicin, rituximab, or a combination thereof.

23. The pharmaceutical composition according to claim 18, wherein at least one of the drugs is administered sequentially or simultaneously.

24. The pharmaceutical composition according to claim 18, wherein at least one of the drugs is co-formulated or co-packaged.

25. A method for regulating GSPT1 activity in at least one mammalian cell in vitro, A method comprising the step of contacting the at least one cell with an effective amount of the at least one compound or a pharmaceutically acceptable salt thereof described in claim 1.

26. The method according to claim 25, wherein the mammal has been diagnosed prior to the contact as requiring regulation of cereblon activity or treatment of a disorder related to cereblon activity.

27. When the compound is determined in a cell viability assay using MV4-11 cells as described herein, the IC50 is less than 11 μM. ５０ This inhibits cell proliferation, The compound obtained by the fluorescence polarization assay described herein yielded an IC of less than 11 μM. ５０ This shows cereblon binding, or When the compound is determined in a cell viability assay using GSPT1 HiBit-tagged cells, the IC50 is less than 22 μM. ５０ The method according to claim 25, wherein cell proliferation is inhibited.

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