Modulators of cereblon protein

Abstract

This disclosure relates, in one aspect, to substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs used as modulators of cereblon (CRBN) activity, methods for their preparation, pharmaceutical compositions comprising the same, and methods of using the same to treat various clinical conditions and diseases, such as uncontrolled cell proliferation diseases that may be associated with cereblon protein dysfunction and / or GSPT1 dysfunction, such as cancer. In various further aspects, the disclosed compounds can selectively modulate the degradation of the GSPT1 protein, i.e., the disclosed compounds can act as GSPT1 degrading agents. This abstract is intended as a scanning tool for searching in a particular field and is not intended to limit the scope of this disclosure.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 082,365, filed September 23, 2020, the entire contents of which are incorporated herein by reference. Background Technology

[0003] A key characteristic of cancer is the increase in the number of abnormal cells originating from a specific normal tissue. These abnormal cells invade neighboring tissues, or malignant cells spread via the lymphatic or bloodstream to local lymph nodes and distant sites (metastases). There is a significant need for new methods, treatments, and compositions that can be used to treat cancer patients.

[0004] Protein degradation plays a role in various cellular functions, modulating the concentration of regulatory proteins by breaking them down into small peptides to maintain cellular health and productivity. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates a wide variety of other proteins. Targeted protein degradation, in particular, offers promising prospects for targeting currently incurable tumor proteins, such as transcription factors and chimeric fusion tumor proteins.

[0005] Despite progress in research aimed at improving the clinical outcomes of cancer, potent, effective, and selective protein degradation regulators, such as those with potent and selective regulatory effects on cereblon, remain lacking. This disclosure addresses these and other needs.

[0006] Overview

[0007] For the purposes of this disclosure, as embodied and broadly described herein, this disclosure relates, in one aspect, to substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs used as modulators of cereblon (CRBN) activity, methods for their preparation, pharmaceutical compositions comprising the same, and methods of using the same to treat various clinical conditions and diseases, such as uncontrolled cell proliferation diseases that may be associated with cereblon protein dysfunction, such as cancer. In various further aspects, the disclosed compounds can selectively modulate the degradation of the GSPT1 protein, i.e., the disclosed compounds can act as GSPT1 degrading agents. In another aspect, the disclosed compounds exhibit at least five times the selectivity for GSPT1 degradation compared to the selectivity for IKZF1 degradation.

[0008] Compounds having the structure shown in the following formula are disclosed:

[0009] ,

[0010] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O) and -CH2-, A 1 and A 2 At least one of them is -(C=O)-; where R 1 Selected from: (a) 5-10 aryl or heteroaryl groups 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; and (b) )Optionally substituted with a 5- to 10-membered cycloalkyl 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 groups; or pharmaceutically acceptable salts thereof.

[0011] Compounds having the structure shown in the following formula were also disclosed:

[0012] ,

[0013] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O) and -CH2-, A 1 and A 2 At least one of them is -(C=O)-; where R 1 Selected from: (a) 5-10 aryl or heteroaryl groups 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; and (b) 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-substituted 5- to 10-membered cycloalkyl groups; or pharmaceutically acceptable salts thereof; the compound is not a compound having the following structures:

[0014] ,

[0015] Where R 20a Selected from bromine, methyl, -CF3 and -OCF3; and wherein R 20b R 20c R 20d and R 20e Each is independently selected from hydrogen, halogen, and methyl; or a pharmaceutically acceptable salt thereof; and a compound having the structure shown in the following formula:

[0016] ,

[0017] Or its pharmaceutically acceptable salt.

[0018] Compounds having the structure shown in the following formula were also disclosed:

[0019] ,

[0020] Where R 1a Selected from bromine, methyl, -CF3 and -OCF3; and wherein R 1b R 1c R 1d and R 1e Each is independently selected from hydrogen, halogen, and methyl; or their pharmaceutically acceptable salts.

[0021] Compounds having the structure shown in the following formula were also disclosed:

[0022] ,

[0023] Or its pharmaceutically acceptable salt.

[0024] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of one or more disclosed compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0025] The method for treating uncontrolled cell proliferation in mammals is also disclosed, 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.

[0026] The method of modulating cereblon activity in mammals is also disclosed, 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.

[0027] The method of regulating cereblon activity in at least one cell is also disclosed, 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.

[0028] The method of modulating GSPT1 activity in mammals is also disclosed, 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.

[0029] The method for regulating GSPT1 activity in at least one cell is also disclosed, 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.

[0030] The use of the disclosed compound or a pharmaceutically acceptable salt thereof, the disclosed manufactured product or a pharmaceutically acceptable salt thereof, or the disclosed pharmaceutical composition is also disclosed.

[0031] The use of the disclosed compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases in mammals associated with dysfunction of the cereblon protein is also disclosed.

[0032] The use of the disclosed compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with GSPT1 dysfunction in mammals is also disclosed.

[0033] The use of the disclosed compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases in mammals associated with cell proliferation dysfunction, such as inhibiting cell proliferation of cancer cells in mammals, including combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0034] The method for preparing a drug that regulates mammalian cereblon protein is also disclosed, comprising combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0035] The method for preparing a drug that regulates the degradation of GSPT1 in mammals is also disclosed, comprising combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0036] The method of preparing a drug that inhibits the proliferation of mammalian cells, such as inhibiting the proliferation of cells in cancer cells, is also disclosed, comprising combining at least one disclosed compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

[0037] The kit also discloses a reagent 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 known agent that increases cereblon activity; (b) at least one known agent that decreases cereblon activity; (c) at least one known agent that increases GSPT1 activity; (d) at least one known agent that decreases GSPT1 activity; (e) at least one known agent that increases cell proliferation; (f) at least one known agent that decreases cell proliferation; (g) at least one known agent that treats diseases related to cereblon activity; (h) at least one known agent that treats diseases related to GSPT1 activity; (i) at least one known agent that treats diseases of uncontrolled cell proliferation; and / or (j) instructions for use in treating diseases of uncontrolled cell proliferation.

[0038] The kit also discloses a reagent 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 known agent that increases cereblon activity; (b) at least one known agent that decreases cereblon activity; (c) at least one known agent that increases cell proliferation; (d) at least one known agent that decreases cell proliferation; (e) at least one known agent for treating diseases associated with cereblon activity; (f) at least one known agent for treating diseases of uncontrolled cell proliferation; and / or (g) instructions for use in treating diseases of uncontrolled cell proliferation.

[0039] The kit also discloses a reagent 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 known agent that increases GSPT1 activity; (b) at least one known agent that decreases GSPT1 activity; (c) at least one known agent that increases cell proliferation; (d) at least one known agent that decreases cell proliferation; (e) at least one known agent that treats a disease associated with GSPT1 activity; (f) at least one known agent that treats a disease of uncontrolled cell proliferation; and / or (g) instructions for use in treating a disease of uncontrolled cell proliferation.

[0040] While various aspects of this disclosure may be described and claimed in specific statutory categories, such as the systems category, 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 statutory category. Unless expressly stated otherwise, no method or aspect set forth herein should be construed as requiring its steps to be performed in a particular order. Therefore, in cases where the steps of a method claim are not specifically defined in the claims or specification as belonging to a particular order, no such order is implied to be inferred. The foregoing applies to any possible non-express basis of interpretation, including logical questions concerning the arrangement of steps or procedures, simple meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. Attached Figure Description

[0041] Many aspects of this disclosure can be better understood by referring to the following accompanying drawings. The components in the drawings are not necessarily drawn to scale; their purpose is to clearly illustrate the principles of this disclosure. Furthermore, in the drawings, the same reference numerals are used to denote corresponding parts in several views.

[0042] Figure 1 Existing thalidomide analogs that induce the degradation of various disease-related proteins are shown. The checkmark indicates that the target can be degraded by its respective IMiDs.

[0043] Figure 2A-2B Representative data show the effect of treatment with increased concentrations of compounds 1 and 5 for 3 days on the viability of MV4-11 cells under the conditions described. Figure 2A The effects of treatment with increased concentrations of compounds 1 and 5 for 3 days on the viability of MV4-11 cells were shown in the absence and presence of lenalidomide (10 µM). Figure 2B The effects of treatment with increased concentrations of compounds 1 and 5 for 3 days on the viability of wild-type MV4-11 cells compared to CRBN- / - MV4-11 cells were shown.

[0044] Figures 3A-3D Representative data on the effects of treatment with increased concentrations of compounds 1 and 5 on GSPT1 and IKZF1 levels in MV4-11 cells are shown. Immunoblotting images are displayed at the top of the figures, with the quantitative band intensities plotted on each image. Labeled immunoblots indicate the detected proteins, namely GSPT1 and IKZF1, compared to the GAPDH control. Each immunoblot is labeled to indicate the concentration of the given compound used to treat MV4-11 cells. Figure 3A Data obtained by treating MV4-11 cells with compound 1 for 4 hours are shown. Figure 3B Data obtained by treating MV4-11 cells with compound 5 for 4 hours are shown. Figure 3CData obtained by treating MV4-11 cells with compound 1 for 24 hours are shown. Figure 3D Data obtained by treating MV4-11 cells with compound 5 for 24 hours are shown. Degradation values ​​were calculated using quantitative band intensities from Western blotting, and DCs were calculated based on the average of at least two independent experiments. 50 value.

[0045] Figure 4 This figure shows representative data obtained from a 24-hour TMT-proteomics experiment using compound 1 (10 nM). The dataset shown represents the average of n = 4 replicates. The upper left region of the figure shows downregulation exceeding 1.5-fold (dashed line on the X-axis, Log2 = -0.58) and a p-value less than 0.001 (on the Y-axis, -Log2 = -0.58). 10 Proteins with a p-value of 3 (dashed line). As shown in the figure, the results for GSPT1, GSPT2, IKZF3, CK1a, and IKZF1 are highlighted in the dataset.

[0046] Figure 5 Representative pharmacokinetic data obtained after single intravenous (IV) and oral (PO) administration of compound 1 in CD1 mice are shown. As shown above, the dose levels were: 3 mg / kg IV and 10 mg / kg PO. Formulation carriers: 5% v / v NMP; 5% v / v solute HS-15 and 90% v / v physiological saline. Pharmacokinetic parameters obtained from this study are shown below the figures.

[0047] Figure 6 Representative Western blot data on the levels of GSPT1 and IKZF1 in MV4-11 cells for compound 2 are shown. Labeled Western blotting indicates the detected proteins, namely GSPT1 and IKZF1, compared to the GAPDH control. Each Western blot is labeled to indicate the concentration of the given compound used to treat MV4-11 cells.

[0048] Figure 7 Representative Western blot data obtained using wild-type and Cereblon-deficient MV4-11 cell lines (clone 4B12) are shown, with CRBN protein detected compared to the GAPDH control.

[0049] Figure 8 Representative data on caspase activation at specified concentrations of compounds 1 and 5 after 4, 8, and 24 hours of treatment, compared to the DMSO control treatment, are shown.

[0050] Figures 9A-9BRepresentative data show the effect of treatment with increased concentrations of a control compound (prior art compound CC-90009) on GSPT1 and IKZF1 levels in MV4-11 cells. The images shown at the top of the figures are immunoblot images, with the quantitative band intensities plotted on each image. Labeled immunoblots indicate the detected proteins, namely GSPT1 and IKZF1, compared to the GAPDH control. Each immunoblot is labeled to indicate the concentration of the given compound used to treat MV4-11 cells. Figure A shows data obtained after treating MV4-11 cells with compound CC-90009 for 4 hours. Figure 9B Data obtained by treating MV4-11 cells with compound CC-90009 for 24 hours are shown.

[0051] Other advantages of this disclosure will be set forth in the description below, and some advantages will be apparent from the description or may be learned by practice of this disclosure. The advantages of this disclosure will be realized and obtained by the elements and combinations particularly pointed out in the appended claims. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory, and not intended to limit the scope of the claimed disclosure.

[0052] Detailed description

[0053] Modifications and other embodiments of this disclosure will be apparent to those skilled in the art from the teachings given in the foregoing description and the accompanying drawings. Therefore, it should be understood that this disclosure is not limited to the specific embodiments disclosed, and that the modifications and other embodiments are also included within the scope of the appended claims. Many variations and modifications of the aspects described herein will be apparent to those skilled in the art. These variations and modifications are included in the teachings of this disclosure and should be included within the scope of the appended claims.

[0054] Although specific terms are used in this article, they are used only in a general and descriptive sense and not for restrictive purposes.

[0055] As will be understood by those skilled in the art upon reading this disclosure, each individual embodiment described and disclosed herein has individual components and features that are readily separable from or combined with features of any other embodiment without departing from the scope or spirit of this disclosure.

[0056] Any described method may be performed in the order of the described events or in any other logically possible order. That is, unless expressly stated otherwise, no method or aspect set forth herein should be construed as requiring its steps to be performed in a particular order. Therefore, unless the claims or specification specifically state that the steps of a method claim are limited to a particular order, no situation implies that their order can be inferred. The above applies to any possible non-express basis for interpretation, including logical problems with the arrangement of steps or procedures, direct meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0057] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials associated with the cited publications. The publications discussed herein are only those disclosed prior to the filing date of this application. Nothing herein should be construed as an admission that this disclosure is not entitled to precede such disclosure by any prior disclosure. Furthermore, the publication dates provided herein may differ from the actual publication dates, which may require separate verification.

[0058] While various aspects of this disclosure may be described and claimed in specific statutory categories, such as the systems statutory category, 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 statutory category.

[0059] It should also be understood that the terminology used herein is for descriptive purposes only and not for limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods pertain. It should also be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having the same meaning as they have in the context of the specification and the relevant field, and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0060] Unless otherwise stated, all aspects of this disclosure will employ techniques from molecular biology, microbiology, organic chemistry, biochemistry, physiology, cell biology, vascular biology, etc., which are well explained in the literature within the scope of the art.

[0061] Before describing various aspects of this disclosure, the following definitions should be specified and used unless otherwise stated. Additional terms may be defined elsewhere in this disclosure.

[0062] A. Definition

[0063] As used herein, “comprising” should be interpreted as specifying the presence of the mentioned feature, integer, step, or component, but does not preclude the presence or addition of one or more features, integers, steps, or components, or combinations thereof. Furthermore, each of the terms “through,” “including,” “comprises,” “involves,” and “for example” is used in an open, non-limiting sense and may be used interchangeably. Additionally, the term “comprising” is intended to include examples and aspects covered by the terms “substantially constitutes” and “consistent with.” Similarly, the term “substantially constitutes” includes examples included by the term “consistent with.”

[0064] As used herein, the term "and / or" includes any and all combinations of one or more of the related listed items. Expressions such as "at least one," when placed before a list of elements, modify the entire list of elements but not individual elements within the list.

[0065] In the specification and appended claims, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural references. Thus, for example, references to “compound,” “substituent,” or “cancer” include, but are not limited to, two or more such compounds, substituents, or cancers, including combinations of compounds, substituents, or cancers.

[0066] When referring to "one / a" compound, protein, and antibody, each refers to one or more molecules of the compound, protein, and antibody, not just a single molecule. Furthermore, the one or more molecules can be the same or different, as long as they fall under the category of compound, protein, and antibody. Thus, for example, an "antibody" is interpreted as including one or more antibody molecules, where the antibody molecules can be the same or different (e.g., different isotypes and / or different antigen-binding sites, as may be found in polyclonal antibodies).

[0067] It should be noted that proportions, concentrations, quantities, and other numerical data may be expressed in the form of ranges herein. It should also be understood that the endpoints of each range are significant both relative to and independent of the other endpoint. Furthermore, it should be understood that while numerical values ​​are disclosed herein, each numerical value is also disclosed herein as “approximately” for that particular value, in addition to the value itself. For example, if the numerical value “10” is disclosed, then “about 10” is also disclosed. Ranges herein may be expressed as from “about” one particular value, and / or to “about” another particular value. Similarly, when a numerical value is expressed as an approximation using the preposition “about”, it can be understood that the particular value forms another aspect. For example, if the numerical value “about 10” is disclosed, then “10” is also disclosed.

[0068] When indicating a range, this also includes a range from one specific value and / or to another specific value. When providing a numerical range, it should be understood that, unless the context explicitly specifies otherwise, every intermediate value between the upper and lower limits of the range, up to one-tenth of the lower limit unit, and any other specified value or intermediate value within the specified range, is included in this disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller range and also included in this disclosure, subject to any specific exclusions within the range. When the range contains one or two limitations, this document also discloses ranges that do not include those containing one or both limitations. For example, when the range contains one or two limitations, the disclosure also includes ranges that do not include any one or both of these included limitations; for example, the phrase “x to y” includes a range from 'x' to 'y', as well as ranges greater than 'x' and less than 'y'. The range may also be expressed as an upper limit, such as “about x, y, z or less”, and should be interpreted as including specific ranges of “about x,” “about y,” and “about z,” as well as ranges of “less than x,” “less than y,” and “less than z.” Similarly, the phrase “about x, y, z or greater” should be interpreted as including 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'.”

[0069] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly, including not only the numerical values ​​explicitly defined as range boundaries, but also all individual numerical values ​​or subranges contained within that range, such as explicitly listing each numerical value and subrange. For example, the numerical range “about 0.1% to 5%” should be interpreted as including not only the explicitly listed numerical values ​​of about 0.1% to about 5%, but also individual numerical values ​​within the specified range (e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible subranges).

[0070] As used herein, terms such as “about,” “approximately,” and “substantially,” when used in conjunction with a numerical variable, generally refer to the value of that variable as well as the values ​​of all variables within experimental error (e.g., within a 95% confidence interval of the mean) or within + / - 10% of the indicated value, whichever is greater. As used herein, the terms “about,” “approximately,” “in or about,” and “substantially” can indicate that the quantity or value in question can be an exact value or a value that provides an equivalent result or effect as described in the claims or taught herein. That is, it should be understood that quantities, sizes, formulations, parameters, and other quantities and characteristics are not necessarily not required to be exact, but can be approximate and / or larger or smaller as needed, reflecting 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 cases, it is not reasonable to determine a value that provides an equivalent result or effect. Generally, quantities, sizes, formulations, parameters, or other quantities or characteristics are “about,” “approximately,” or “in or about,” whether explicitly stated otherwise. It should be understood that, unless otherwise specified, when “about,” “approximately,” or “equal to or approximately” is used before a quantity value, the parameter also includes the specific quantity value itself.

[0071] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both instances where the event or situation occurs and instances where it does not occur.

[0072] As used herein, “cereblon” and “CRBN” are used interchangeably to refer to the protein encoded by the human CRBN gene, which is located at 3p26.2 on chromosome 3, with base pairs 3,148,489 to 3,179,716 (UCSC Genome Browser on Human, dec. 2013 (grch 38 / hg38) Assembly). The human CRBN gene consists of 11 exons. CRBN is the substrate recognition component of the DCX (DDB1-CUL4-X-box) E3 protein ligase complex, which mediates the ubiquitination of target proteins and subsequent proteasome degradation. The DCX (DDB1-CUL4-X-box) E3 protein ligase complex consists of at least CRBN, CUL4A, DDB1, and RBX1. CRBN protein has two isotypes generated through alternative splicing: isotype 1 has 442 amino acids and a molecular weight of 50,546 Da; isotype 2 has 441 amino acids and a molecular weight of 50,475 Da.

[0073] As used herein, “CC-220” refers to the compound with CAS # 1323403-33-3; its IUPAC name is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione; and its structure is as follows:

[0074] .

[0075] As used herein, “CC-885” refers to the compound with CAS# 1010100-07-8; IUPAC name N-(3-chloro-4-methylphenyl)-N'-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-urea; and structure as follows:

[0076] .

[0077] As used herein, “CC-90009” refers to the compound with CAS # 1860875-51-9; the IUPAC name of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)methyl)-2,2-difluoroacetamide; and the structure as follows:

[0078] .

[0079] As used herein, “application” can mean the active or passive (e.g., by diffusion) delivery of a composition to the perivascular space and adventitia via oral, local, intravenous, subcutaneous, percutaneous, transdermal, intramuscular, intra-articular, intra-articular, intradermal, intravenous, intracardiac, intraperitoneal, intralesional, intranasal, intracardiac, intra-articular, intracavitary, intrathecal, intravenous, intracerebral and intraventricular, tympanic cavity, cochlea, rectum, vagina, inhalation, via catheter, stent, or via implanted reservoir or other device. For example, a medical device such as a stent may contain a composition or formulation placed on its surface, which may then dissolve or otherwise distribute to the surrounding tissues and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Application can be continuous or intermittent. In various respects, the formulation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further aspects, preparations can be administered preventively; that is, for the prevention of disease or ailment.

[0080] As used herein, "therapeutic agent" can refer to any substance, compound, molecule, etc., that is biologically active or that can induce pharmacological, immunogenic, biological, and / or physiological effects in a subject by administration, either locally or systemically. A therapeutic agent can be a primary active agent, 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 can be a secondary therapeutic agent, or in other words, a component of a composition to which additional and / or other effects of the composition are attributed. Therefore, the term includes those compounds or chemicals traditionally considered as drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc. Examples of therapeutic agents described in well-known references, such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), include, but are not limited to, drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or alleviate diseases; and substances that affect the structure or function of the body, or prodrugs, which become biologically active or more active when placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions used in all major therapeutic areas, including but not limited to adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and combinations of analgesics; anorexia nervosa; anti-inflammatory drugs; antiepileptic drugs; local and general anesthetics; hypnotics; sedatives; antipsychotics; tranquilizers; antidepressants; anxiolytics; antagonists; neuronal blocking agents; anticholinergics and cholinergics; antimuscarinic and muscarinic drugs; antiadrenergics; antiarrhythmics; antihypertensives; hormones and nutritional supplements; antiarthritis drugs; bronchodilators; anticonvulsants; antihistamines; antiemetics; antitumor drugs; antipruritics; antipyretics; anticonvulsants; cardiovascular preparations (including calcium channel blockers, β- Drugs include: antagonists, beta-agonists, and antiarrhythmics; antihypertensives; diuretics; vasodilators; central nervous system stimulants; cough and cold remedies; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressants; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized, or recombinant); and nucleic acid molecules (polymers of two or more nucleotides, ribonucleotides (RNA) or deoxyribonucleotides (DNA), including double-stranded and single-stranded molecules, gene constructs, expression vectors, antisense molecules, etc.), small molecules (e.g., doxorubicin), and other bioactive macromolecules such as proteins and enzymes. These agents can be used in medicine, including veterinary medicine, applied and agricultural fields such as plants, and other areas of bioactivity.The term therapeutic agent also includes, but is not limited to, drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure or alleviate disease; or substances that affect the structure or function of the body; or prodrugs that become biologically active or more active when placed in a predetermined physiological environment.

[0081] As used herein, a “kit” refers to a collection of at least two components that constitute a kit. These components together form a functional unit for a given purpose. The individual components may be physically packaged together or packaged separately. For example, a kit containing instructions for use may or may not physically include instructions with other individual components. Conversely, instructions may be provided as separate components, in print or electronic form, available on computer-readable storage devices or downloaded from the internet, or as a recorded demonstration.

[0082] As used herein, “instructions for use” refers to a document describing the materials or methods associated with the kit. These materials may include any combination of the following: background information, a list of components and their availability (purchasing information, etc.), a brief or detailed protocol for using the kit, troubleshooting, references, technical support, and any other relevant documentation. Instructions for use may be provided with the kit or as a separate component, and may be in print or electronic form, available on a computer-readable storage device or downloaded from an internet website, or as a recorded demonstration. Instructions for use may contain one or more documents and include future updates.

[0083] As used in this article, “connection” can refer to covalent or non-covalent interactions between two or more molecules. Non-covalent interactions can include ionic bonds, electrostatic interactions, van der Waals forces, dipole-dipole interactions, dipole-induced 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.

[0084] As used herein, the term "subject" can refer to a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Therefore, the subjects of the methods disclosed herein can be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cats, guinea pigs, or rodents. This term does not indicate a specific age or sex. Therefore, adults and adolescents, regardless of gender, are included. On the one hand, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes both human and veterinary subjects.

[0085] As used herein, the terms “treatment” and “curative action” generally refer to achieving a desired pharmacological and / or physiological effect. The effect may be, but is not necessarily, preventative in relation to the prevention or partial prevention of a disease, symptom, or condition, such as an uncontrolled cellular disease, like cancer, such as acute leukemia or medulloblastoma. The effect may be therapeutic in relation to the partial or complete cure of a disease, condition, symptom, or side effect attributable to that disease, disorder, or condition. The term “curative action” as used herein may include any treatment of an uncontrolled cellular disease, such as cancer, like acute leukemia or medulloblastoma, in a subject, particularly a human, and may include any or more of the following: (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with it; (b) inhibiting the disease, i.e., preventing its development; and (c) alleviating the disease, i.e., reducing or improving the disease and / or its symptoms or condition. The term “curative action” as used herein may refer to a therapeutic treatment alone, a preventative treatment alone, or both a therapeutic and preventative treatment. A person in need of treatment (a subject requiring treatment) may include a person who already has a disease and / or a person who needs to prevent a disease. As used herein, the term "treatment" may include suppressing a disease, disorder, or condition, such as hindering its development; and alleviating a disease, disorder, or condition, such as causing its resolution. Treating a disease, disorder, or condition may include improving at least one symptom of a particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, such as treating a subject's pain by administering an analgesic, even if the agent does not treat the cause of the pain.

[0086] As used herein, “unit dose” or “dose” may refer to a physically discrete unit applicable to a subject, each unit containing a predetermined amount of the disclosed compound and / or its pharmaceutical composition, calculated to produce the desired response in relation to its administration.

[0087] As used in this article, "therapeutic" may refer to treating, curing, and / or improving a disease, disorder, symptom, or side effect, or to slowing the progression of a disease, disorder, symptom, or side effect.

[0088] As used herein, "effective amount" can refer to an amount of the disclosed compound or pharmaceutical composition provided herein that is sufficient to produce a beneficial or desired physiological, psychological, medical, or clinical response in cells, tissues, systems, animals, or humans. An effective amount may be administered in a single or multiple dose, application, or dosage. Within its scope, the term may also include amounts that effectively enhance or restore substantially normal physiological function.

[0089] As used herein, the term "therapeutic effective dose" refers to an amount sufficient to achieve the desired therapeutic outcome or to have an effect on adverse symptoms, but generally insufficient to cause adverse side effects. The specific therapeutic effective dose level for any particular patient will depend on a variety of factors, including the disease being treated and its severity; the specific ingredient used; the patient's age, weight, general health condition, sex, and diet; the timing of administration; the route of administration; the excretion rate of the specific compound used; the duration of treatment; and, to the knowledge and expertise of a healthcare professional and as is well known in the medical field, the use of other drugs in combination with or in competition with the specific compound used and similar factors. In some cases of treating a particular disease or condition, the desired response may be to suppress the development of the disease or condition. This may involve only temporarily slowing the development of the disease. However, in other cases, it may be necessary to permanently stop the development of the disease. Monitoring can be performed using routine diagnostic methods known to those skilled in the art for any particular disease. The desired response to treatment of a disease or condition may also be to delay the onset of the disease or condition or even to prevent its onset.

[0090] For example, gradually increasing the dose from below the amount of compound required to achieve the desired therapeutic effect until the desired effect is achieved is within the scope of the art. If necessary, the effective daily dose can be divided into multiple doses for administration purposes. Therefore, a single-dose composition can contain such an amount or an approximation thereof to constitute the daily dose. If any contraindications exist, the dose can be adjusted by an individual physician. Generally, the maximum dose of the drug of the invention (alone or in combination with other therapeutic agents) is preferred, i.e., the highest safe dose based on reasonable medical judgment. However, those skilled in the art will understand that patients may adhere to a lower or tolerable dose for medical, psychological, or virtually any other reason.

[0091] For example, the response to a therapeutically effective dose of the disclosed compound and / or pharmaceutical composition can be measured by determining the physiological effect of the treatment or drug, such as the reduction or disappearance of disease symptoms after administration of the treatment or drug. Other assays will be known to those skilled in the art, and these assays can be used to measure the level of response. The amount of treatment can be varied, for example, by increasing or decreasing the amount of the disclosed compound and / or pharmaceutical composition, by changing the administration of the disclosed compound and / or pharmaceutical composition, by changing the route of administration, by changing the time of administration, etc. The dosage can be varied and can be administered once or multiple times daily, for one day or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in the literature.

[0092] As used in this article, the term "preventive effective dose" refers to the amount that is effective in preventing the onset or onset of a disease or symptom.

[0093] As used herein, the term “prevention” or “avoidance” means to exclude, avoid, exclude, prevent, stop, or stop something from happening, especially through preemptive action. It should be understood that, unless otherwise specified, the use of “reduce,” “suppress,” or “prevent” herein also explicitly discloses the use of the other two terms.

[0094] The term "pharmaceutically acceptable" refers to a substance that is not biologically or otherwise undesirable, meaning it will not cause undesirable biological effects at unacceptable levels or interact with the substance in a harmful manner.

[0095] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of an active agent prepared from an acid or base that is tolerated by the biological system or by the subject, or both, when administered in a therapeutically effective amount. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, which may be pure 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 groups, magnesium, lithium, strontium, or similar substances. When the compounds of this disclosure contain relatively basic functional groups, 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 pure or in a suitable inert solvent. Pharmaceutically acceptable examples of acid addition salts include, but are not limited to: salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are amino acid salts such as arginine salts, and organic acid salts such as glucuronic acid or galacturonic acid.

[0096] The term "pharmaceutically acceptable ester" refers to an ester of the compounds of the present invention that hydrolyzes in vivo, and includes esters that readily decompose in the human body, leaving behind the parent compound or its salts. Examples of pharmaceutically acceptable non-toxic esters of the present invention include C1 to C6 alkyl esters and C5 to C7 cycloalkyl esters, preferably C1 to C4 alkyl esters. Esters of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be added to a hydroxyl group by reacting a hydroxyl-containing compound with an acid and an alkyl carboxylic acid such as acetic acid, or with an acid and an aryl carboxylic acid such as benzoic acid. In the case of compounds containing a carboxylic acid group, pharmaceutically acceptable esters are prepared by reacting the compound with a base such as triethylamine and an alkyl halide, for example with methyl iodine, benzyl iodine, cyclopentyl iodine, or alkyl trifluoromethanesulfonate. They can also be prepared by reacting the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0097] The term "pharmaceutically acceptable amide" refers to the non-toxic amide of the present invention, which is derived from ammonia, C1-C6 alkyl primary amines, and C1-C6 dialkyl secondary amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 to C3 alkyl primary amines, and C1 to C2 dialkyl secondary amines are preferred. The amides of the disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reacting an amino-containing compound with an alkyl anhydride, aryl anhydride, acyl halide, or aromatic acyl halide. In the case of compounds containing carboxylic acid groups, pharmaceutically acceptable amides are prepared from compounds containing carboxylic acid groups by reacting the compound with a base such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkylamine, dialkylamine such as methylamine, diethylamine, and piperidine. They can also be prepared by reacting the compound with an acid such as sulfuric acid and an alkyl carboxylic acid such as acetic acid, or with an acid and an aryl carboxylic acid such as benzoic acid under dehydrating conditions, such as the addition of a molecular sieve. The composition may comprise a pharmaceutically acceptable prodrug form of a compound disclosed herein.

[0098] The term "pharmaceuticalally acceptable prodrug" or "prodrug" refers to a prodrug of the compounds of this invention that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., has a reasonable benefit / risk ratio, and is effective for its intended use. The prodrugs of this invention can be rapidly converted in vivo into a parent compound having the structure of the disclosed compound, for example, by hydrolysis in the blood. This is discussed in detail in T. Higuchi, V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACSSymposium Series and Edward B. Roche, ed. Ioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0099] As used herein, the term "derivative" refers to a compound having a structure derived from a parent compound (e.g., compounds disclosed herein), and whose structure is sufficiently similar to those disclosed herein, and based on that similarity, a person skilled in the art would expect it to exhibit the same or similar activities and uses as the claimed compound, or to induce the same or similar activities and uses as a precursor. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of parent compounds.

[0100] As used herein, the naming of compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rule of stereochemistry can be used to specify stereochemical priority, E / Z specification, etc. Given a name, those skilled in the art can easily determine the structure of the compound, either through systematic reduction of the compound structure using nomenclature conventions or through commercially available software such as CHEMDRAW. TM (Cambridge Soft Corporation, USA.).

[0101] The term "one" in compound refers to one or more molecules of that compound, not just a single molecule. Furthermore, the one or more molecules can be the same or different, as long as they fall under the category of chemical compounds. Thus, for example, "one" in chemical compound is interpreted as including one or more molecules of that chemical substance, which can be the same or different (e.g., different isotope ratios, enantiomers, etc.).

[0102] It should be noted that proportions, concentrations, quantities, and other numerical data may be expressed in the form of ranges herein. It should also be understood that the endpoints of each range are significant both relative to and independent of the other endpoint. Furthermore, it should be understood that while numerical values ​​are disclosed herein, each numerical value is also disclosed herein as “approximately” for that particular value, in addition to the value itself. For example, if the numerical value “10” is disclosed, then “about 10” is also disclosed. Ranges herein may be expressed as from “about” one particular value, and / or to “about” another particular value. Similarly, when a numerical value is expressed as an approximation using the preposition “about”, it can be understood that the particular value forms another aspect. For example, if the numerical value “about 10” is disclosed, then “10” is also disclosed.

[0103] When indicating a range, on the other hand, it includes a range from one specific value and / or to another specific value. For example, when the range contains one or two limits, the disclosure also includes ranges that do not include any one or both of these included limits. For example, the phrase "x to y" includes a range from 'x' to 'y', as well as ranges greater than 'x' and less than 'y'. The range can also be expressed as an upper limit, such as "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 of "less than x", "less than y", and "less than z". Similarly, the phrase "about x, y, z or greater" should be interpreted as including 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'".

[0104] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly, including not only the numerical values ​​explicitly defined as range boundaries, but also all individual numerical values ​​or subranges contained within that range, just as if each numerical value and subrange were explicitly listed. For clarification, the numerical range “about 0.1% to 5%” should be interpreted as including not only the explicitly listed numerical values ​​of about 0.1% to about 5%, but also individual numerical values ​​within the specified range (e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible subranges).

[0105] As used herein, the terms “approximately,” “around,” “at or approximately,” and “substantially” can indicate that the quantity or value in question can be an exact value or a value that provides an equivalent result or effect as described in the claims or taught herein. That is, it should be understood that quantities, dimensions, formulations, parameters, and other quantities and characteristics are not necessarily not required to be exact, but can be approximate and / or larger or smaller as needed, reflecting 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 cases, it is not reasonable to determine a value that provides an equivalent result or effect. In such cases, as used herein, unless otherwise stated or inferred, “approximately” and “equal to or approximately” are generally understood to be indicative values ​​representing a variation of ±10%. Generally, quantities, sizes, formulations, parameters, or other quantities or characteristics are “approximately,” “around,” or “at or approximately,” whether or not explicitly stated so. It should be understood that, unless otherwise specifically stated, when “approximately,” “around,” or “equal to or approximately” is used before a quantity value, the parameter also includes the specific quantity value itself.

[0106] As used herein, the term "contact" means bringing the disclosed compound or pharmaceutical composition into close proximity with cells, target proteins, or other biological entities such that the disclosed compound or pharmaceutical composition can directly affect the activity of the cells, target proteins, or other biological entities; that is, through interaction with the cells, target proteins, or other biological entities themselves, or indirectly through interaction with another molecule, cofactor, factor, or protein on which the activity of the cells, target proteins, or other biological entities depends.

[0107] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired change in the physical properties of a composition or material. For example, an "effective amount" of a disclosed compound or pharmaceutical composition refers to an amount sufficient to achieve the desired degree of modulation to achieve a target, such as modulation of the cereblon protein, or a desired improvement or enhancement of a clinical condition, such as cancer remission. The specific level of the amount of the disclosed compound or pharmaceutical composition required as an effective amount, such as milligrams, or concentrations, such as micromoles, will depend on a variety of factors: route of administration or contact with the target, severity of the clinical condition, degree of modulation required, etc.

[0108] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes both the possibility that the event or situation may occur and the possibility that it may not occur.

[0109] As used herein, the term “substituted” is considered to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy the heteroatom valence as described herein. This disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Furthermore, the terms “substituted” or “substituted” include the implicit limiting condition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. In addition, in some respects, unless the contrary is explicitly stated, a single substituent may be further optionally substituted (i.e., further substituted or unsubstituted).

[0110] When defining various terms, "A" 1 “A” 2 “A” 3 "and "A 4"These symbols are used in this document as general symbols to represent various specific substituents. These symbols can be any substituents, not limited to those disclosed herein, and while they are defined as certain substituents in one case, they can be defined as some other substituents in another case."

[0111] 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, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetradecyl, 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, as described herein, an alkyl group can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl-oxy, or thiol. "Lower alkyl" refers to an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl can also be 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., up to and including C1-C24 alkyl.

[0112] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying a particular substituent on the alkyl group. For example, the term "halogenated alkyl" or "halogenated alkyl" specifically refers to an alkyl group substituted with one or more halogens such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohalogenated alkyl" specifically refers to an alkyl group substituted with a single halogen such as fluorine, chlorine, bromine, or iodine. The term "polyhalogenated alkyl" specifically refers to an alkyl group independently substituted with two or more halogens, meaning that each halide substituent need not be the same halide as another halide substituent, and the multiple halide substituents need not be on the same carbon atom. 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 context and a specific term such as "hydroxyalkyl" is used in another context, it does not mean that the term "alkyl" does not also refer to the specific term such as "hydroxyalkyl," etc.

[0113] The above practice also applies to the other groups described herein. That is, while terms such as “cycloalkyl” refer to both the unsubstituted and substituted cycloalkyl moieties, the substituted moieties may also be specifically indicated herein; for example, a particular substituted cycloalkyl group may be referred to as, for example, “alkylcycloalkyl.” Similarly, a substituted alkoxy group may be specifically referred to as, for example, “haloalkoxy,” and a particular substituted alkenyl group may be, for example, “alkenyl alcohol,” etc. Likewise, the use of general terms such as “cycloalkyl” and specific terms such as “alkylcycloalkyl” does not mean that general terms exclude specific terms.

[0114] As used herein, the term "cycloalkyl" refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. The term "heterocyclic alkyl" is a cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl" in which at least one carbon atom of the ring is substituted with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocyclic alkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocyclic alkyl groups can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl-oxy, or thiol groups as described herein.

[0115] As used in this article, the terms "alkoxy" and "alkoxy group" refer to alkyl or cycloalkyl groups bonded by ether linkages; that is, "alkoxy group" can be defined as OA. 1 A 1 It is an alkyl or cycloalkyl group as defined above. "Alkoxy" also includes polymers of alkoxy groups just described; that is, alkoxy groups can be polyethers, such as -OA. 1 -OA 2 or -OA 1 -(OA 2 ) a -OA 3 Where "a" is an integer from 1 to 200, A 1 A 2 and A 3 It is an alkyl and / or cycloalkyl group.

[0116] The term "amine" or "amino" as used in this article is derived from the formula NA. 1 A 2 It means that A 1 and A 2 It can be hydrogen independently or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl group as described herein. A specific example of an amino group is -NH2.

[0117] As used herein, the term "alkylamino" is represented by the formulas -NH(-alkyl) and -N(-alkyl)2, where the alkyl group is as described herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentamino, isopentylamino, (tert-pentyl)amino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, etc.

[0118] The term "ether" as used in this article is derived from formula A. 1 OA 2 It means that A 1 and A 2 It can be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl group as described herein. The term "polyether" as used herein is derived from the formula -(A 1 OA 2 O) a - indicates that A 1 and A 2 It can be independently an alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl, or heteroaryl group as described herein, and "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutane oxide.

[0119] The term "hydroxyl" or "hydroxyl group" as used in this article is represented by the formula -OH.

[0120] The term “thiol” used in this article is represented by the formula -SH.

[0121] The term “azide” or “azido group” used in this article is represented by the formula -N3.

[0122] The term “nitro” as used in this article is represented by the formula -NO2.

[0123] The term “nitrile” or “cyano” as used in this article is represented by the formula -CN.

[0124] The terms “halogen”, “halogen”, or “halide” used in this article are used interchangeably to refer to F, Cl, Br, or I.

[0125] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalogen” used herein are interchangeable and refer to functional groups that behave substantially like halides. Examples of such functional groups include cyano, thiocyanate, azide, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy.

[0126] 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, wherein nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroalkyl groups may be substituted with alkyl groups as defined above.

[0127] As used herein, the term "heterocyclic alkyl" refers to aliphatic, partially unsaturated, or fully saturated 3- to 14-membered ring systems, including monocyclic, bicyclic, and tricyclic systems with 3 to 8 atoms. Heterocyclic alkyl ring systems comprise 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be substituted. Representative heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolinyl, isothiazolyl, and tetrahydrofuranyl.

[0128] The term "carbonyl" as used herein is represented by the formula -C(O)-. Throughout this specification, "C(O)" or C=O is the abbreviation for carbonyl.

[0129] As used herein, the term "aromatic group" refers to a ring structure with a ring cloud of delocalized π electrons above and below the molecular plane, wherein the π cloud contains (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd's *Organic Chemistry* (5th ed., 1987), Chapter 13, entitled "Aromaticity," pp. 477–497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

[0130] As used herein, the term "aryl" refers to a group containing any carbonyl aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene, etc. Alkyl groups may also be substituted or unsubstituted. An aryl group may be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halogen, hydroxyl, ketone, azide, nitro, silyl, thiooxy, or thiol. The term "biaryl" is a specific type of aryl group included in the definition of "aryl". Furthermore, an aryl group may be a monocyclic structure or contain multiple ring structures, which may be fused ring structures or linked by one or more bridging groups such as carbon-carbon bonds. For example, a biaryl group may be attached to two aryl groups bonded together by a fused ring structure, as in naphthalene, or linked by one or more carbon-carbon bonds, as in biphenyl.

[0131] As used herein, the term "heteroaryl" refers to an aromatic group in which at least one heteroatom is incorporated into the ring of an aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, wherein N-oxides, sulfur oxides, and dioxides are permitted heteroatom substitutions. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted by one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halogen, hydroxyl, nitro, silyl, sulfonyl-oxy, or thiol groups as described herein. Heteroaryl groups can be monocyclic or fused-ring systems. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrroleyl, N-methylpyrroleyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazinyl, benzofuranyl, benzodiazolyl, benzothiophene, indolyl, inazolyl, benzimidazolyl, imidazopyridyl, pyrazolopyridyl, and pyrazolopyrimidinyl. Other non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thiopheneyl, pyrazolyl, imidazoleyl, benzo[d]azoleyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazoleyl, imidazole[1,2-b]pyridinyl, imidazole[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl and pyrido[2,3-b]pyrazinyl.

[0132] The term “heterocyclic” as used in this article is used interchangeably to refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Therefore, the term includes, but is not limited to, "heterocyclic alkyl," "heteroaryl," "bicyclic heterocyclic," and "polycyclic heterocyclic." Heterocyclic compounds include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole; thiadiazole including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole; triazole including 1,2,3-triazole, and 1,3,4-triazole; tetrazolium including 1,2,3,4-tetrazolium and 1,2,4,5-tetrazolium; pyrazine, pyrazine; triazine including 1,2,4-triazine and 1,3,5-triazine; and tetrazine including 1,2,4,5-triazine. -Tetraazine, pyrrolidine, piperidine, piperazine, morpholine, aziridine, tetrahydropyran, tetrahydrofuran, dioxane, etc. The term heterocyclic group can also refer to C2 heterocyclic group, C2-C3 heterocyclic group, C2-C4 heterocyclic group, C2-C5 heterocyclic group, C2-C6 heterocyclic group, C2-C7 heterocyclic group, C2-C8 heterocyclic group, C2-C9 heterocyclic group, C2-C10 heterocyclic group, C2-C11 heterocyclic group, etc., up to and including C2-C18 heterocyclic group. For example, C2 heterocyclic group includes groups having two carbon atoms and at least one heteroatom, including but not limited to aziridinyl, diazadialkyl, dihydrodiazaacetyl, ethylene oxide, thiapropylcycloalkyl, etc. Alternatively, for example, C5 heterocyclic groups include groups having two carbon atoms and at least one heteroatom, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, diazacyclopropane, pyridinyl, etc. It should be understood that heterocyclic groups can be bonded by a heteroatom in the ring, where chemically possible, or by a carbon atom comprising the heterocyclic ring.

[0133] “R 1 “R” 2 “R” 3 "...R" n The phrase “”, where n is an integer and can independently contain one or more of the groups listed above. For example, if R1 is a straight-chain alkyl group, one hydrogen atom of the alkyl group can optionally be substituted with a hydroxyl, alkoxy, alkyl, halogen, etc. Depending on the chosen groups, the first group can be incorporated into the second group, or the first group can be a side chain (i.e., linked) to the second group. For example, for the phrase “alkyl group containing an amino group”, the amino group can be incorporated into the main chain of the alkyl group. Alternatively, the amino group can be linked to the main chain of the alkyl group. The nature of the chosen group will determine whether the first group is inserted into or linked to the second group.

[0134] As described herein, the compounds of this disclosure may comprise an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified portion are substituted by a suitable substituent. Unless otherwise stated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from a particular group. The combinations of substituents contemplated in this disclosure preferably result in combinations of substituents forming stable or chemically viable compounds. Furthermore, in some respects, unless explicitly stated otherwise, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0135] The residues of a chemical substance used in the specification and claims refer to a portion of the product obtained from the chemical substance in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether that portion is actually derived from the chemical substance. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol is used to prepare the polyester. Similarly, a sebacic acid residue in a 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 its esters to obtain the polyester.

[0136] The term "organic residue" defines a carbon-containing residue, that is, a residue containing at least one carbon atom, including but not limited to carbon-containing groups, residues, or groups as defined above. Organic residues may contain various heteroatoms, or be linked to another molecule through heteroatoms, including oxygen, nitrogen, sulfur, phosphorus, etc. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl groups, alkoxy or substituted alkoxy groups, mono- or disubstituted amino groups, amide groups, etc. Organic residues 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. Alternatively, 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.

[0137] A very close synonym for the term "residue" is the term "group," as used in the specification and concluding claims, which refers to a fragment, group, or substructure of the molecule described herein, regardless of how the molecule is prepared. For example, the 2,4-thiazolidinedione group in a particular compound has the following structure:

[0138]

[0139] Regardless of whether a thiazolidinedione is used to prepare the compound, in some embodiments, the group (e.g., alkyl) may be further modified by incorporating one or more "substituents" (i.e., substituted alkyl groups). The number of atoms in a given group is not important to this invention unless otherwise stated herein.

[0140] As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that allow it to be produced, detected, and in some respects, recovered, purified, and used for one or more purposes disclosed herein.

[0141] The compounds described herein may contain one or more double bonds, and thus may produce cis / trans (E / Z) isomers as well as other conformational isomers. Unless otherwise stated, this disclosure includes all such possible isomers, as well as mixtures of such isomers.

[0142] Unless otherwise stated, molecular formulas showing chemical bonds only as solid lines rather than wedges or dashed lines consider every possible isomer, such as every enantiomer and diastereomer, and mixtures of isomers, such as racemic mixtures or proportioned mixtures. The compounds described herein may contain one or more asymmetric centers, thus potentially yielding diastereomers and optical isomers. Unless otherwise stated, the invention includes all such possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers and isolated specific stereoisomers are also included. In the synthesis used to prepare these compounds, or in processes using racemization or epimerization known to those skilled in the art, the products of these processes may be mixtures of stereoisomers.

[0143] Many organic compounds exist in an optically active form, possessing the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to indicate the rotation sign of the compound with respect to plane polarized light, where (-) or indicates 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 non-overlapping mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. An asterisk (…) can be used if desired. The chiral carbon is indicated by the symbol '(R)'. When the bond with a chiral carbon is described as a straight line in the disclosed formula, it should be understood that the (R) and (S) configurations of the chiral carbon, and therefore the enantiomers and mixtures thereof, are included in the formula. As used in the art, when it is necessary to determine the absolute configuration of a chiral carbon, one bond of the chiral carbon may be described as a wedge (bond of the atom above the plane), and the other may be described as a series or wedge-shaped short parallel lines (bonds of the atom below the plane). The Cahn-Inglod-Prelog system can be used to specify the (R) or (S) configuration of the chiral carbon.

[0144] The compounds described herein contain atoms of both natural and non-natural abundance. The disclosed compounds may be isotopically labeled or isotopically substituted compounds, identical to those described except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally 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, respectively, for example… 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36 Cl. Further compounds comprising their prodrugs, and other isotopes containing the aforementioned isotopes and / or other atoms, or pharmaceutically acceptable salts of the said compounds or prodrugs, are within the scope of this disclosure. Certain isotope-labeled compounds of the present invention, for example, those doped with radioactive isotopes such as… 3 H and 14 Compounds of C can be used for drug and / or substrate tissue distribution determination. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by performing a procedure in which readily available isotopically labeled reagents are substituted for non-isotopically labeled reagents.

[0145] The compounds described in this disclosure can exist as solvates. In some cases, the solvent used to prepare the solvate is an aqueous solution, and therefore the solvate is often referred to as a hydrate. These compounds can exist as hydrates, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this respect, one, two, three, or any number of solvent or water molecules can combine with the compounds of the present invention to form solvates and hydrates. Unless otherwise stated, this disclosure includes all such possible solvates.

[0146] The term "cocrystal" refers to the physical bond of two or more molecules that acquire stability through non-covalent interactions. One or more components of such a molecular complex provide a stable framework within a crystal lattice. In some cases, the guest molecule is incorporated into the lattice as a dehydrated or solvated form; 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.

[0147] It should also be understood that some of the compounds described herein can exist in equilibrium tautomer forms. For example, ketones having α-hydrogen can exist in equilibrium in both ketone and enol forms.

[0148]

[0149] Similarly, amides having an N-hydrogen can exist in a balance of amide and imine forms. Unless otherwise stated, this disclosure includes all such possible tautomers.

[0150] It is well known that chemical substances form solids existing in different ordered states, known as polymorphs or variants. Different modifications to polymorphic substances can result in significant differences in physical properties. Compounds according to this disclosure can exist in different polymorphic forms, and certain modifications may be metastable. Unless otherwise stated, this disclosure includes all such possible polymorphic forms.

[0151] In some respects, the structure of a compound can be represented by the following formula:

[0152] ,

[0153] It is understood to be equivalent to the formula:

[0154] ,

[0155] Where n is usually an integer. That is, Rn is understood to represent five independent substituents, R n(a) R n(b) R n (c) R n(d) 、 and R n(e) "Independent substituents" means that each R substituent can be defined independently. For example, if in one case R n(a) If it is a halogen, then in this case R n(b) It's not necessarily halogen.

[0156] Unless otherwise stated, the temperatures referred to in this article are based on atmospheric pressure (i.e., one atmosphere).

[0157] Some of the materials, compounds, compositions, and components disclosed herein are commercially available or readily synthesized using techniques generally known to those skilled in the art. For example, the raw materials and reagents used to prepare the disclosed compounds and compositions may be obtained 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 by methods known to those skilled in the art, in accordance with 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 (VCHPublishers Inc., 1989).

[0158] Unless otherwise expressly stated, this document does not imply that any method described herein requires its steps to be performed in a particular order. Therefore, when a method claim does not actually state the order in which its steps are followed, or when the claims or specification do not specifically state that these steps are limited to a particular order, no order can be inferred in any way. The above applies to any possible non-express basis for interpretation, including logical questions concerning the arrangement of steps or procedures, direct meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0159] The components used to prepare the compositions disclosed herein, as well as the compositions themselves used in the methods disclosed herein, are disclosed herein. These and other materials are disclosed herein, and it should be understood that while specific references to every different individual and collective combination and arrangement of these materials are not explicitly disclosed when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed, and many modifications that can be made to many molecules, including that compound, are discussed, then every combination and arrangement of that compound, and possible modifications, is particularly contemplated unless specifically stated to the contrary. Thus, if a class of molecules A, B, and C, and a class of molecules D, E, and F are disclosed, and an example of the combination molecule AD is disclosed, then each can be considered individually and collectively, even if each is not individually enumerated; that is, combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered disclosed. Similarly, any subsets or combinations of these are also disclosed. Thus, for example, the grouping of AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including but not limited to the steps in methods of making and using the compositions of the invention. Therefore, if there are various additional steps that can be operated, it should be understood that each of these additional steps can be operated with any particular embodiment or combination of embodiments of the methods disclosed herein.

[0160] It should be understood that the compositions disclosed herein have certain functions. This document discloses certain structural requirements for performing the disclosed functions, and it should be understood that multiple structures exist capable of performing the same functions associated with the disclosed structures, and these structures will generally achieve the same results.

[0161] Abbreviations used throughout this article ADME (Absorption, Distribution, Metabolism, Excretion); AL (Acute Leukemia); AlogP (Lipophilic); CK1α (Casein Kinase 1α); CL (Clearance); CRBN (Cereblon); F (Bioavailability); GSPT1 (G1-S Phase Transition 1); HBA (Hydrogen Bond Receptor); HBD (Hydrogen Bond Donor); IMiDs (Immunomodulatory Drugs); IKZF (Icarus Family Zinc Finger); IV (Intravenous Injection); LCMS (Liquid Chromatography-Mass Spectrometry); MB (Medioblastoma); MG (Molecular Gel); MW (Molecular Weight); PPB (Plasma Protein Binding); PK (Pharmacokinetics); PROTAC (Protein Chimera); PSA (Polylactic Aspect Ratio); SBDD (Structure-Based Drug Design); SAR (Structure-Activity Relationship); TMT (Tandem Mass Tagging); and TPD (Targeted Protein Degradation).

[0162] This document describes substituted N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs for therapeutic or clinical use as regulators of the cereblon protein. This document also describes methods for synthesizing substituted N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs. This document further describes methods for administering substituted N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs to subjects in need. In some respects, subjects may suffer from uncontrolled cell proliferation disorders, such as cancer. Other compositions, compounds, methods, features, and advantages of this disclosure will become apparent to those skilled in the art after studying the following figures, detailed description, and examples. The purpose is that all these additional compositions, compounds, methods, features and advantages are included in this specification and within the scope of this disclosure.

[0163] B. Biological environment

[0164] Targeted protein degradation (TPD) is a novel approach in chemical biology that has the potential to profoundly impact basic biology and drug discovery research by uncovering opportunities for drug action on untargetable targets (see References 1-2). The TPD paradigm encompasses two main approaches to molecular design that generate small molecules with similar proteasome-dependent mechanisms of action: proteolytic-targeting chimeras (PROTACs, see References 3-4) and molecular glues (MGs, see References 5-8). Mgs are small molecules capable of binding to E3 ligases and altering their surface and specificity, leading to growth, ubiquitination, and subsequent degradation of substrates (novel substrates) that are not normally targeted by the ligases. Recognition of the novel substrate is controlled by protein-ligase surface interactions (structural decodon motifs) and does not require a ligand-available pocket. This provides an opportunity to degrade targets that have been non-degradable until now, such as fusion oncoproteins and transcription factors (see references 9-10), immunomodulatory drugs (IMiDs), thalidomide and its similar analogues pomalidomide and lenalidomide, which are “original” molecular gels, providing the mechanism and clinical validation of this approach (see references 7 and 11).

[0165] Interestingly, despite their highly similar molecular structures, IMiDs exhibited different protein degradation patterns. Both lenalidomide and pomalidomide degraded transcription factors IKZF1 / 3, but only lenalidomide induced the degradation of CSNK1A1 (CK1α), demonstrating how small changes in molecular structure can significantly alter the specificity of novel substrates. Figure 1(See reference 12). Furthermore, the diversification of imine scaffolds has been shown to influence the potency and kinetics of new substrate degradation (e.g., CC-220, which is 10-fold more potent in cells than lenalidomide; see reference 13) or specificity, leading to the discovery of new substrates, as demonstrated by the GSPT1 (G1 to S phase transition 1) degrader CC-885 developed by Celgene. Figure 1 (See reference 14). These chemical modifications lead to significant changes in cellular responses, creating new opportunities for clinical translation.

[0166] For IMiDs and closely related analogues, an increasing number of novel substrates have been discovered containing common C2H2 zinc finger recognition degron motifs (IKZF2 / 4, SALL4, RNF166, ZFP91, ZNF692, ZNF276, ZNF653, and ZNF827, see references 11 and 15). Each IMiD exhibits a distinct substrate-specific pattern, supporting the idea that novel substrate diversity can be modulated by ligand structural alterations and is not limited to traditionally known targets. This also suggests that achieving selective protein degradation is challenging, and understanding the structural basis of how ligand modifications alter the interaction of novel substrates at the cereblon (CRBN) interface is important (reference 16). Several recently reported studies have shown that simple structural modifications can lead to the unintended transformation of PROTAC into a GSPT1 molecular gel degrader (see references 17-18).

[0167] Aberrant activation, dysregulation, and / or mutations of C2H2 zinc finger transcription factors are common in high-risk cancers such as childhood acute leukemia (AL) and medulloblastoma (MB), limiting the scope of targeted therapies. Representative examples include the ZNF384 fusion oncoprotein observed in lineage-indeterminate AL, 19 IKZF1 mutations observed in acute lymphoblastic leukemia (ALL, see reference 20), deregulation of MECOM in high-risk AL, and enhancer hijacking-dependent activation of GFI1, GFI1B, and PRDM6 in high-risk group 3 and group 4 MB subgroups (see references 21-24).

[0168] Small molecule degradables, commonly referred to as molecular glues, offer promising prospects for targeting currently non-degradable oncoproteins such as transcription factors and chimeric fusion oncoproteins. This disclosure relates to methods and uses of small molecule degradables that modulate CRBN protein and exhibit high antiproliferative activity.

[0169] C. Compounds

[0170] In one aspect, the present invention relates to potent modulators of CRBN proteins and provides a novel method for targeting previously non-degradable oncoproteins, such as GSPT1. In another aspect, the disclosed compounds are potent and selective GSPT1 degraders, exhibiting 30-fold higher selectivity and high oral bioavailability in mice compared to IKZF1 degradation. Without wishing to be bound by any particular theory, the disclosed compounds are believed to possess CRBN-binding chemical signatures while maximizing the three-dimensionality of the chemical diversity displayed on CRBN substrate-binding surfaces.

[0171] More specifically, in one aspect, this disclosure relates to compounds having a structure represented by the following formula:

[0172] ,

[0173] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O)- and -CH2-, A 1 and A 2 At least one of them is -(C=O)-; where R 1 Selected from: (a) 5-10 aryl or heteroaryl groups 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; and (b) Optionally substituted with a 5- to 10-membered cycloalkyl group 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 groups; or pharmaceutically acceptable salts thereof. In the various structures disclosed herein, substituents are as described throughout, including those disclosed in the claims.

[0174] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0175] .

[0176] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0177] .

[0178] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0179] .

[0180] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0181] .

[0182] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0183] .

[0184] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0185] .

[0186] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0187] .

[0188] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0189] .

[0190] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0191] .

[0192] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0193] .

[0194] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0195] .

[0196] On the other hand, Ar 1 It is a 5-membered heteroaryl group, optionally substituted with a group 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 groups.

[0197] On the other hand, Ar 1 Selected from: (a) 5-membered heteroaryl group, having one heteroatom and substituent R 11 R 12 and R 13 ; and R 11 R 12 and R 13 Each 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-membered heteroaryl group having two heteroatoms and a substituent R. 11 R 12 and R 13 ; and R 11 R 12 and R 13 Each 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.

[0198] On the other hand, Cy 1 It is a 5-10 membered cycloalkyl group, optionally substituted with 1, 2, 3, 4 or 5 groups independently 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 groups. In another aspect, Cy 1 It is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and is 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.

[0199] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0200] or .

[0201] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0202] or .

[0203] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0204] or .

[0205] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0206] or .

[0207] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0208] or .

[0209] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0210] or .

[0211] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0212] or .

[0213] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0214] or .

[0215] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0216] or .

[0217] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0218] or .

[0219] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0220] or .

[0221] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0222] or .

[0223] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0224] ,

[0225] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O)- and -CH2-, A 1 and A 2 At least one of them is -(C=O)-; where R 11 R 12 R 13 R 14 and R 15 Each 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 pharmaceutically acceptable salts thereof.

[0226] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0227] .

[0228] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0229] .

[0230] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0231] .

[0232] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0233] .

[0234] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0235] .

[0236] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0237] .

[0238] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0239] .

[0240] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0241] .

[0242] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0243] .

[0244] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0245] .

[0246] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0247] .

[0248] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0249] .

[0250] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0251] .

[0252] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0253] .

[0254] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0255] .

[0256] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0257] , , , , or .

[0258] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0259] .

[0260] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0261] , , , , , or .

[0262] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0263] .

[0264] In another respect, this disclosure relates to compounds having the structure shown in the following formula:

[0265] , , , , , or .

[0266] On the other hand, the disclosed compound has the following structure:

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] On the other hand, the disclosed compound has the following structure:

[0274]

[0275] On the other hand, the disclosed compound has the following structure:

[0276]

[0277] On the other hand, the disclosed compound has the following structure:

[0278]

[0279]

[0280] In all respects, the compounds disclosed herein are expected to also include their bioisosteres. The term "bioisostere" refers to compounds or groups having approximately equal molecular shapes and volumes, approximately identical electron distributions, and exhibiting similar physical and biological properties. Examples of such isosteres include: (i) fluorine to hydrogen, (ii) oxo to thio, (iii) hydroxyl to amide, (iv) carbonyl to oxime, and (v) carboxylate to tetrazolium. Examples of such bioisostere substitutions can be found in the literature, for example: (i) Burger A, Relation of chemical structure and biology 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) BurgerA, "Isosterism and bioanalogy in drug design", Med.Chem.Res. 1994, 4, 89-92;(iv) Clark RD, Ferguson AM, Cramer RD, "Bioisosterism and moleculardiversity", Perspect. Drug Discovery Des. 1998, 9 / 10 / 11, 213-224; (v) KoyanagiT, 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 CA.; "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 ligands”, Curr.Med.Chem. 1998, 5, 493-512 (x) Thornber CW, "Isosterism and molecular modification in drug design", Chem.Soc.Rev. 1979, 8, 563-80.

[0281] In a further aspect, bioisosteres are atoms, ions, or molecules with substantially identical outer electron shells. The term bioisostere is generally used to refer to a portion of a whole molecule, relative to the whole molecule itself. Bioisostere substitution involves replacing one bioisostere with another, with the expectation of maintaining or slightly altering the biological activity of the first bioisostere. Thus, in this case, bioisosteres are atoms or groups of atoms having similar size, shape, and electron density. Preferred bioisosteres of esters, amides, or carboxylic acids are compounds containing two hydrogen bond accepting sites. In one embodiment, the bioisostere of an ester, amide, or carboxylic acid is a 5-membered monocyclic heteroaryl ring, such as optionally substituted 1H-imidazolyl, optionally substituted oxazolyl, 1H-tetrazole, [1,2,4]triazolyl, or optionally substituted [1,2,4]oxadiazolyl.

[0282] In all respects, the compounds disclosed herein may also be expected to contain isotopically labeled or isotopically substituted variants thereof, i.e., one or more atoms of the described compounds are substituted with atoms having a different atomic mass or mass number than those commonly 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, respectively, for example... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F and 36 Cl. The compound also contains its prodrug, and is a pharmaceutically acceptable salt of the compound or the prodrug containing the aforementioned isotopes and / or other isotopes of other atoms within the scope of this disclosure. Certain isotope-labeled compounds of the present invention, for example, doped with radioactive isotopes such as 3 H and 14 Compounds of type C can be used for the determination of drug and / or substrate tissue distribution. Tritium is particularly preferred. 3 H, and carbon-14, i.e. 14 C, an isotope, is used due to its ease of preparation and detectability. Additionally, heavier isotopes such as deuterium are used... 2 H, substitution can provide certain therapeutic advantages due to its greater metabolic stability, such as increased in vivo half-life or reduced dose requirement, and may therefore be preferred in some cases. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by performing a procedure in which readily available isotopically labeled reagents are substituted for non-isotopically labeled reagents.

[0283] In all respects, the disclosed compounds may have at least one asymmetric center, and they may exist as their racemic form, as pure enantiomers and / or diastereomers, or as a mixture of the aforementioned enantiomers and / or diastereomers. Stereoisomers may exist in the mixture in any proportion. In some respects, the disclosed compounds may exist as tautomers, if possible.

[0284] Therefore, known methods can be used, for example, to separate the disclosed compound having one or more chiral centers and existing in racemic form, to obtain its optical isomers, i.e., enantiomers or diastereomers. The above separation can be achieved by column separation on a chiral phase, or by recrystallization from an optically active solvent, or 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.

[0285] In all respects, the disclosed compounds may be in the form of cocrystals. The term "cocrystal" refers to the physical bonding of two or more molecules that acquire stability through non-covalent interactions. One or more components of such a molecular complex provide a stable framework in a crystal lattice. In some cases, guest molecules are incorporated into the crystal lattice as dehydrates or solvates, 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.

[0286] The term "pharmaceutically acceptable cocrystal" refers to a cocrystal that is compatible with other components of a formulation and is harmless to its recipients.

[0287] On the other hand, the disclosed compounds can be separated as solvates, particularly as hydrates of the disclosed compounds, which can be obtained, for example, by crystallization from a solvent or aqueous solution. In this respect, one, two, three, or any number of solvent or water molecules can combine with the compounds of the present invention to form solvates and hydrates.

[0288] The disclosed compounds may be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include those containing acidic or basic groups in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts formed with suitable organic ligands, such as quaternary ammonium salts, which can be similarly prepared by reacting the pharmaceutical compound with a suitable pharmaceutically acceptable base. The salts may be prepared in situ during the final separation and purification of the disclosed compounds; or after final separation, by reacting the free basic functional group of the disclosed compound, such as a secondary or tertiary amine, with a suitable inorganic or organic acid; or by reacting the free acid functional group of the disclosed compound, such as a carboxylic acid, with a suitable inorganic or organic base.

[0289] Acid addition salts can be prepared in situ during the final isolation and purification of the disclosed compound, or prepared separately by reacting a portion containing one or more nitrogen groups with a suitable acid. In various aspects, acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. In another aspect, the salts further include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentianate, fumarate, gluconate, gluconate disodium, sucrose disodium, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and p-toluene. Sulfonates, butyrates, camphor sulfonates, digluconate, glycerol phosphates, hemisulfates, heptanates, hexanoates, fumarates, hydrochlorides, 2-hydroxyethanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, pectinates, persulfates, 3-phenylpropionates, picrates, pentanoates, propionates, succinates, tartrates, thiocyanates, phosphates, glutamates, bicarbonates, undecanoates, palmitates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarboxylate)). Similarly, basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl sulfates; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc.

[0290] Basic addition salts can be prepared in situ during the final separation and purification of the disclosed compounds, or individually by reacting the carboxylic acid moiety with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, magnesium, and aluminum salts, as well as non-toxic ammonium, quaternary ammonium, and ammonium cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines used to form basic addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. In a further aspect, bases that can be used to prepare pharmaceutically acceptable salts include the following: ammonia, L-arginine, phenylethylamine, benzylamine, calcium hydroxide, choline, decanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methylglucosamine, hydrazine, 1H-imidazolium, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0291] D. Methods for preparing the above compounds.

[0292] In one aspect, this disclosure relates to methods for preparing compounds that can be used as antibacterial agents, said compounds being used to treat bacterial infections. In another aspect, this disclosure relates to the disclosed synthetic operations. In yet another aspect, the disclosed compounds include products of the synthetic methods described herein.

[0293] In another aspect, the disclosed compounds include compounds produced by the synthetic methods described herein. In a further aspect, the invention includes pharmaceutical compositions comprising a therapeutically effective amount of the product of the disclosed methods and a pharmaceutically acceptable carrier. In a further aspect, the invention includes a method of preparing a medicament comprising combining at least one product of the methods of the invention with a pharmaceutically acceptable carrier or diluent.

[0294] In addition to other standard operations known in the literature, illustrated in the experimental section, or apparent to those skilled in the art, the compounds of this disclosure can be prepared by employing the reactions shown in the disclosed schemes. For clarity, examples with fewer substituents may be disclosed, while multiple substituents are permitted under the definitions disclosed herein. Therefore, the following examples are provided to provide a more complete understanding of this disclosure; these examples are merely illustrative and should not be construed as limiting.

[0295] It is contemplated that each disclosed method may further include additional steps, operations, and / or components. It is also contemplated that any one or more steps, operations, and / or components may be optionally omitted from this disclosure. It should be understood that the disclosed methods can be used to provide the disclosed compounds. It should also be understood that the products of the disclosed methods can be used in the disclosed compositions, kits, and uses.

[0296] Synthesis Route 1

[0297] In one aspect, useful intermediates for preparing the aryl-substituted aminomethylspectrobamycin analogs of this disclosure can generally be prepared by the synthetic scheme shown below. All positions are as defined herein.

[0298] Option 1A

[0299]

[0300] Compounds are represented in the general form, with substituents as described elsewhere in this document. More specific examples follow.

[0301] Option 1B

[0302]

[0303] The substituted N-(2-(2,6-dioxocyclopentadienyl-3-yl)-1,3-dioxoisoindoline-5-yl)arylsulfonamide analogs of the present invention, such as compounds 1.3 and related compounds in reaction scheme 1B above, can be prepared by reacting 5-amino-2-(2,6-dioxocyclopentadienyl-3-yl)isoindoline-1,3-dione, compound 1.1, with a suitable sulfonyl chloride, compound 1.2, in a suitable solvent, such as pyridine, for a suitable time, such as 8 to 24 hours, at a suitable temperature, such as about 70 °C to about 100 °C, under an inert gas, such as nitrogen. After the reaction, the reaction mixture can be concentrated to a solid (or oil) and the resulting solid (or oil) can be reconstituted (or diluted) in a suitable solvent, such as DMSO. Further purification can be carried out as described in detail in the examples, i.e., using a Waters purification / analysis LC / UV / ELSD system and parallel evaporation using a Genevac HT-24. Other purification methods known to those skilled in the art, such as recrystallization, may also be used. Those skilled in the art will understand that alternative or improved conditions may be used for the above reactions.

[0304] It is contemplated that each disclosed method may further include additional steps, operations, and / or components. It is also contemplated that any one or more steps, operations, and / or components may be optionally omitted from this disclosure. It should be understood that the disclosed methods can be used to provide the disclosed compounds. It should also be understood that the products of the disclosed methods can be used in the disclosed methods of use.

[0305] E. Pharmaceutical Composition

[0306] In all respects, this disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, a product of at least one disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, a “pharmaceutically acceptable carrier” refers to one or more pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, colorants, release agents, coating agents, sweeteners, flavoring agents, and aromatizers, as well as adjuvants. The disclosed pharmaceutical compositions are readily available in unit dose form and can be prepared by any method known in the fields of pharmacy and pharmaceutical science.

[0307] In another aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of the disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agents, and optionally one or more adjuvants. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration; in any given case, the most suitable route depends on the specific host and the nature and severity of the condition to which the active ingredient is administered. In another aspect, the disclosed pharmaceutical compositions can be formulated to allow for oral, nasal, inhalation, parenteral, adjacent to cancer, transmucosal, transdermal, intramuscular, intravenous, intradermal, subcutaneous, intraperitoneal, intravenous, intracranial, and intratumoral administration.

[0308] As used herein, “parenteral administration” includes administration by rapid concentration or infusion, as well as administration by intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intracapsular, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subcutaneous, intra-articular, subarachnoid, epidural, and intrasternal injection and infusion.

[0309] In various aspects, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent, and a therapeutically effective amount of the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or a stereochemical isomer thereof as an active ingredient. In another aspect, the disclosed compound, the product of the disclosed preparation method, the pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or a stereochemical isomer thereof, or any subgroup or combination thereof, may be formulated into various pharmaceutical forms for administration purposes.

[0310] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable, non-toxic bases or acids. For therapeutic uses, the counterions of the salts of the disclosed compounds are pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are considered in this invention. Pharmaceutically acceptable acid and base addition salts mean including the therapeutically active, non-toxic acid and base addition salt forms that the disclosed compounds can form.

[0311] In various respects, the disclosed compounds, which contain an acidic group or portion, such as a carboxylic acid group, can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds may include a separation step involving treatment with a suitable inorganic or organic base. In some cases, in practice, it may be possible to first separate the pharmaceutically unacceptable salt form of the compound from the reaction mixture and then simply convert the latter back to a free acid compound by treatment with an acidic reagent, subsequently converting the free acid into a pharmaceutically acceptable base addition salt. These base addition salts are readily prepared using conventional techniques, for example, by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing a lower alkane solution of the acidic compound with the desired alkali metal alkoxide, and then evaporating the resulting solution to dryness in the same manner as described above.

[0312] Pharmaceutically acceptable bases for preparing alkali compounds are those that form non-toxic base addition salts, i.e., 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-methylglucosamine-(glucosamine), lower alkanol ammonium, and other organic amine bases. On the other hand, bases derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines, as well as cyclic and substituted amines, such as naturally occurring and synthetic substituted amines. In all respects, this pharmaceutically acceptable non-toxic organic alkaloid includes, but is not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, N,N'-dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinine ring, pyridine, quinoline, and isoquinoline; benzothiophene, N-methyl-D-glucosamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, halamine salts, and amino acid salts such as histidine, arginine, and lysine. The aforementioned salt forms can be converted back to their free acid forms by acid treatment.

[0313] In various respects, the disclosed compounds containing protonable groups or portions, such as amino groups, can be used to prepare pharmaceutically acceptable salts. For example, such disclosed compounds may include a separation step involving treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to first separate the pharmaceutically unacceptable salt form of the compound from the reaction mixture and then simply convert the latter back to a free base compound by treatment with a basoc reagent, subsequently converting the free base into a pharmaceutically acceptable acid addition salt. These acid addition salts are readily prepared using conventional techniques, for example, by treating the corresponding basic compound with an aqueous solution containing the desired pharmacologically acceptable anion, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they 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.

[0314] Acids that can be used to prepare pharmaceutically acceptable acid addition salts of basic compounds are those acids that can form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions formed from their respective 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, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, palmitic acid, pantothenic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc. On the other hand, acid addition salts contain anions formed from hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0315] In practice, the compounds of the present invention or their pharmaceutically acceptable salts can be tightly mixed with a drug carrier as active ingredients using conventional pharmaceutical mixing techniques. Depending on the desired formulation for administration, the carrier can take various forms, such as oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention can be present in discrete units suitable for oral administration, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be present as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the commonly used dosage forms described above, the compounds of the present invention and / or their pharmaceutically acceptable salts can also be administered via controlled-release methods and / or delivery devices. The compositions can be prepared by any pharmaceutical method. Typically, the methods described above involve the step of combining the active ingredient with a carrier of one or more essential ingredients. Generally, the compositions are prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a subdivided solid carrier, or both. The product can then be conveniently shaped into the desired appearance.

[0316] For ease of administration and uniform dosage, it is particularly advantageous to formulate the above-described pharmaceutical compositions into unit dosage forms. As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a single dose, each unit containing a predetermined amount of the active ingredient, calculated together with the desired drug carrier to produce the desired therapeutic effect. That is, a "unit dosage form" refers to a single dose in which all active and inactive ingredients are mixed in a suitable system so that the patient or the person administering the medication can open a single container or package containing the entire dose without having to mix any ingredients from two or more containers or packages together. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules, or pills for oral administration; single-dose vials for injectable solutions or suspensions; suppositories for rectal administration; powder packets; cakes; and their separation multiples. The list of unit dosage forms is not intended to be limiting in any way, but merely represents typical examples of unit dosage forms.

[0317] The pharmaceutical compositions disclosed herein comprise the disclosed compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more other therapeutic agents. In various aspects, the disclosed pharmaceutical compositions may include a pharmaceutically acceptable carrier and the disclosed compound or a pharmaceutically acceptable salt thereof. In another aspect, the disclosed compound or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration; in any given case, the most suitable route will depend on the specific host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be conveniently present in unit dose form and prepared by any method known in the pharmaceutical field.

[0318] Techniques and compositions for preparing dosage forms that can be used with 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, 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; JG Hardy,SS Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes,Eds.).Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,1993); Modern Pharmaceutics Drugs and thePharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes,Eds.).

[0319] The compounds described herein are typically administered in combination with a suitable drug diluent, excipient, filler, or carrier (referred to herein as a pharmaceutically acceptable carrier or delivery system), which is appropriately selected based on the intended form of administration and in accordance with standard pharmaceutical practice. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous, or parenteral administration. The carrier may be solid or liquid, and the type of carrier is selected based on the type of administration used. The compound may be administered in a known dose.

[0320] Due to ease of administration, preferred dosage forms are oral administration, with tablets and capsules being the most advantageous oral dosage units, obviously using solid drug carriers in the above cases. However, other dosage forms may be suitable depending on the clinical population (e.g., age and severity of clinical condition), the solubility of the specific disclosed compound used, etc. Therefore, the disclosed compounds can 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, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used to form oral liquid formulations, such as suspensions, elixirs, and solutions; carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used to form oral solid dosage forms such as powders, capsules, and tablets. Due to ease of administration, preferred oral dosage units are tablets and capsules, in which solid drug carriers are used. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

[0321] The disclosed oral dosage form pharmaceutical composition may contain one or more pharmaceutical excipients and / or additives. Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starch (e.g., corn starch or amylose), dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginate, tylosin, talc, phycocyanin, silica gel (e.g., colloids), cellulose, cellulose derivatives (e.g., cellulose ethers, wherein the cellulose hydroxyl groups are partially etherified with lower saturated fatty alcohols and / or lower saturated fatty alcohols, such as methyloxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate), fatty acids, and magnesium, calcium, or aluminum salts of fatty acids having 12 to 22 carbon atoms, particularly saturated (e.g., stearates), emulsifiers, oils and fats, particularly vegetable oils (e.g., peanut oil, castor oil, olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower oil, cod liver oil, optionally hydrated in each case); saturated fatty acid C 12 H 24 O2 to C 18 H 36Glyceryl esters and polyglycerol esters and mixtures thereof of O2, wherein the glycerol hydroxyl group may be fully or only partially esterified (e.g., monoglycerides, diglycerides, and triglycerides); pharmaceutically acceptable monovalent or polyvalent alcohols and polyethylene glycols, such as polyethylene glycol and its derivatives; esters of aliphatic saturated or unsaturated fatty acids (2-22 carbon atoms, especially 10-18 carbon atoms) with monovalent aliphatic alcohols (1-20 carbon atoms) or polyvalent alcohols such as ethylene glycol, glycerol, diethylene glycol, pentylenetetrazol, sorbitol, mannitol, etc., which may also be optionally etherified; esters of citric acid with primary alcohols, acetic acid, urea, benzyl benzoate, dioxolane, glycerol formaldehyde, tetrahydrofurfuryl alcohol; polyethylene glycol ethers with C1-C12 alcohols, dimethylacetamide, lactams, lactates, ethyl carbonate, silicones (especially medium viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, etc.

[0322] Other excipients used in the preparation of oral dosage forms are disintegrating substances (so-called disintegrants), such as croscarmellose, sodium carboxymethyl starch, sodium carboxymethyl cellulose, or microcrystalline cellulose. Conventional coating substances can also be used in the production of oral dosage forms. Examples include polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters; copolymers of acrylic acid and methacrylates with a low ammonium content (e.g., Eudragit R RS); copolymers of acrylic acid and methacrylates with trimethylammonium methacrylate (e.g., Eudragit R RS). RL); polyvinyl acetate; fats, oils, waxes, fatty alcohols; hydroxypropyl methylcellulose phthalate or acetate succinate; cellulose acetate phthalate, starch acetate phthalate, and polyvinyl acetate phthalate, carboxymethyl cellulose; methylcellulose phthalate, methylcellulose succinate, phthalate succinate, and methylcellulose phthalate half-ester; zein; ethyl cellulose and ethyl cellulose succinate; shellac, gluten; ethyl carboxyethyl cellulose; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxymethyl ethyl cellulose glycerol monooctanoate; cellulose acetate succinate; polyarginine.

[0323] Plasticizers that can be considered coating substances in the disclosed oral dosage forms are: citric acid and tartrate esters (acetylated triethyl citrate, acetylated tributyl-, tributyl-, triethyl citrate); glycerol and glycerides (diacetic acid glycerides, triacetic acid glycerides, acetylated monoglycerides, castor oil); phthalates (dibutyl, dipentyl, diethyl, dimethyl, dipropyl phthalate), di(2-methoxy- or 2-ethoxyethyl) phthalate, ethyl glycolate, ethyl phthalate... Butyl glycolate and butyl glycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di-(2-methoxy- or 2-ethoxyethyl)-adipate); benzophenone; diethyl sebacate and dibutyl sebacate, dibutyl succinate, dibutyl tartrate; diethylene glycol dipropionate; ethylene glycol diacetate, dibutyrate, dipropionate; tributyl phosphate, glyceryl tartrate; polyethylene glycol sorbitan monooleate (polysorbate, such as polysorbate 50); sorbitan monooleate.

[0324] In addition, suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow inducers, and melting agents may be included as carriers. The drug carrier used can be, for example, solid, liquid, or gas. Examples of solid carriers include, but are not limited to, lactose, gypsum powder, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0325] In various aspects, binders may include, for example, starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. On the other hand, disintegrants may include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.

[0326] In various aspects, oral dosage forms, such as solid dosage forms, may contain publicly disclosed compounds attached to the polymer as targeted drug carriers or as prodrugs. Suitable biodegradable polymers for achieving controlled drug release include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and hydrogels, preferably covalently cross-linked hydrogels.

[0327] Tablets may contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet manufacturing. Excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action.

[0328] Tablets containing the disclosed compounds can be prepared by compression or molding, optionally containing one or more excipients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0329] In various applications, solid oral dosage forms, such as tablets, may be coated with enteric coatings to prevent rapid breakdown in the stomach. Enteric coating agents include, but are not limited to, hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate 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 can be selected experimentally to obtain an enteric-coated dosage form with an optimal combination of dissolution time, coating thickness, and radial crushing strength designed from the outset (e.g., see SC Porter et al. “The Properties of Enteric Tablet Coatings Made From Polyvinyl Acetate-phthalate and Cellulose acetate Phthalate”, J. Pharm. Pharmacol. 22:42p (1970)). Alternatively, the enteric coating may contain hydroxypropyl methylcellulose phthalate, methacrylate-methacrylate copolymer, polyvinyl acetate-phthalate, and cellulose acetate phthalate.

[0330] In all respects, oral dosage forms can be solid dispersions containing water-soluble or water-insoluble carriers. 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 ethyl cellulose or hydroxypropyl methylcellulose, ethyl cellulose or stearic acid.

[0331] In various respects, oral dosage forms can be liquid dosage forms, including those that are ingested or administered as mouthwashes or gargles. For example, liquid dosage forms may include aqueous suspensions containing an active substance mixed with excipients suitable for preparing aqueous suspensions. Alternatively, oily suspensions can be formulated by suspending the active ingredient in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils such as liquid paraffin. Oily suspensions may also contain a variety of excipients. The pharmaceutical compositions disclosed herein may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweeteners and flavoring agents.

[0332] For the preparation of solutions or suspensions, water, especially sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propanediol, polyethylene glycol and its derivatives, fatty alcohols, esters of glycerol), oils (e.g., peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil, castor oil, cow hoof oil), paraffin, dimethyl sulfoxide, triglycerides, etc., can be used.

[0333] In liquid dosage forms such as drinking solutions, the following substances may be used as stabilizers or solubilizers: lower aliphatic monovalent and polyvalent alcohols having 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycol with a molecular weight of 200-600 (e.g., 1-40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propanediol, organic amides, such as amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1-C4-hydroxyamines such as urea, ethyl carbamate, acetamide, N-methylacetamide, N,N-diethylacetamide, N,N-dimethylacetamide, lower aliphatic amines and diamines having 2-6 carbon atoms, such as ethylenediamine, hydroxyethyltheophylline, tromethamine (e.g., 0.1-20% aqueous solution), and aliphatic amino acids.

[0334] In preparing the disclosed liquid dosage form, a solubilizer and emulsifier may be included, such as the following non-limiting examples: polyvinylpyrrolidone, sorbitol fatty acid esters such as sorbitol trioleate, phospholipids such as lecithin, gum arabic, tragacanth, polyoxyethyleneized sorbitol monooleate and other ethoxylated fatty acid esters of sorbitol, polyoxyethyleneized fatty acids, polyoxyethyleneized triglycerides, linoleic acid triglycerides, fatty alcohols, alkylphenols or polyoxyethylene condensation products of fatty acids or 1-methyl-3-(2-hydroxyethyl)imidazolidinone-(2). In this document, polyoxyethyleneization refers to the presence of polyoxyethylene chains in the substance, typically with a degree of polymerization between 2 and 40, particularly between 10 and 20. Such polyoxyethylene compounds can be obtained, for example, by reacting hydroxyl-containing compounds (e.g., monoglycerides or diglycerides, or unsaturated compounds, such as unsaturated compounds containing oleic acid groups) with ethylene oxide (e.g., 40 moles of ethylene oxide for every 1 mole of glyceride). Examples of oleic triglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, and corn oil. See also Dr. HP Fiedler, “Lexikon der Hillsstoffe für Pharmazie, Kostnetik undangrenzende Gebiete” 1971, pages 191-195.

[0335] In various aspects, liquid dosage forms can further include preservatives, stabilizers, buffers, flavoring agents, sweeteners, colorants, antioxidants, and complexing agents. For example, chelating agents that can be considered include ethylenediaminetetraacetic acid (EDTA), hypozinotriacetic acid (HTA), diethylenetriaminepentaacetic acid (DTA) and their salts.

[0336] It may be optional to stabilize the liquid dosage form to a pH range of approximately 6-9 using a physiologically acceptable base or buffer. A pH that is as neutral or weakly alkaline as possible (maximum pH 8) is preferred.

[0337] To improve the solubility and / or stability of the disclosed compounds in the disclosed liquid, parenteral, or intravenous dosage forms, α-, β-, or γ-cyclodextrins or their derivatives, particularly hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin, are used. Furthermore, cosolvents such as alcohols can improve the solubility and / or stability of the compounds of the present invention in pharmaceutical compositions.

[0338] In various aspects, the disclosed liquid, parenteral, or intravenous dosage forms may further include liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearamine, or phosphatidylcholine.

[0339] The pharmaceutical compositions disclosed herein are suitable for injection, such as parenteral administration, intravenous, intramuscular, or subcutaneous administration. The injectable pharmaceutical compositions can be prepared as aqueous solutions or aqueous suspensions of the active compound. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0340] Pharmaceutical compositions of this disclosure suitable for parenteral administration may include sterile aqueous or oily solutions, suspensions, or dispersions. Furthermore, the composition may be in the form of a sterile powder for the ad hoc preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be an effective fluid for use in a syringe. The pharmaceutical composition should be stable under the conditions of production and storage; therefore, the pharmaceutical composition should preferably be protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0341] For example, injectable solutions can be prepared in which the carrier includes an aqueous saline solution, a glucose solution, or a mixture of saline and glucose solutions. Injectable suspensions can also be prepared, in which case a suitable liquid carrier, suspending agent, etc., can be used. In some aspects, the disclosed parenteral formulations may contain about 0.01-0.1 M, for example, about 0.05 M, phosphate buffer. In other aspects, the disclosed parenteral formulations may contain about 0.9% saline.

[0342] In various aspects, the disclosed parenteral drug compositions may contain pharmaceutically acceptable carriers, such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include, but are not limited to, water, alcohol / aqueous solutions, emulsions, or suspensions, including saline and buffer media. Parenteral carriers may include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextran, dextran and sodium chloride, lactated Ringer's solution, and fixed oils. Intravenous carriers include fluids and nutritional supplements, electrolyte supplements such as Ringer's dextran-based supplements, etc. Preservatives and other additives may also be present, such as antibacterial agents, antioxidants, finishing agents, inert gases, etc. On the other hand, the disclosed parenteral drug compositions may contain small amounts of additives, such as substances that enhance isotonicity and chemical stability, such as buffers and preservatives. Injectable drug compositions also include formulations in solid form that are converted to liquid form shortly before use. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the subject or patient.

[0343] In addition to the pharmaceutical compositions described above, the disclosed compounds can also be formulated into long-acting formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0344] The pharmaceutical compositions of the present invention can be in forms suitable for topical administration. As used herein, the phrase "topical application" means application to a biological surface, including, for example, skin areas (e.g., hands, forearms, elbows, legs, face, nails, anus, and genital areas) or mucous membranes. By selecting suitable carriers and optional other ingredients that may be included in the composition, as detailed below, the compositions of the present invention can be formulated into any form commonly used for topical application. Topical pharmaceutical compositions can be in the form of creams, ointments, pastes, gels, lotions, milks, suspensions, aerosols, sprays, foams, powders, pads, and patches. Furthermore, the composition can be in the form suitable for transdermal devices. These formulations can be prepared using the compounds of the present disclosure or pharmaceutically acceptable salts thereof, by conventional processing methods. For example, creams or ointments are prepared by mixing hydrophilic materials and water, along with about 5% to about 10% by weight of the compound, to produce a cream or ointment with a desired consistency.

[0345] In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally combined with a small amount of a suitable additive of any nature that will not produce significant adverse effects on the skin. The additive may facilitate transdermal administration and / or aid in the preparation of the desired composition. These compositions can be administered in various ways, e.g., as a transdermal patch, as a spot, or as an ointment.

[0346] Ointments are semi-solid formulations, typically based on petrolatum or petroleum derivatives. The specific ointment matrix to be used is the matrix that provides optimal delivery of the active agent selected for a given formulation, and preferably, also provides other desired properties (e.g., lubricity). Like other carriers or excipients, ointment matrices should be inert, stable, non-irritating, and non-sensitizing. As explained by Remington: *The Science and Practice of Pharmacy*, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment matrices can be classified into four categories: oily matrices; emulsions; emulsion matrices; and water-soluble bases. Oily ointment matrices include, for example, vegetable oils, fats derived from animals, and semi-solid hydrocarbons derived from petroleum. Emulsifiable ointment matrices, also known as absorbent ointment matrices, contain little or no water and include, for example, hydroxystearyl sulfate, anhydrous lanolin, and hydrophilic petrolatum. The emulsion ointment base is a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion, including, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weights.

[0347] Lotions are preparations applied to the skin surface without friction. Lotions are typically liquid or semi-liquid preparations in which solid particles, including active agents, are present in an aqueous or alcoholic matrix. Lotions are generally preferred for treating larger body areas because they facilitate application of a more fluid composition. Lotions are typically solid suspensions and often contain oil-in-water emulsions. It is usually necessary to separate insoluble substances in the lotion. Lotions typically contain suspending agents to produce a better dispersion, as well as compounds for positioning and maintaining the active agents in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc.

[0348] Creams are viscous liquid or semi-solid emulsions, which can be oil-in-water or water-in-oil. The cream base is typically washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, is usually composed of petrolatum and / or fatty alcohols such as cetyl alcohol or stearyl alcohol. Although not mandatory, the aqueous phase usually has a larger volume than the oil phase and often contains a wetting agent. Emulsifiers in cream formulations are typically nonionic, anionic, cationic, or amphoteric surfactants. See Remington: The Science and Practice of Pharmacy, above, for more information.

[0349] Pastes are semi-solid dosage forms in which bioactive agents are suspended in a suitable matrix. Based on the nature of the matrix, pastes are classified as fatty pastes or pastes made from single-phase hydrogels. The matrix in fatty pastes is typically petrolatum, hydrophilic petrolatum, etc. Pastes made from single-phase hydrogels usually incorporate carboxymethyl cellulose, etc., as a matrix. For more information, please refer to Remington: The Science and Practice of Pharmacy.

[0350] Gel formulations are semi-solid, suspension systems. Single-phase gels contain organic macromolecules that are substantially uniformly distributed throughout a carrier liquid, which is typically aqueous but preferably contains alcohols and optionally oils. Preferred organic macromolecules, i.e., gelling agents, are cross-linked acrylic polymers, such as members of the carbomer family, such as commercially available carboxylated polyalkylene compounds, under the trademark Carbopol. TM In this context, other preferred polymers are hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; modified celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth gum and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersant such as alcohol or glycerol can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, stirring, or a combination thereof.

[0351] Sprays typically provide the active agent in a solution of water and / or alcohol, which can be sprayed onto the skin for delivery. Such sprays include those formulated to provide a solution concentration of the active drug at the administration site after delivery; for example, the spray solution may consist primarily of alcohol or other similar volatile liquids in which the active drug can be dissolved. Once delivered to the skin, the carrier evaporates, leaving a concentrated active agent at the administration site.

[0352] Foam compositions are typically formulated as single-phase or multi-phase liquids and packaged in suitable containers, optionally with a propellant that facilitates the expulsion of the composition from the container, thereby transforming it into foam upon application. Other foam-forming techniques include, for example, "can-bag" formulations. Such formulated compositions typically contain low-boiling-point hydrocarbons, such as isopropane. Applying and agitating this composition at body temperature, similar to a pressurized aerosol foaming system, causes the isopropane to evaporate and produce foam. The foam can be water-based or hydrous alkanols, but is typically formulated with a high alcohol content, which evaporates rapidly when applied to the user's skin, driving the active ingredients through the upper layers of the skin to the treatment site.

[0353] Skin patches typically include a backing onto which a reservoir containing an active agent is attached. The reservoir can be, for example, a pad in which the active agent or composition is dispersed or impregnated, or a liquid reservoir. The patch also typically includes a water-permeable adhesive on the front side, which adheres and secures the device to the treatment area. Optionally, self-adhesive silicone rubber can be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch before use. Skin patches may further include a removable cover for protecting the patch during storage.

[0354] Examples of patch configurations that can be used in this invention include single-layer or multi-layer drug-adhesive systems, characterized by the direct inclusion of the drug within the skin-contact adhesive. In this transdermal patch design, the adhesive serves not only to secure the patch to the skin but also as a formulation base, containing the drug and all excipients under a single backing film. In multi-layer adhesive drug patches, the film is positioned between two distinct adhesive drug layers, or multiple adhesive drug layers are bonded under a single backing film.

[0355] Depending on the final form of the composition, examples of pharmaceutically acceptable carriers suitable for topical application of pharmaceutical compositions include carrier materials well-known in the cosmetic and medical fields as matrices for, for example, emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, emulsions, foams, suspensions, aerosols, etc. Therefore, representative examples of suitable carriers according to the invention 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 substances commonly used in cosmetic and pharmaceutical compositions. Other suitable carriers according to this disclosure include, but are not limited to, alcohols, such as mono- and polyols, such as ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexanediol, mannitol, and propylene glycol; ethers, such as diethyl ether or dipropyl ether; polyethylene glycol and methoxypolyoxyethylene (polyethylene glycol with a molecular weight of 200-20,000); polyoxyethylene glycerol, polyoxyethylene sorbitol, stearoyl diacetate, etc.

[0356] If desired, the topical compositions of this disclosure may be contained in a packaging or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient. The dispenser device may, for example, include a tube. The packaging or dispenser device may be accompanied by instructions for administration. The packaging or dispenser device may also be accompanied by a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the composition form for human or veterinary administration. For example, such a notification may include a prescription drug label approved by the U.S. Food and Drug Administration (FDA) or an approved product information label. Compositions containing the topical compositions of this invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in a suitable container, and labeled for a therapeutic indication.

[0357] Another patch system configuration usable with this invention is a reservoir transdermal system design, characterized by including a liquid compartment containing a drug solution or suspension, separated from the release liner by a semi-permeable membrane and an adhesive. The adhesive component of this patch system can be introduced as a continuous layer between the membrane and the release liner, or in a concentric configuration surrounding the membrane. Another patch system configuration usable with this invention is a matrix system design, characterized by including a semi-solid matrix containing a drug solution or suspension in direct contact with the release liner. Components responsible for skin adhesion are incorporated into a capping layer and formed in a concentric configuration around the semi-solid matrix.

[0358] The pharmaceutical compositions disclosed herein can be in a form suitable for rectal administration, wherein the carrier is solid. Preferably, the mixture is formed into a unit-dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier, then cooling and molding it in a mold.

[0359] Pharmaceutical compositions containing compounds of the present invention and / or their pharmaceutically acceptable salts may also be prepared in the form of powders or liquid concentrates.

[0360] Pharmaceutical compositions (or formulations) can be packaged in a variety of ways. Typically, articles intended for sale include containers containing a pharmaceutical composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, foil blister packs, etc. Containers may also include anti-interference components to prevent accidental contact with the contents of the package. Furthermore, a label is usually deposited on the container describing its contents and any appropriate warnings or instructions.

[0361] If desired, the disclosed pharmaceutical composition may be contained in a packaging or dispenser device, which may comprise one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispenser device may be accompanied by instructions for administration. The packaging or dispenser may also be accompanied by a notification related to the container, in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting that agency's approval of the form of the drug for human or veterinary administration. For example, such a notification may include a prescription drug label or approved product information approved by the U.S. Food and Drug Administration (FDA). Pharmaceutical compositions comprising the disclosed compound formulated in a compatible drug carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0362] The exact dosage and frequency of administration depend on the specific disclosed compound, the product of the disclosed method of preparation, its pharmaceutically acceptable salt, solvate or polymorph, its hydrate, its solvate, its polymorph or its stereochemical isomer; the specific condition being treated and the severity of the condition; various factors specific to the subject taking the dosage, such as age; the specific subject's weight, sex, degree of disorder and general physical condition, and other medications the individual may be taking; as is well known to those skilled in the art. Furthermore, it will be apparent that the effective daily dose may be reduced or increased based on the subject's response and / or the assessment of the physician prescribing the compound of the invention.

[0363] Depending on the route of administration, the pharmaceutical composition will contain 0.05 to 99% by weight, preferably 0.1 to 70% by weight, 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, more preferably 50 to 99.9% by weight, of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

[0364] In cases requiring modulation of cereblon protein, appropriate dosage levels are typically from about 0.01 to 1000 mg per kilogram of patient body weight per day, administered as a single or multiple dose. In various applications, dosage levels range from about 0.1 to about 500 mg / kg per day, from about 0.1 to 250 mg / kg per day, or from about 0.5 to 100 mg / kg per day. Appropriate dosage levels can be from about 0.01 to 1000 mg / kg per day, from about 0.01 to 500 mg / kg per day, from about 0.01 to 250 mg / kg per day, from about 0.05 to 100 mg / kg per day, or from about 0.1 to 50 mg / kg per day. Within this range, the dosage can be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 mg of 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 active ingredient, for dose adjustment to symptom management in the patient to be treated. The compound can be administered in a regimen of 1 to 4 times daily, preferably 1 to 2 times daily. The dosing regimen can be adjusted to provide an optimal therapeutic response.

[0365] In therapeutic cases requiring modulation of GSPT1 activity, appropriate dose levels are typically from about 0.01 to 1000 mg / kg of patient body weight per day, administered as a single or multiple dose. In various applications, dose levels range from about 0.1 to about 500 mg / kg per day, from about 0.1 to 250 mg / kg per day, or from about 0.5 to 100 mg / kg per day. Appropriate dose levels may be from about 0.01 to 1000 mg / kg per day, from about 0.01 to 500 mg / kg per day, from about 0.01 to 250 mg / kg per day, from about 0.05 to 100 mg / kg per day, or from about 0.1 to 50 mg / kg per day. Within this range, the dose may be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 mg of 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 active ingredient, for dose adjustment to symptom management in the patient to be treated. The compound can be administered in a regimen of 1 to 4 times daily, preferably 1 to 2 times daily. The dosing regimen can be adjusted to provide an optimal therapeutic response.

[0366] In cases requiring treatment to inhibit cell proliferation, appropriate dosage levels are typically from about 0.01 to 1000 mg per kilogram of patient body weight per day, administered as a single or multiple dose. In various applications, dosage levels range from about 0.1 to about 500 mg / kg per day, from about 0.1 to 250 mg / kg per day, or from about 0.5 to 100 mg / kg per day. Appropriate dosage levels can be from about 0.01 to 1000 mg / kg per day, from about 0.01 to 500 mg / kg per day, from about 0.01 to 250 mg / kg per day, from about 0.05 to 100 mg / kg per day, or from about 0.1 to 50 mg / kg per day. Within this range, the dosage can be 0.05 to 0.5, 0.5 to 5.0, or 5.0 to 50 mg / kg per day. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 mg of 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 active ingredient, for dose adjustment to symptom management in the patient to be treated. The compound can be administered in a regimen of 1 to 4 times daily, preferably 1 to 2 times daily. The dosing regimen can be adjusted to provide an optimal therapeutic response.

[0367] As described above and below, such unit doses can be administered more than once a day, for example, two, three, four, five, or six times a day. In each respect, such unit doses can be administered once or twice a day, so that for a 70 kg adult, the total dose per administration ranges from 0.001 to approximately 15 mg / kg of the subject's body weight. In the other respect, the dose is from 0.01 to approximately 1.5 mg / kg of the subject's body weight per administration, and this treatment can continue for weeks or months, and in some cases, for years. However, it should be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the individual's age, weight, general health condition, sex, and diet; the time and route of administration; the excretion rate; other medications previously taken; and the severity of the specific disease being treated, as is well known to those skilled in the art.

[0368] Typical dosages may be tablets of 1 mg to approximately 100 mg once daily, or tablets of 1 mg to approximately 300 mg once daily, or sustained-release capsules or tablets taken once daily, containing a proportionally higher concentration of the active ingredient. Time-release effects can be achieved through capsule materials dissolved at different pH values, through capsules that release slowly under osmotic pressure, or through any other known controlled-release mechanism.

[0369] In some cases, it may be necessary to use doses outside the range mentioned above, which will be apparent to those skilled in the art. Furthermore, it should be noted that clinicians or treating physicians will know how and when to start, interrupt, adjust, or terminate treatment based on the individual patient's response.

[0370] The present invention also relates to a method for preparing a medicament for regulating cereblon proteins in mammals (e.g., humans) (e.g., for treating one or more diseases associated with cereblon function or dysfunction, such as cancer), comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Therefore, in one aspect, the present invention also relates to a method for preparing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament can be used to regulate cereblon proteins.

[0371] The present invention also relates to a method for preparing a medicament for regulating GSPT1 in mammals (e.g., humans) (e.g., for treating one or more diseases associated with cereblon function or dysfunction, such as cancer), comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Therefore, in one aspect, the present invention also relates to a method for preparing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament is available for regulating the GSPT1 protein.

[0372] The present invention also relates to a method for preparing a medicament for inhibiting cell proliferation in mammals (e.g., humans) (e.g., for treating one or more diseases associated with cereblon function or dysfunction, such as cancer), comprising combining one or more disclosed compounds, products, or compositions with a pharmaceutically acceptable carrier or diluent. Therefore, in one aspect, the present invention also relates to a method for preparing a medicament comprising combining at least one disclosed compound or at least one disclosed product with a pharmaceutically acceptable carrier or diluent, wherein the medicament can be used to inhibit cell proliferation.

[0373] The disclosed pharmaceutical compositions may further include other therapeutically active compounds that are typically used to treat the aforementioned pathological or clinical conditions.

[0374] It should be understood that the disclosed compositions can be prepared from the disclosed compounds. It should also be understood that the disclosed compositions can be used in the disclosed methods of application.

[0375] As already mentioned, this invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compound, the product of the disclosed preparation method, a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, and a pharmaceutically acceptable carrier. Furthermore, this disclosure relates to a method for preparing such a pharmaceutical composition, characterized by tightly mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound according to this disclosure.

[0376] As already mentioned, this disclosure also relates to pharmaceutical compositions comprising the disclosed compound, the product of the disclosed method of preparation, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and one or more other drugs, for the treatment, prevention, control, improvement, or reduction of the risk of a disease or condition to which the disclosed compound or other drugs may be effective, and the use of such compositions in the preparation of medicaments. This disclosure also relates to combinations of the disclosed compound, the product of the disclosed method of preparation, its pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and additional therapeutic agents, such as cell proliferation inhibitors or anticancer therapeutic agents. This disclosure also relates to the above combinations used as medicaments. The invention also relates to a product comprising (a) the disclosed compound, the product of the disclosed method of preparation, a pharmaceutically acceptable salt, its hydrate, its solvate, its polymorph, and (b) additional therapeutic agents, as a combined preparation for the simultaneous, separate, or sequential treatment or prevention of diseases in mammals, including humans, where the treatment or prevention of said disease is influenced or promoted by the moderating effects of the disclosed compound and said additional therapeutic agents. The different drugs in this combination or product can be combined with a pharmaceutically acceptable carrier or diluent in a single formulation, or they can each exist in a separate formulation with a pharmaceutically acceptable carrier or diluent.

[0377] F. The method of using the above-mentioned compounds.

[0378] In various respects, this disclosure provides treatment methods, including administering a therapeutically effective amount of the disclosed compound or pharmaceutical composition as disclosed above to a subject in need.

[0379] In another aspect, the present invention provides a method for treating uncontrolled cell proliferation diseases in mammals, the steps of which include: 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.

[0380] In another aspect, the present invention provides a method for modulating cereblon activity in mammals, the steps of which include: 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.

[0381] In another aspect, the present invention provides a method for regulating cereblon activity in at least one cell, the steps of which include 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.

[0382] On the other hand, uncontrolled cell proliferation is a disease of cancer, such as brain cancer, lung cancer, leukemia, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, stomach cancer, colorectal cancer, prostate cancer, pancreatic cancer, urogenital tract cancer, lymphatic system cancer, stomach cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof. In another respect, the cancer is a hematologic 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 lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

[0383] On the other hand, the disclosed method for treating uncontrolled cell proliferation diseases in mammals also includes the step of administering a therapeutically effective amount of at least one known cancer-treating drug, such as uracil. Mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, fluxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabinePhosphate), pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine Ribine, Pemextresed, Idarubicin, Paclitaxel, Docetaxel, Ixabepilone, Mitramycin, Topotecan, Irinotecan, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide, Teniposide 17α-ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, DromostanolonePropionate, testolactone, megestrolacetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin n), hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrozole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, oxaliplatin, gefinitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0384] On the other hand, the disclosed method for regulating cereblon activity in at least one cell further includes the step of contacting the at least one cell with an effective amount of at least one known cancer-treating drug, such as uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, thiamethoxam, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil. Glycosides, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Pentostatin, Bortezomib, Vincristine, Vincristine, Vinorelbine, Vindysine, Bleomycin, Actinomycin D, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemetrexed, Idarubicin, Paclitaxel, Docetaxel, Ixaspirone, Glucosinolates, Topotecan, Irinotecan, Deoxymyopicillin, Mitomycin-C, L-Asparaginase, Interferon, Etoposide, Teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0385] On the other hand, the disclosed method for modulating cereblon activity in mammals further includes the step of administering a therapeutically effective amount of at least one known cancer-treating drug, such as uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, methamidophos, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, or cytarabine. 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatin, Bortezomib, Vincristine, Vincristine, Vinorelbine, Vindysine, Bleomycin, Actinomycin D, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemetrexed, Idarubicin, Paclitaxel, Docetaxel, Ixaspiron, Glechomyc, Topotecan, Irinotecan, Deoxymyopicillin, Mitomycin-C, L-Asparaginase, Interferon, Etoposide, Teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0386] G. Reagent kit

[0387] In another aspect, this disclosure relates to a kit comprising at least one compound as disclosed above or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition as disclosed above; and one or more of the following: (a) at least one known agent that enhances cereblon activity; (b) at least one known agent that inhibits cereblon activity; (c) at least one known agent that enhances GSPT1 activity; (d) at least one known agent that inhibits GSPT1 activity; (e) at least one known agent that enhances cell proliferation; (f) at least one known agent that inhibits cell proliferation; (g) at least one known agent that treats a disease associated with cereblon activity; (h) at least one known agent that treats a disease associated with GSPT1 activity; (i) at least one known agent that treats a disease of uncontrolled cell proliferation; and / or (j) instructions for treating a disease of uncontrolled cell proliferation.

[0388] The disclosed compounds and / or pharmaceutical compositions comprising the disclosed compounds can be conveniently provided in the form of a kit containing two or more components, which may be active or inactive ingredients, carriers, diluents, etc., and instructions for preparing the actual dosage form must be provided to the patient or the person administering the medication. Such a kit may be provided with all the necessary materials and ingredients contained therein, or it may contain instructions for the materials or ingredients used or manufactured thereto, which the patient or the person administering the medication must obtain independently. In a further aspect, the kit may include optional components to facilitate the administration of a unit dose to a patient, such as vials for reconstructing powder form, syringes, custom IV delivery systems, inhalers, etc. Furthermore, the kit may contain instructions for the preparation and administration of the composition. The kit may be manufactured for a single-use unit dose for one patient, for multiple uses for a particular patient (with a constant dose or the potency of the compounds may vary with the progression of treatment); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk”). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0389] In another aspect, the disclosed kit can be packaged in a daily dosing regimen (e.g., packaged on a card, packaged with a dosing card, packaged in a blister pack or blow-molded plastic, etc.). Such packaging enhances the product and increases patient compliance with drug therapy. This packaging can also reduce patient confusion. The invention also discloses such a kit further comprising instructions for use.

[0390] In another aspect, the present invention also provides a pharmaceutical package or box comprising one or more containers containing one or more ingredients of the pharmaceutical composition of the present invention. Associated with such a container may be a notification in the form prescribed by a government agency regulating the manufacture, use, or sale of a drug or biological product, reflecting that agency's approval for its manufacture, use, or sale for human administration.

[0391] In various respects, the disclosed kits may also include compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, drug manufacturers, drug distributors, physicians, dispensaries, or pharmacists may offer kits containing the disclosed compounds and / or products, along with another component, for delivery to patients.

[0392] It is anticipated that the disclosed kit can be used in conjunction with the disclosed preparation method, the disclosed use or treatment method and / or the disclosed composition.

[0393] H. Research Tools

[0394] The disclosed compounds and pharmaceutical compositions have activity as regulators of the cereblon protein. In another aspect, the disclosed compounds and pharmaceutical compositions have activity as regulators of GSPT1 expression and / or activity. In yet another aspect, the disclosed compounds and pharmaceutical compositions have activity as inhibitors of cell proliferation. Therefore, the disclosed compounds can also be used as research tools. Accordingly, one aspect of this disclosure relates to a method of using the disclosed compounds as a research tool, the method comprising performing a bioassay using the disclosed compounds. The disclosed compounds can also be used to evaluate novel compounds. Therefore, another aspect of this disclosure relates to a method of evaluating a test compound in a bioassay, comprising: (a) performing a bioassay with the test compound to provide a first assay value; (b) performing a bioassay with the compound of the present invention to provide a second assay value; wherein step (a) is performed before, after, or simultaneously with step (b); and (c) comparing the first assay value from step (a) with the second assay value from step (b). Exemplary bioassays include cereblon assays or GSPT1 assays, which can be performed in vitro or in the cell culture systems disclosed herein, or alternatively, cell proliferation assays using the cell lines and cell proliferation assays disclosed herein. Another aspect of this disclosure relates to a method for studying a biological system, such as an animal model for a clinical condition or a biological sample containing the cereblon protein, the method comprising: (a) contacting the biological system or sample with a compound of the present invention; and (b) determining the effect of the compound on the biological system or sample. Another aspect of this disclosure relates to a method for studying a biological system, such as an animal model for a clinical condition or a biological sample containing the GSPT1 protein, the method comprising: (a) contacting the biological system or sample with a compound of the present invention; and (b) determining the effect of the compound on the biological system or sample. In various aspects, the disclosed compounds can be used as chemical probes for studying GSPT1 / 2 in vitro and in vivo.

[0395] I. References

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[0438] @@@

[0439] J. aspect

[0440] The following list of exemplary aspects supports and is supported by the disclosures provided herein.

[0441] Aspect 1. A compound having a structure represented by the following formula:

[0442] ,

[0443] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O)- and -CH2-, A 1 and A 2 At least one of them is -(C=O)-; where R 1 Selected from: (a) 5-10 aryl or heteroaryl groups 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; and (b) )Optionally substituted with a 5- to 10-membered cycloalkyl 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 groups; or pharmaceutically acceptable salts thereof.

[0444] Aspect 2. Compound 2, wherein the compound does not include compounds having the following structures:

[0445] ,

[0446] Where R 20a Selected from bromine, methyl, -CF3 and -OCF3; and wherein R 20b R 20c R 20d and R 20e Each is independently selected from hydrogen, halogen, and methyl; or a pharmaceutically acceptable salt thereof; and a compound having the structure shown in the following formula:

[0447] ,

[0448] Or its pharmaceutically acceptable salt.

[0449] Aspect 3. Compounds of Aspect 2, wherein the excluded compounds

[0450] Aspect 4. Compound 2, wherein R 20a It is bromine.

[0451] Aspect 5. Compound 4, wherein R 20a It is a methyl group.

[0452] Aspect 6. Compound 2, wherein R 20a Selected from -CF3 and -OCF3.

[0453] Aspect 7. Compounds of any one of Aspects 2-6, wherein each R 20b R 20c R 20d and R 20e It is hydrogen.

[0454] Aspect 8. Compounds from any of Aspects 2-6, wherein R 20b R 20c R 20d and R 20e At least one of them is a halogen.

[0455] Aspect 9. Compounds from any of Aspects 2-6, wherein R 20b R 20c R 20d and R 20e At least one of them is a methyl group.

[0456] Aspect 10. Compounds of any one of Aspects 2-9 have a structure represented by the following formula:

[0457] ; ;

[0458] ; ;

[0459] ; ;or ; or its subgroups.

[0460] Compounds of any one of aspects 11.1 to 10, where n is selected from 0 and 1.

[0461] Compounds of any one of aspects 12.1-10, where n is 0.

[0462] Compounds of any one of aspects 13.1 to 10, where n is 1.

[0463] Aspect 14.1-Aspect 13 of any compound, wherein A 1 It is -(C=O)-; and where A 2 It is -CH2-.

[0464] A compound of any one of Aspects 15.1-13, wherein A 1 It is -CH2-; and A is in it. 2 It is -(C=O)-.

[0465] Aspect 16.1-Aspect 13 of any compound, wherein A 1 and A 2 Each is -(C=O)-.

[0466] Compounds of any one of aspects 17.1-16, wherein R1 is Ar 1 ; and among them Ar 1 It is a 5-10 aryl or heteroaryl group 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.

[0467] Aspect 18. Compounds of aspect 17, in which Ar 1 It has a substituent R 11 R 12 R 13 and R 14 The pyridinyl group; and wherein R 11 R 12 R 13 and R 14Each 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.

[0468] Aspect 19. Compounds of aspect 18, wherein R 11 R 12 R 13 and R 14 Each of these terms is independently selected from 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.

[0469] Compounds of aspect 20 and aspect 19, wherein R 11 R 12 R 13 and R 14Each 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.

[0470] Compounds of aspect 21. Compounds of aspect 19, wherein R 11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0471] Compounds of aspect 22. Compounds of aspect 19, wherein R 11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0472] Compounds of aspect 23. Compounds of aspect 18, wherein R 11 R 12 R 13 and R 14 Each 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, R 11 R 12 R 13 and R 14 At least one of them is not hydrogen.

[0473] Aspect 24. Compounds of aspect 23, wherein R 11 R 12 R 13 and R 14Each of these terms is independently selected from 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, R 11 R 12 R 13 and R 14 At least one of them is not hydrogen.

[0474] Compounds of aspect 25. Compounds of aspect 23, wherein 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, R 11 R 12 R 13 and R 14 At least one of them is not hydrogen.

[0475] Aspect 26. Compounds of aspect 23, wherein R11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 R 13 and R 14 At least one of them is not hydrogen.

[0476] Aspect 27. Compounds of aspect 23, wherein R 11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 R 13 and R 14 At least one of them is not hydrogen.

[0477] Aspect 28. Compounds of aspect 18, wherein R 11 R 12 R 13 and R 14 Each 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, R 11 R 12 R 13 and R 14 Only one of them is not hydrogen.

[0478] Compounds of aspect 29. Compounds of aspect 28, wherein R 11 R 12 R 13 and R 14Each of these terms is independently selected from 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, R 11 R 12 R 13 and R 14 Only one of them is not hydrogen.

[0479] Compounds of aspect 30 and aspect 28, wherein 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, R 11 R 12 R 13 and R 14 Only one of them is not hydrogen.

[0480] Compounds of aspect 31 and aspect 28, wherein R11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 R 13 and R 14 Only one of them is not hydrogen.

[0481] Compounds of aspect 32. Compounds of aspect 28, wherein R 11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 R 13 and R 14 Only one of them is not hydrogen.

[0482] Compounds of aspect 33. Compounds of aspect 18, wherein R 11 R 12 R 13 and R 14 Each 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, R 11 R 12 R 13 and R 14 Only two of them are not hydrogen.

[0483] Aspect 34. Compounds of aspect 33, wherein R 11 R 12 R 13 and R 14Each of these terms is independently selected from 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, R 11 R 12 R 13 and R 14 Only two of them are not hydrogen.

[0484] Compounds of aspect 35. Compounds of aspect 33, wherein 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, R 11 R 12 R 13 and R 14 Only two of them are not hydrogen.

[0485] Compounds of aspect 36. Compounds of aspect 33, wherein R11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 R 13 and R 14 Only two of them are not hydrogen.

[0486] Aspect 37. Compounds of aspect 33, wherein R 11 R 12 R 13 and R 14 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 R 13 and R 14 Only two of them are not hydrogen.

[0487] Aspect 38. Compounds of aspect 18, wherein each R 11 R 12 R 13 and R 14 It is hydrogen.

[0488] Aspect 39. Compounds of aspect 17, in which Ar 1 It has a substituent R 11 R 12 and R 13 The pyridyl group; and wherein each R 11 R 12 R 13 、 and R 14 Each 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.

[0489] Compounds of aspect 40 and aspect 39, wherein R 11 R 12 and R 13Each is independently selected from 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.

[0490] Compounds of aspect 41. Compounds of aspect 40, wherein R 11 R 12 and R 13 Each 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.

[0491] Aspect 42. Compounds of aspect 40, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0492] Aspect 43. Compounds of aspect 40, wherein R 11R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0493] Compounds of aspect 44 and aspect 39, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0494] Compounds of aspect 45. Compounds of aspect 44, wherein R 11 R 12 and R 13 Each is independently selected from 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0495] Aspect 46. Compounds of aspect 44, wherein R 11 R 12 and R13 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0496] Compounds of aspect 47. Compounds of aspect 44, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0497] Compounds of aspect 48. Compounds of aspect 44, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0498] Aspect 49. Compounds of aspect 39, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0499] Compounds in aspect 50 and aspect 49, wherein R11 R 12 and R 13 Each is independently selected from 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0500] Compounds of aspect 51 and aspect 49, wherein 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, R 11 R 12 R 13、 R 14 and R 15 Only one of them is not hydrogen.

[0501] Compounds of aspect 52 and aspect 49, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0502] Compounds of aspect 53 and aspect 49, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0503] Compounds of aspect 54 and aspect 39, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0504] Compounds of aspect 55 and 54, wherein R 11 R 12 and R 13Each is independently selected from 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, R 11 R 12 and R 13 Two of them are not hydrogen.

[0505] Compounds of aspect 56. Compounds of aspect 54, wherein 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, R 11 R 12 and R 13 Two of them are not hydrogen.

[0506] Compounds of aspect 57 and 54, wherein R 11 R 12 and R 13Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 Two of them are not hydrogen.

[0507] Compounds of aspect 58 and 54, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 Two of them are not hydrogen.

[0508] Aspect 59. Compounds of aspect 39, wherein each R 11 R 12 and R 13 It is hydrogen.

[0509] Compounds in aspect 60 and aspect 17, Ar 1 It is a 5-membered heteroaryl group 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.

[0510] Compounds of aspect 61. Compounds of aspect 60, in which Ar 1 Selected from: (a) 5-membered heteroaryl group, having one heteroatom and substituent R 11 R 12 and R 13 ; and R 11 R 12 and R 13 Each 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-membered heteroaryl group having two heteroatoms and a substituent R. 11 R 12 and R 13 ; and R 11 R 12 and R 13Each 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.

[0511] Compounds of aspect 62. Compounds of aspect 61, wherein Ar 1 It is a 5-membered heteroaryl group having one heteroatom; and the heteroatom is selected from O and S.

[0512] Aspect 63. Compounds of aspect 61, wherein Ar 1 It is a 5-membered heteroaryl group having two heteroatoms; and wherein the two heteroatoms comprise a first heteroatom and a second heteroatom.

[0513] Aspect 64. A compound of aspect 63, wherein the first heteroatom is -N; and wherein the second heteroatom is selected from -NR. 12 -、-O- and -S-.

[0514] Aspect 65. A compound of aspect 63, wherein the first heteroatom is -N=; and wherein the second heteroatom is -NR. 12 -

[0515] Aspect 66. Compounds of any one of Aspects 61-65, wherein R 11 R 12 and R 13Each is independently selected from 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.

[0516] Compounds of aspect 67. Compounds of aspect 66, wherein R 11 R 12 and R 13 Each 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.

[0517] Compounds of aspect 68. Compounds of aspect 66, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0518] Compounds of aspect 69. Compounds of aspect 66, wherein R 11R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0519] Compounds of any one of aspects 70, 61-65, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0520] Compounds of aspect 71. Compounds of aspect 70, wherein R 11 R 12 and R 13 Each is independently selected from 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0521] Compounds of aspect 72. Compounds of aspect 70, wherein R 11 R12 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, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0522] Compounds of aspect 73. Compounds of aspect 70, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0523] Compounds of aspect 74. Compounds of aspect 70, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 At least one of them is not hydrogen.

[0524] A compound of any one of aspects 75. A compound of any one of aspects 61-65, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0525] Compounds of aspect 76 and 75, wherein R 11 R 12 and R 13 Each is independently selected from 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0526] Compounds of aspect 77. Compounds of aspect 75, wherein 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, R 11 R 12 R 13、 R 14 and R 15 Only one of them is not hydrogen.

[0527] Compounds of aspect 78 and 75, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0528] Compounds of aspect 79. Compounds of aspect 75, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0529] Compounds of any one of aspects 80, 61-65, wherein R 11 R 12 and R 13 Each 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, R 11 R 12 and R 13 Only one of them is not hydrogen.

[0530] Compounds of aspect 81 and aspect 78, wherein R 11 R 12 and R 13Each is independently selected from 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, R 11 R 12 and R 13 Two of them are not hydrogen.

[0531] Compounds of aspect 82 and aspect 78, wherein 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, R 11 R 12 and R 13 Two of them are not hydrogen.

[0532] Compounds of aspect 83 and aspect 78, wherein R 11 R 12 and R 13Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl, R 11 R 12 and R 13 Two of them are not hydrogen.

[0533] Compounds of aspect 84 and aspect 78, wherein R 11 R 12 and R 13 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl, and tert-butyl, R 11 R 12 and R 13 Two of them are not hydrogen.

[0534] Compounds of aspects 85. Compounds of aspects 61-65, wherein each R 11 R 12 and R 13 It is hydrogen.

[0535] Aspect 86. A compound of any one of Aspects 61-85, wherein Ar 1 It has a structure represented by the following formula:

[0536] , , ,or .

[0537] Aspect 87. A compound of any one of Aspects 61-85, wherein Ar 1 It has a structure represented by the following formula:

[0538] or .

[0539] Compounds in aspect 88 and aspect 60, in which Ar 1 It is a 5-membered heteroaryl group with two heteroatoms, including a first heteroatom and a second heteroatom; wherein the first heteroatom is -N=; and wherein the second heteroatom is selected from O and S; wherein Ar 1 R 11 and R 12 Replace; and where R 11 and R 12 Each 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;

[0540] Compounds of aspect 89. Compounds of aspect 88, wherein R 11 and R 12 Each is independently selected from 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.

[0541] Compounds in aspect 90 and aspect 88, wherein R 11 and R 12 Each 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.

[0542] Compounds of aspect 91 and aspect 88, wherein R 11 and R 12 Each is independently selected from hydrogen, -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0543] Compounds of aspect 92 and aspect 88, wherein R 11 and R 12 Each is independently selected from hydrogen, -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0544] Aspect 93. Compounds of any one of Aspects 88-92, wherein each R 11 and R 12 It is hydrogen.

[0545] Aspect 94. Compounds of any one of Aspects 88-92, wherein each R 11 and R 12 It is hydrogen.

[0546] Compounds of any one of aspects 95, 88-94, wherein Ar 1 It has a structure represented by the following formula:

[0547] or .

[0548] A compound of any one of aspects 96.1-13, wherein R1 is Cy1 and Cy1 is a 5- to 10-membered cycloalkyl group, optionally substituted with 1, 2, 3, 4 or 5 groups independently 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 groups.

[0549] Compounds of aspect 97. Compounds of aspect 96, wherein Cy1 is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0550] Compounds of aspect 98. Compounds of aspect 97, wherein Cy1 is selected from cyclopentyl, cyclohexyl, and cycloheptyl.

[0551] Compounds in aspect 99 and 97, wherein Cy1 is cyclohexyl.

[0552] Compounds of any one of aspects 100, 96-99, wherein Cy1 is monosubstituted with a group 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 groups.

[0553] Aspect 101. Compounds in aspect 100, wherein Cy1 is selected from -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, monosubstituted groups of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0554] Aspect 102. Compounds of aspect 100, wherein Cy1 is monosubstituted by 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 groups.

[0555] Aspect 103. Aspect 100 compounds wherein Cy1 is monosubstituted by a group selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0556] Compounds of aspect 104. Compounds of aspect 100, wherein Cy1 is monosubstituted by a group selected from -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0557] Compounds of any one of aspects 96-99, wherein Cy1 is disubstituted by two groups 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.

[0558] Aspect 106. Compounds in aspect 105, wherein Cy1 is selected from -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 groups are disubstituted.

[0559] Compounds of aspect 107. Compounds of aspect 105, wherein Cy1 is disubstituted by two groups 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.

[0560] Compounds of aspect 108 and aspect 105, wherein Cy1 is disubstituted by two groups selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0561] Compounds of aspect 109 and aspect 105, wherein Cy1 is disubstituted by two groups selected from -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0562] Compounds of any one of aspects 110, 96-99, wherein Cy1 is unsubstituted.

[0563] A compound of any one of aspects 111.1-16, wherein said compound has a structure represented by the following formula:

[0564] ,

[0565] Where n is an integer selected from 0, 1, and 2; where A 1 and A 2 Each is independently selected from -(C=O) and -CH2-, and at least one of A1 and A2 is -(C=O)-; where R 11 R 12 R 13 R 14 R15 and R15 are each 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 pharmaceutically acceptable salts thereof.

[0566] Aspect 112. Compounds of aspect 111, wherein R 11 R 12 R 13 R 14 R15 and R25 are each 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. 11 R 12 R 13 R 14 At least one of R15 is not hydrogen.

[0567] Aspect 113. Compounds of aspect 111, wherein R11 R 12 and R 13 Each 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 11 R 12 and R 13 At least one of them is not hydrogen; wherein each R 14 R15 is hydrogen.

[0568] Aspect 114. Compounds of aspect 111, wherein R 11 and R 12 Each of the following 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, wherein each R 13 R 14 R15 is hydrogen.

[0569] Aspect 115. Compounds of aspect 111, wherein R 11 and R 13 Each of the following 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, wherein each R 12 R 14 R15 is hydrogen.

[0570] Aspect 116. Compounds of aspect 111, wherein R 11 and R 14 Each of the following 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, wherein each R 12 R 13 R15 is hydrogen.

[0571] Aspect 117. Compounds of aspect 111, wherein R 11Selected from halogens, -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, wherein each R 12 R 13 R 14 R15 and R2 are hydrogen.

[0572] Compounds of aspect 118. Compounds of aspect 117, wherein R 11 Selected from -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.

[0573] Compounds of aspect 119. Compounds of aspect 117, wherein R 11 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.

[0574] Compounds of aspect 120 and aspect 117, wherein R 11 Selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0575] Compounds of aspect 121. Compounds of aspect 117, wherein R 11 Selected from -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0576] Compounds of aspect 122 and aspect 111, wherein R 12 Selected from halogens, -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, wherein each R 12 R 13 R 14 R15 and R2 are hydrogen.

[0577] Aspect 123. Compounds of aspect 122, wherein R 11 Selected from -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.

[0578] Aspect 124. Compounds of aspect 122, wherein R 12Selected 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.

[0579] Compounds of aspect 125. Compounds of aspect 122, wherein R 12 Selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0580] Compounds of aspect 126. Compounds of aspect 122, wherein R 12 Selected from -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0581] Compounds of aspect 127. Compounds of aspect 111, wherein R 13 Selected from halogens, -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, wherein each R 12 R 13 R 14 R15 and R2 are hydrogen.

[0582] Compounds of aspect 128. Compounds of aspect 127, wherein R 13Selected from -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.

[0583] Compounds of aspect 129. Compounds of aspect 127, wherein R 13 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.

[0584] Compounds of aspect 130 and aspect 127, wherein R 13 Selected from -Cl, -CCl3, -OCF3, -OCCl3, -OCH3, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0585] Compounds of aspect 131 and aspect 127, wherein R 13 Selected from -Cl, -OCF3, methyl, ethyl and tert-butyl.

[0586] Compounds of aspect 132.111 have a structure represented by the following formula:

[0587] ,

[0588] Where R 11 and R 12 Each 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.

[0589] Compounds of aspect 133.111 have a structure represented by the following formula:

[0590] ,

[0591] Where R 11 and R 13 Each 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.

[0592] Compounds of aspect 134.111 have a structure represented by the following formula:

[0593] ,

[0594] Where R 11 and R 14 Each 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.

[0595] Compounds of aspect 135 and aspect 111 have a structure represented by the following formula:

[0596] ,

[0597] R 11 It is 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.

[0598] Compounds of aspect 136.111 have a structure represented by the following formula:

[0599] ,

[0600] R 12 It is 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.

[0601] Compounds of aspect 137.111 have a structure represented by the following formula:

[0602] ,

[0603] R 13 It is 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.

[0604] Compounds of aspect 138 and aspect 111 have a structure represented by the following formula:

[0605] ,

[0606] Where R 11 and R 12 Each 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.

[0607] Compounds of aspect 139 and aspect 111 have a structure represented by the following formula:

[0608] ,

[0609] Where R 11 and R 13Each 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.

[0610] Compounds of aspect 140 and aspect 111 have a structure represented by the following formula:

[0611] ,

[0612] Where R 11 and R 14 Each 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.

[0613] Compounds of aspect 141. Compounds of aspect 111 have a structure represented by the following formula:

[0614] ,

[0615] R 11 It is 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.

[0616] Compounds of aspect 142.111 have a structure represented by the following formula:

[0617] ,

[0618] R 12 It is 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.

[0619] Compounds of aspect 143.111 have a structure represented by the following formula:

[0620] ,

[0621] R 13It is 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.

[0622] Compounds of aspect 144.111 have a structure represented by the following formula:

[0623] ,

[0624] Where R 11 and R 12 Each 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.

[0625] Compounds of aspect 145.111 have a structure represented by the following formula:

[0626] ,

[0627] Where R 11 and R 13 Each 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.

[0628] Compounds of aspect 146.111 have a structure represented by the following formula:

[0629] ,

[0630] Where R 11 and R 14 Each 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.

[0631] Compounds of aspect 147.111 have a structure represented by the following formula:

[0632] ,

[0633] R 11 It is 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.

[0634] Compounds of aspect 148 and aspect 111 have a structure represented by the following formula:

[0635] ,

[0636] R 12 It is 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.

[0637] Compounds of aspect 149 and aspect 111 have a structure represented by the following formula:

[0638] ,

[0639] R 13 It is 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.

[0640] Aspect 150 Compound 1, wherein the compound is:

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647] Aspect 151. Compound 1, wherein the compound is:

[0648]

[0649] Aspect 152. Compound 1, wherein the compound is:

[0650]

[0651] Aspect 153. Compound 1, wherein the compound is:

[0652]

[0653]

[0654] Aspect 154. A pharmaceutical composition comprising a therapeutically effective amount of any one of aspects 1-153 of a compound, or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable carrier.

[0655] Aspect 155. The pharmaceutical composition of aspect 154 further comprises at least one known agent for treating cancer.

[0656] Aspect 156. A pharmaceutical composition of aspect 155, wherein the at least one known cancer-treating agent is a hormone therapy agent; an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, other chemotherapeutic agents, or combinations thereof.

[0657] Aspect 157. The pharmaceutical composition of aspect 156, wherein the at least one known cancer-treating agent is a hormone therapy agent selected from one or more of leuprorelin, tamoxifen, raloxifene, medroxyprogesterone acetate, fulvestrant, triptorelin, medroxyprogesterone acetate, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histamine-releasing peptide, flumethasone, estradiol, flutamide, toremifene, degarelix, nilutel, abalenelin, and testosterone, or a pharmaceutically acceptable salt thereof.

[0658] Aspect 158. Aspect 156 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is an antitumor antibiotic selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dacamycin, epirubicin, idarubicin, vomica, mitomycin, pentostatin, and vararubicin, or a pharmaceutically acceptable salt thereof.

[0659] Aspect 159. The pharmaceutical composition of aspect 156, wherein the at least one known cancer-treating agent is an antimetabolite selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0660] Aspect 160. Aspect 156 of pharmaceutical compositions, wherein the at least one known agent for treating cancer is an alkylating agent selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt thereof.

[0661] Aspect 161. Aspect 156 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is a mitotic inhibitor selected from one or more of irinotecan, topotecan, rubotecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0662] Aspect 162. Aspect 156 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is an mTor inhibitor selected from one or more of everolimus, sirolimus, and tesimolimus, or a pharmaceutically acceptable salt thereof.

[0663] Aspect 163. Aspect 156 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, thiamethoxam, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, phosphate. Fludarabine, pentostatin, bortezomib, vincristine, vinorelbine, vindesine, bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemetrexed, idarubicin, paclitaxel, docetaxel, ixaprilone, safflower, topotecan, irinotecan, deoxymyopicrin, mitomycin-C, L-asparaginase, interferon, etoposide, teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0664] Aspect 164. A method for treating uncontrolled cell proliferation in mammals; comprising the steps of: administering to the mammal a therapeutically effective amount of at least one compound of aspect 153, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition of aspect 154-aspect 163.

[0665] Aspect 165. The method of aspect 164, wherein the mammal is human.

[0666] Aspect 166. Aspect 164, wherein prior to the administration step, the mammal has been diagnosed as requiring treatment for a disease of uncontrolled cell proliferation.

[0667] Aspect 167. The method of aspect 164 also includes the step of identifying mammals with diseases of uncontrolled cell proliferation that require treatment.

[0668] Aspect 168. The method of aspect 164, wherein the uncontrolled cell proliferation disease is associated with cereblon (CRBN) dysfunction.

[0669] Aspect 169. The method of aspect 168, wherein the uncontrolled cell proliferation disease is cancer.

[0670] Aspect 170. Aspect 169, wherein the cancer is pediatric cancer.

[0671] Aspect 171. Aspect 169, wherein the cancer is childhood acute leukemia (AL) or medulloblastoma (MB) cancer.

[0672] Aspect 172. The method of aspect 169, wherein the cancer is selected from brain cancer, lung cancer, leukemia, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, stomach cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic system cancer, gastric cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof.

[0673] Aspect 173. The method of aspect 172, wherein the cancer is selected from lung cancer, ovarian cancer and brain cancer.

[0674] Aspect 174. The method of aspect 173, wherein the lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof.

[0675] Aspect 175. The method of aspect 173, wherein the renal cell carcinoma is clear cell renal carcinoma.

[0676] Aspect 176. The method of aspect 173, wherein the brain cancer is selected from glioblastoma, medulloblastoma, glioma, and combinations thereof.

[0677] Aspect 177. The method of aspect 173, wherein the bladder cancer is bladder urothelial carcinoma.

[0678] Aspect 178. Aspect 173, in which liver cancer is a hepatocellular carcinoma.

[0679] Aspect 179. In another aspect, the cancer is a hematologic 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 lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

[0680] The method of any one of aspects 180, 164-179, further includes the step of: administering a therapeutically effective amount of at least one known agent for treating cancer.

[0681] Aspect 181. The method of aspect 180, wherein the at least one drug is selected from uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, methamidophos, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, Pentostatin, Bortezomib, Vincristine, Vincristine, Vinorelbine, Vindysine, Bleomycin, Actinomycin D, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemetrexed, Idarubicin, Paclitaxel, Docetaxel, Ixaspiron, Glechomyc, Topotecan, Irinotecan, Deoxymyomycin, Mitomycin-C, L-Asparaginase, Interferon, Etoposide, Teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0682] Aspect 182. The method of aspect 180, 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.

[0683] Aspect 183. The method of aspect 182, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination thereof.

[0684] Aspect 184. The method of Aspect 182, wherein the HDAC inhibitor is vorinostat, entinostat, pabistat, trichomonadine A, mocetinostat, belistat, danostat, givinostat, tubastat A, pracinostat, droxinostat, quinsinostat, romidixin, valproic acid, AR-42 (OSU-HDAC42), acetyldenalin, rocilinostat, apicillin, or a combination thereof.

[0685] Aspect 185. Aspect 182, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0686] Aspect 186. The method of aspect 182, wherein the mTor inhibitor is BEZ235, everolimus, tesiromolimus, rapamycin, AZD8055 or a combination thereof.

[0687] Aspect 187. The method of aspect 182, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, or other chemotherapeutic agent.

[0688] Aspect 188. The method of aspect 187, wherein the antitumor antibiotic is selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, actinomycin D, epirubicin, idarubicin, sclerosomycin, mitomycin, pentostatin, and pentorubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0689] Aspect 189. The method of aspect 187, wherein the antimetabolite is selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0690] Aspect 190. The method of aspect 187, wherein the alkylating agent is selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0691] Methods of aspect 191 and aspect 187, wherein the mitotic inhibitor is selected from one or more of irinotecan, topotecan, rubotecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprone, vinorelbine, vinblastine, and teniposide, or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof.

[0692] Methods in aspect 192 and aspect 187, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0693] Aspect 193. Aspect 187, wherein the other chemotherapeutic agent is anthracycline antibiotics, cytarabine, purine analogs, sorafenib, gemtuzumab, oxazolidin, rituximab, or a combination thereof.

[0694] Aspect 194. Aspect 193, wherein the anthracycline antibiotic is daunorubicin, idarubicin, or a combination thereof.

[0695] Aspect 195. Aspect 193, wherein the purine analogue is cladribine, fludarabine, chlorofarabine, or a combination thereof.

[0696] Aspect 196. The method of any one of Aspects 180-195, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are administered sequentially.

[0697] Aspect 197. A method of any one of Aspects 180-195, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are administered simultaneously.

[0698] Aspect 198. The method of any one of Aspects 180-195, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are formulated together.

[0699] Aspect 199. A method of any one of Aspects 180-195, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are co-packaged.

[0700] Aspect 200. A method for modulating cereblon activity in mammals; comprising the steps of: administering to the mammal a therapeutically effective amount of at least one of the compounds of aspect 1-153, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of at least one of aspect 154-163.

[0701] Aspect 201. The method of aspect 200, wherein the mammal is human.

[0702] Aspect 202. A method of aspect 200, wherein prior to the administration step, the mammal has been diagnosed as requiring modulation of cereblon activity.

[0703] Aspect 203. The method of aspect 200 also includes the step of identifying mammals for which cereblon activity needs to be regulated.

[0704] Aspect 204. A method for regulating cereblon activity in at least one cell; comprising the step of contacting said at least one cell with a therapeutically effective amount of at least one compound of aspect 1-aspect 153, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of at least one aspect 154-aspect 163.

[0705] Aspect 205. The method of aspect 204, wherein the cell is a mammalian cell.

[0706] Aspect 206. The method of aspect 204, wherein the cell is a human cell.

[0707] Aspect 207. Aspect 204 method, wherein the cells have been isolated from mammals prior to the contact step.

[0708] Aspect 208. The method of aspect 204, wherein the contact is made by administration to a mammal.

[0709] Aspect 209. The method of aspect 208, wherein prior to the administration step, the mammal has been diagnosed as requiring modulation of cereblon activity.

[0710] Aspect 210. Aspect 208, wherein prior to the administration step, the mammal is diagnosed with a disease requiring treatment related to cereblon activity.

[0711] Aspect 211. Aspect 164, Aspect 200 or Aspect 204, wherein the compound inhibits cell proliferation and, when measured in a cell viability assay using MV4-11 cells as described herein, has an IC50 of less than about 20 µM; and / or, when used in a fluorescence polarization assay as described herein, the compound has an IC50 of less than about 10 µM when binding to cereblon.

[0712] Aspect 212. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 15 µM; and / or wherein the compound binds to cereblon with an IC50 of less than about 7.5 µM.

[0713] Aspect 213. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 10 µM; and / or wherein the compound binds to cereblon with an IC50 of less than about 7.5 µM.

[0714] Aspect 214. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 10 µM; and / or wherein the compound binds to cereblon with an IC50 of less than about 1 µM.

[0715] Aspect 215. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 5 µM; and / or wherein the compound binds to cereblon with an IC50 of less than about 500 nM.

[0716] Aspect 216. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 1 µM; and / or wherein the compound binds to cereblon with an IC50 of less than about 100 nM.

[0717] Aspect 217. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 100 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 500 nM.

[0718] Aspect 218. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 10 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 50 nM.

[0719] Aspect 219. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 1 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 50 nM.

[0720] Aspect 220. Aspect 211 method, wherein the compound inhibits cell proliferation with an IC50 of less than about 0.1 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 50 nM.

[0721] Aspect 221. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 0.01 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 50 nM.

[0722] Aspect 222. The method of aspect 211, wherein the compound inhibits cell proliferation with an IC50 of less than about 0.01 nM; and / or wherein the compound binds to cereblon with an IC50 of less than about 25 nM.

[0723] Aspect 223. A kit comprising at least one compound of any one of Aspects 1-153 or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition of any one of Aspects 154-163; and one or more of the following: (a) at least one known agent that enhances cereblon activity; (b) at least one known agent that inhibits cereblon activity; (c) at least one known agent that enhances GSPT1 activity; (d) at least one known agent that inhibits GSPT1 activity; (e) at least one known agent that enhances cell proliferation; (f) at least one known agent that inhibits cell proliferation; (g) at least one known agent that treats a disease associated with cereblon activity; (h) at least one known agent that treats a disease associated with GSPT1 activity; (i) at least one known agent that treats a disease of uncontrolled cell proliferation; and / or (j) instructions for use in treating a disease of uncontrolled cell proliferation.

[0724] Aspect 224. A kit for aspect 223, wherein the at least one compound or the at least one product is formulated together with the at least one pharmaceutical agent.

[0725] Aspect 225. A kit for aspect 223, wherein the at least one compound or the at least one product is co-packaged with the at least one pharmaceutical agent.

[0726] Aspect 226. The kit for any one of Aspects 223-225, and also includes instructions for use specifying compounds related to the procedure.

[0727] Aspect 227. Aspect 226 kit, wherein the instructions specify that surgery should be performed before the administration of at least one compound.

[0728] Aspect 228. Aspect 226 kit, wherein the instructions specify that surgery should be performed after administration of at least one compound.

[0729] Aspect 229. The kit for aspect 226, wherein the instructions specify that at least one compound is administered to achieve preoperative shrinkage of the tumor.

[0730] Aspect 230. Aspect 226 kit, wherein the instructions specify that surgery should be performed approximately simultaneously with the administration of at least one compound.

[0731] A kit according to any one of Aspects 223-230, further comprising at least one compound or pharmaceutical composition as specified in the instructions for use in relation to radiotherapy.

[0732] Aspect 232. A kit for aspect 231, wherein the instructions specify that radiation therapy should be performed prior to the administration of at least one compound.

[0733] Aspect 233. A kit for aspect 231, wherein the instructions specify that radiotherapy should be performed after administration of at least one compound.

[0734] Aspect 234. A kit for aspect 231, wherein the instructions specify that radiation therapy should be performed approximately simultaneously with the administration of at least one compound.

[0735] Aspect 235. The kit of any one of Aspects 223-234 further comprises multiple dosage forms, said multiple dosage forms comprising one or more doses; wherein each dose comprises a therapeutically effective amount of at least one compound or pharmaceutical composition and at least one agent.

[0736] Aspect 236. A kit for aspect 235, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent, which are co-formulated.

[0737] Aspect 237. A kit for aspect 235, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent co-packaged.

[0738] Aspect 238. A kit for aspect 235, wherein the dosage form is formulated for oral and / or intravenous administration.

[0739] Aspect 239. A kit for aspect 235, wherein the dosage form is formulated for oral administration.

[0740] Aspect 240. Aspect 235 kit in which the dosage form is formulated for intravenous administration.

[0741] Aspect 241. A kit for aspect 235, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for oral administration, and the dosage form of said at least one pharmaceutical agent is formulated for intravenous administration.

[0742] Aspect 242. A kit for aspect 235, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for intravenous administration, and the dosage form of said at least one pharmaceutical agent is formulated for oral administration.

[0743] Aspect 243. A kit comprising at least one compound of any one of Aspects 1-153 or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition of any one of Aspects 154-163; and one or more of the following: (a) at least one known agent that enhances cereblon activity; (b) at least one known agent that inhibits cereblon activity; (c) at least one known agent that enhances cell proliferation; (d) at least one known agent that inhibits cell proliferation; (e) at least one known agent for treating diseases associated with cereblon activity; (f) at least one known agent for treating diseases of uncontrolled cell proliferation; and / or (g) instructions for use in treating diseases of uncontrolled cell proliferation.

[0744] Aspect 244. A kit for aspect 243, wherein the at least one compound or the at least one product is formulated together with the at least one pharmaceutical agent.

[0745] Aspect 245. A kit for aspect 243, wherein the at least one compound or the at least one product is co-packaged with the at least one pharmaceutical agent.

[0746] Aspect 246. The kit for any one of Aspects 243-245, and also includes instructions for use specifying compounds related to the procedure.

[0747] Aspect 247. Aspect 246 kit, wherein the instructions specify that surgery should be performed before the administration of at least one compound.

[0748] Aspect 248. Aspect 246 kit, wherein the instructions specify that surgery should be performed after administration of at least one compound.

[0749] Aspect 249. The kit for aspect 246, wherein the instructions specify that at least one compound is administered to achieve preoperative shrinkage of the tumor.

[0750] Aspect 250. Aspect 246 kit, wherein the instructions specify that surgery should be performed approximately simultaneously with the administration of at least one compound.

[0751] A kit according to any one of aspects 243-250, further comprising at least one compound or pharmaceutical composition as specified in the instructions for use in relation to radiotherapy.

[0752] Aspect 252. A kit for aspect 251, wherein the instructions specify that radiation therapy should be performed prior to the administration of at least one compound.

[0753] Aspect 253. A kit for aspect 251, wherein the instructions specify that radiation therapy should be performed after administration of at least one compound.

[0754] Aspect 254. A kit for aspect 251, wherein the instructions specify that radiation therapy should be performed approximately simultaneously with the administration of at least one compound.

[0755] Aspect 255. The kit of any one of Aspects 243-254 further comprises multiple dosage forms, said multiple dosage forms comprising one or more doses; wherein each dose comprises a therapeutically effective amount of at least one compound or pharmaceutical composition and at least one agent.

[0756] Aspect 256. A kit for aspect 255, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent co-formulated.

[0757] Aspect 257. A kit for aspect 255, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent co-packaged.

[0758] Aspect 258. Aspect 255 kit in which the dosage form is formulated for oral and / or intravenous administration.

[0759] Aspect 259. A kit for aspect 255, wherein the dosage form is formulated for oral administration.

[0760] Aspect 260. Aspect 255 kits in which dosage forms are formulated for intravenous administration.

[0761] Aspect 261. A kit for aspect 255, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for oral administration, and the dosage form of said at least one pharmaceutical agent is formulated for intravenous administration.

[0762] Aspect 262. A kit for aspect 255, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for intravenous administration, and the dosage form of said at least one pharmaceutical agent is formulated for oral administration.

[0763] A kit comprising at least one compound of any one of aspects 1-153 or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition of any one of aspects 154-163; and one or more of the following: (a) at least one known agent that enhances GSPT1 activity; (b) at least one known agent that inhibits GSPT activity; (c) at least one known agent that enhances cell proliferation; (d) at least one known agent that inhibits cell proliferation; (e) at least one known agent that treats a disease associated with GSPT1 activity; (f) at least one known agent that treats a disease of uncontrolled cell proliferation; and / or (g) instructions for use in treating a disease of uncontrolled cell proliferation.

[0764] Aspect 264. A kit for aspect 263, wherein the at least one compound or the at least one product is formulated together with the at least one pharmaceutical agent.

[0765] Aspect 265. A kit for aspect 263, wherein the at least one compound or the at least one product is co-packaged with the at least one pharmaceutical agent.

[0766] Aspect 266. The kit for any one of Aspects 263-265, and also includes instructions for specifying compounds related to the procedure.

[0767] Aspect 267. Aspect 266 kit, wherein the instructions specify that surgery should be performed before the administration of at least one compound.

[0768] Aspect 268. Aspect 266 kit, wherein the instructions specify that surgery should be performed after administration of at least one compound.

[0769] Aspect 269. The kit for aspect 266, wherein the instructions specify that at least one compound is administered to achieve preoperative shrinkage of the tumor.

[0770] Aspect 270. Aspect 266 kit, wherein the instructions specify that surgery should be performed approximately simultaneously with the administration of at least one compound.

[0771] A kit according to any one of aspects 271. or 263-270, further comprising at least one compound or pharmaceutical composition as specified in the instructions for use in relation to radiotherapy.

[0772] Aspect 272. A kit for aspect 271, wherein the instructions specify that radiation therapy should be performed prior to the administration of at least one compound.

[0773] Aspect 273. A kit for aspect 271, wherein the instructions specify that radiation therapy should be performed after administration of at least one compound.

[0774] Aspect 274. A kit for aspect 271, wherein the instructions specify that radiation therapy should be performed approximately simultaneously with the administration of at least one compound.

[0775] Aspect 275. The kit of any one of Aspects 263-274 further comprises multiple dosage forms, said multiple dosage forms comprising one or more doses; wherein each dose comprises a therapeutically effective amount of at least one compound or pharmaceutical composition and at least one agent.

[0776] Aspect 276. A kit for aspect 275, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent co-formulated.

[0777] Aspect 277. A kit for aspect 275, wherein each dose contains at least one compound or pharmaceutical composition and at least one pharmaceutical agent co-packaged.

[0778] Aspect 278. Aspect 275 kit in which the dosage form is formulated for oral and / or intravenous administration.

[0779] Aspect 279. Aspect 275 kit in which the dosage form is formulated for oral administration.

[0780] Aspect 280. Aspect 275 kits in which dosage forms are formulated for intravenous administration.

[0781] Aspect 281. A kit for aspect 275, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for oral administration, and the dosage form of said at least one pharmaceutical agent is formulated for intravenous administration.

[0782] Aspect 282. A kit for aspect 275, wherein the dosage form of said at least one compound or pharmaceutical composition is formulated for intravenous administration, and the dosage form of said at least one pharmaceutical agent is formulated for oral administration.

[0783] Use of at least one compound of any one of aspects 1-153, or a pharmaceutically acceptable salt thereof; or at least one pharmaceutical composition of any one of aspects 154-163; or combinations thereof in the preparation of a medicament for treating diseases associated with cereblon dysfunction in mammals.

[0784] Use of at least one compound or a pharmaceutically acceptable salt thereof from any one of aspects 154-163; or at least one pharmaceutical composition thereof from any one of aspects 154-163; or combinations thereof in the preparation of a medicament for treating diseases of uncontrolled proliferation of mammalian cells.

[0785] Aspect 285. A compound having a structure represented by the following formula:

[0786] ,

[0787] Where R 1a Selected from bromine, methyl, -CF3 and -OCF3; and wherein R 1b R 1c R 1d and R 1e Each is independently selected from hydrogen, halogen, and methyl; or their pharmaceutically acceptable salts.

[0788] Aspect 286. Compounds of aspect 286, wherein R 1a It is bromine.

[0789] Compounds of aspect 287 and aspect 286, wherein R 1a It is a methyl group.

[0790] Compounds of aspect 288. Compounds of aspect 286, wherein R 1a Selected from -CF3 and -OCF3.

[0791] Compounds of aspect 289. Compounds of aspect 286, wherein each R 1b R 1c R 1d 、 and R 1e It is hydrogen.

[0792] Compounds of aspect 290 and aspect 286, wherein R 1b R 1c R 1d and R 1e At least one of them is a halogen.

[0793] Compounds of aspect 291 and aspect 286, wherein R 1b R 1c R 1d and R 1e At least one of them is a methyl group.

[0794] Compounds of aspect 292 and 286 have structures represented by the following formula:

[0795] ; ;

[0796] ; ;

[0797] ; ;or

[0798] ; or its subgroups.

[0799] Aspect 293. A compound having a structure represented by the following formula:

[0800] ,

[0801] Or its pharmaceutically acceptable salt.

[0802] Aspect 294. A pharmaceutical composition comprising a therapeutically effective amount of any one of aspects 286-293, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier.

[0803] Aspect 295. The pharmaceutical composition of aspect 294 further comprises at least one known agent for treating cancer.

[0804] Aspect 296. The pharmaceutical composition of aspect 295, wherein the at least one known cancer-treating agent is a hormone therapy agent; an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, other chemotherapeutic agents, or combinations thereof.

[0805] Aspect 297. The pharmaceutical composition of aspect 296, wherein the at least one known cancer-treating agent is a hormone therapy agent selected from one or more of leuprorelin, tamoxifen, raloxifene, medroxyprogesterone acetate, fulvestrant, triptorelin, medroxyprogesterone acetate, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histamine-releasing peptide, flumethasone, estradiol, flutamide, toremifene, degarelix, nilumet, abalenelin, and testosterone, or a pharmaceutically acceptable salt thereof.

[0806] Aspect 298. A pharmaceutical composition of aspect 296, wherein the at least one known cancer-treating agent is an antitumor antibiotic selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dacamycin, epirubicin, idarubicin, vomica, mitomycin, pentostatin, and vararubicin, or a pharmaceutically acceptable salt thereof.

[0807] Aspect 299. The pharmaceutical composition of aspect 296, wherein the at least one known cancer-treating agent is an antimetabolite selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.

[0808] Aspect 300. Aspect 296 of pharmaceutical compositions, wherein the at least one known agent for treating cancer is an alkylating agent selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt thereof.

[0809] Aspect 301. Aspect 296 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is a mitotic inhibitor selected from one or more of irinotecan, topotecan, rubotecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.

[0810] Aspect 302. Aspect 296 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is an mTor inhibitor selected from one or more of everolimus, sirolimus and tesimolimus, or a pharmaceutically acceptable salt thereof.

[0811] Aspect 303. Aspect 296 of pharmaceutical compositions, wherein the at least one known cancer-treating agent is uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, thiamethoxam, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, phosphate. Fludarabine, pentostatin, bortezomib, vincristine, vinorelbine, vindesine, bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemetrexed, idarubicin, paclitaxel, docetaxel, ixaprilone, safflower, topotecan, irinotecan, deoxymyopicrin, mitomycin-C, L-asparaginase, interferon, etoposide, teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0812] Aspect 304. A method for treating a disease of uncontrolled cell proliferation in mammals; comprising the steps of: administering to the mammal a therapeutically effective amount of at least one compound of aspect 285-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of at least one aspect 294-303.

[0813] Aspect 305. The method of aspect 304, wherein the mammal is human.

[0814] Aspect 306. Aspect 304 method, wherein prior to the administration step, the mammal has been diagnosed as requiring treatment for a disease of uncontrolled cell proliferation.

[0815] Aspect 307. The method of aspect 304, which further includes the step of identifying mammals with diseases of uncontrolled cell proliferation that require treatment.

[0816] Aspect 308. The method of aspect 304, wherein the uncontrolled cell proliferation disease is associated with GSTP1 dysfunction.

[0817] Aspect 309. The method of aspect 308, wherein the uncontrolled cell proliferation disease is cancer.

[0818] Aspect 310. Aspect 309, wherein the cancer is pediatric cancer.

[0819] Aspect 311. Aspect 309, wherein the cancer is childhood acute leukemia (AL) or medulloblastoma (MB) cancer.

[0820] Aspect 312. Aspect 309 of the method, wherein the cancer is selected from brain cancer, lung cancer, leukemia, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, stomach cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic system cancer, gastric cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof.

[0821] Aspect 313. The method of aspect 312, wherein the cancer is selected from lung cancer, ovarian cancer and brain cancer.

[0822] Aspect 314. The method of aspect 313, wherein the lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof.

[0823] Aspect 315. The method of aspect 313, wherein the renal cell carcinoma is clear cell renal carcinoma.

[0824] Aspect 316. The method of aspect 313, wherein the brain cancer is selected from glioblastoma, medulloblastoma, glioma, and combinations thereof.

[0825] Methods of aspect 317 and aspect 173, wherein the bladder cancer is bladder urothelial carcinoma.

[0826] Aspect 318. Aspect 313, in which liver cancer is a hepatocellular carcinoma.

[0827] Aspect 319. In another aspect, the cancer is a hematologic 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 lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

[0828] The method of any one of aspects 320, 304-319, further includes the step of: administering a therapeutically effective amount of at least one known agent for treating cancer.

[0829] Aspect 321. The method of Aspect 320, wherein the at least one drug is selected from uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, thiamethoxam, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, Pentostatin, Bortezomib, Vincristine, Vincristine, Vinorelbine, Vindysine, Bleomycin, Actinomycin D, Daunorubicin, Doxorubicin, Epirubicin, Dexamethasone, Clofarabine, Cladribine, Pemetrexed, Idarubicin, Paclitaxel, Docetaxel, Ixaspiron, Glechomyc, Topotecan, Irinotecan, Deoxymyomycin, Mitomycin-C, L-Asparaginase, Interferon, Etoposide, Teniposide 17 Alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymethyltestosterone, drotaldophenone propionate, testosterone lactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorestradiol, hydroxyprogesterone, aminoglutethimide, estradiol, medroxyprogesterone acetate, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.

[0830] Aspect 322. The method of aspect 320, 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.

[0831] Aspect 323. The method of aspect 322, wherein the DNA methyltransferase inhibitor is 5-aza-2′-deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or a combination thereof.

[0832] Aspect 324. The method of aspect 322, wherein the HDAC inhibitor is vorinostat, entinostat, pabistat, trichomonadine A, mocetinostat, belistat, danostat, givinostat, tubastat A, pracinostat, droxinostat, quinsinostat, romidesin, valproic acid, AR-42 (OSU-HDAC42), acetyldenalin, rocilinostat, apicillin, or a combination thereof.

[0833] Aspect 325. The method of aspect 322, wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or a combination thereof.

[0834] Aspect 326. The method of aspect 322, wherein the mTor inhibitor is BEZ235, everolimus, tesiromolimus, rapamycin, AZD8055 or a combination thereof.

[0835] Aspect 327. The method of aspect 322, wherein the cytotoxic agent is an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, an mTor inhibitor, or other chemotherapeutic agent.

[0836] Aspect 328. The method of aspect 327, wherein the antitumor antibiotic is selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, actinomycin D, epirubicin, idarubicin, sclerosomycin, mitomycin, pentostatin, and pentorubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0837] Aspect 329. The method of aspect 327, wherein the antimetabolite is selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0838] Aspect 330. The method of aspect 327, wherein the alkylating agent is selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine, and streptozotocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0839] Aspect 331. Aspect 327 of the method wherein the mitotic inhibitor is selected from one or more of irinotecan, topotecan, rubotecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0840] Aspect 332. Aspect 327, wherein the mTor inhibitor is everolimus, sirolimus, tesimolimus, or a combination thereof.

[0841] Aspect 333. The method of aspect 327, wherein the other chemotherapeutic agent is anthracycline antibiotics, cytarabine, purine analogs, sorafenib, gemtuzumab, oxazolidin, rituximab, or a combination thereof.

[0842] Aspect 334. The method of aspect 333, wherein the anthracycline antibiotic is daunorubicin, idarubicin, or a combination thereof.

[0843] Aspect 335. The method of aspect 333, wherein the purine analogue is cladribine, fludarabine, clofarabine, or a combination thereof.

[0844] Aspect 336. The method of any one of Aspects 180-335, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are administered sequentially.

[0845] Aspect 337. A method of any one of Aspects 180-335, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are administered simultaneously.

[0846] Aspect 338. The method of any one of Aspects 180-335, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are formulated together.

[0847] Aspect 339. A method of any one of Aspects 180-335, wherein the at least one compound, the at least one pharmaceutical composition, and the at least one pharmaceutical agent are co-packaged.

[0848] Aspect 340. A method for modulating GSPT1 activity in mammals; comprising the steps of: administering to a mammal a therapeutically effective amount of at least one of the compounds of aspects 285-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of at least one of aspects 294-303.

[0849] Aspect 341. The method of aspect 340, wherein the mammal is human.

[0850] Aspect 342. A method of aspect 340, wherein prior to the administration step, the mammal has been diagnosed as needing to modulate GSPT1 activity.

[0851] Aspect 343. The method of aspect 340 further includes the step of identifying mammals for which GSPT1 activity needs to be regulated.

[0852] Aspect 344 A method for modulating GSPT1 activity in at least one cell; comprising the step of contacting the at least one cell with a therapeutically effective amount of at least one compound of aspect 285-293, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of at least one aspect 294-303.

[0853] Aspect 345. The method of aspect 344, wherein the cell is a mammalian cell.

[0854] Aspect 346. The method of aspect 344, wherein the cell is a human cell.

[0855] Aspect 347. A method of aspect 344, wherein the cells have been isolated from mammals prior to the contact step.

[0856] Aspect 348. The method of aspect 344, wherein the contact is made by administration to a mammal.

[0857] Aspect 349. Aspect 208, wherein the mammal has been diagnosed with a need to modulate GSPT1 activity prior to the administration step.

[0858] Aspect 350. Aspect 208, wherein prior to the administration step, the mammal is diagnosed with a disease requiring treatment related to GSPT1 activity.

[0859] Aspect 351. Aspect 304, Aspect 340 or Aspect 344, wherein the IC50 of the compound inhibiting cell proliferation is less than about 20 µM, as determined in a cell viability assay using MV4-11 cells as described herein; and / or in a cell viability assay using a cell line containing a HEK293 HiBit marker, wherein the IC50 of the compound binding to GSPT1 is less than about 10 µM.

[0860] Aspect 352. The method of aspect 351, wherein the IC50 of the compound inhibiting cell proliferation is less than about 15 µM; and / or wherein the IC50 of the compound binding to GSPT1 is less than about 7.5 µM.

[0861] Aspect 353. The method of aspect 351, wherein the compound inhibits cell proliferation with an IC50 of less than about 10 µM; and / or wherein the compound binds to GSPT1 with an IC50 of less than about 5 µM.

[0862] Aspect 354. The method of aspect 351, wherein the compound inhibits cell proliferation with an IC50 of less than about 10 µM; and / or wherein the compound binds to GSPT1 with an IC50 of less than about 1 µM.

[0863] Aspect 355. The method of aspect 351, wherein the compound inhibits cell proliferation with an IC50 of less than about 5 µM; and / or wherein th...

Claims

1. A compound with the structure shown in the following formula: wherein R 11 selected from bromo, chloro, C1-C3haloalkyl, -0-(Ci-C3haloalkyl), and C1-C6alkyl; R 12 , R 13 , R 14 , and R 15 are each independently selected from hydrogen, bromo, chloro, C1-C3haloalkyl, -O-(C1-C3haloalkyl), and C1-C6alkyl; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein the compound has a structure represented by the following formula: Where R 1a Selected from bromine, methyl, -CF3 and -OCF3; Where R 1b R 1d and R 1e Each is independently selected from hydrogen, bromine, chlorine, and methyl; and R 1c Selected from hydrogen, bromine, chlorine, and methyl; Or its pharmaceutically acceptable salt.

3. The compound of claim 2, wherein R 1a Selected from -CF3 and -OCF3.

4. The compound of claim 2, wherein each R 1b R 1c R 1d and R 1e It is hydrogen.

5. The compound of claim 1, having a structure represented by the following formula:

6. The compound of claim 5, having a structure represented by the following formula:

7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, further comprising at least one known agent for treating cancer.

9. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancers associated with GSPT1 dysfunction in mammals, comprising the step of administering a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof to the mammal.

10. The application as described in claim 9, wherein the mammal has been diagnosed as requiring cancer treatment prior to the application step.

11. The application as described in claim 9, further comprising the step of identifying mammals in need of cancer treatment.

12. The application as described in claim 9, wherein the cancer is associated with cereblon (CRBN) dysfunction.

13. The application as described in claim 9, wherein the cancer is selected from brain cancer, lung cancer, leukemia, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, stomach cancer, colorectal cancer, prostate cancer, pancreatic cancer, urogenital tract cancer, lymphatic system cancer, gastric cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, and combinations thereof.

14. The application as described in claim 13, wherein the lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof; The renal cell carcinoma mentioned above is clear cell renal cell carcinoma; The brain cancer mentioned therein is selected from glioblastoma, medulloblastoma, glioma, and combinations thereof; The bladder cancer mentioned above is urothelial carcinoma of the bladder; The liver cancer mentioned above is a hepatocellular carcinoma; and The blood cancers mentioned therein are 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 lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and combinations thereof.

15. The application as described in claim 9, further comprising the step of administering a therapeutically effective amount of at least one known cancer-treating agent.

16. The application as described in claim 15, wherein the at least one known cancer-treating agent is uracil mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bromoperazine, triethylene melamine, thiamethoxam, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, temozolomide, thiotepa, hexamethylmelamine, methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, bortezomib, vincristine, vinorelbine, vinorelbine, vindesin, bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemetrexed, idarubicin, paclitaxel, docetaxel, ixaspirin, safflower, topotecan, irinotecan. Kang, Deoxymyotrophic Acid, Mitomycin-C, L-Asparaginase, Interferon, Etoposide, Teniposide, 17α-ethynylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoroxymethylene Testosterone, Drotahistone Propionate, Testrolide, Medroxyprogesterone Acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone Acetonide, Chlorestrin, Hydroxyprogesterone, Ammoniaglutide, Estrostine, Methylstilbestrol, Methylstilbestrol Acetate Progesterone, leuprorelin, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, acridine, procarbazine, mitotane, mitoxantrone, levamisole, novibone, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, oxaliplatin, gefitinib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, or combinations thereof.

17. The application of claim 15, wherein the at least one known cancer treatment agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

18. The application as described in claim 17, wherein the DNA methyltransferase inhibitor is 5-aza-2'-deoxycytidine, 5-azacytidine, zablaline, epigallocatechin-3-gallate, procaine, or a combination thereof; The HDAC inhibitors mentioned therein are vorinostat, entinostat, pabistat, trichomycin A, mosetinostat, belistat, danostat, givinostat, tobasistat, plasinostat, derosinostat, quinsinostat, romidesin, valproic acid, AR-42, acetyldinaline, roxilinostat, aspirin, or combinations thereof; The glucocorticoids mentioned therein are dexamethasone, prednisolone, methylprednisolone, betamethasone, triamcinolone, fludrocortisone, beclomethasone, or combinations thereof; The mTor inhibitors mentioned above are BEZ235, everolimus, tesiromolimus, rapamycin, AZD8055, or combinations thereof; and The cytotoxic agent is an alkylating agent, antimetabolite, antitumor antibiotic, mitotic inhibitor, mTor inhibitor, or other chemotherapeutic agent, wherein the other chemotherapeutic agent is selected from anthracycline antibiotics, cytarabine, cladribine, fludarabine, clofarapine, sorafenib, gemtuzumab, oxazolidin, rituximab, or combinations thereof.

19. The application as described in claim 18, wherein the antitumor antibiotic is selected from one or more of doxorubicin, mitoxantrone, bleomycin, daunorubicin, actinomycin D, epirubicin, idarubicin, scintillans, mitomycin, pentostatin, and pentorubicin, or a pharmaceutically acceptable salt thereof. The antimetabolite is selected from one or more of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nerabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, fluorouridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof. The alkylating agent is selected from one or more of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, nitrogen mustard, temozolomide, thiotepa, bendamustine and streptozotocin, or a pharmaceutically acceptable salt thereof. The mitotic inhibitor is selected from one or more of irinotecan, topotecan, rubotecan, cabazitaxel, docetaxel, paclitaxel, etoposide, vincristine, ixaprone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof. The mTor inhibitors mentioned therein are everolimus, sirolimus, tesimolimus, or combinations thereof.

20. The application as described in claim 15, wherein the at least one compound as described in claim 1 and the at least one known cancer treatment agent are administered sequentially or simultaneously.

21. The application of claim 15, wherein the at least one compound of claim 1 and the at least one known cancer treatment agent are co-formulated or co-packaged.

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