Imide-based modulator of proteolysis and associated method of use

Abstract

To provide compounds useful as modulators of targeted ubiquitination, and as inhibitors with respect to a variety of polypeptides and other proteins.SOLUTION: A specific compound has the chemical structure comprising: L-CLM, wherein: L is a linker group; CLM is a cereblon E3 ubiquitin ligase binding moiety; and the linker group is chemically linked to the CLM. Pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates or polymorphs are also provided.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international PCT application claiming the benefit of and priority to U.S. Provisional Application No. 61 / 979,351, filed April 14, 2014, entitled "IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE," which is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference In accordance with 37 CFR §1.52(e), a computer readable form of the sequence listing information has been submitted herewith using PatentIn-3.5 in .txt format with filename: Sequence_Listing_ST25.txt; size 2KB; created on April 14, 2015, and the sequence listing information is hereby incorporated by reference in its entirety.

[0003] FIELD OF THEINVENTION The present description provides imide-based compounds, and bifunctional compounds comprising same, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly with respect to various polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds according to the invention. [Background technology]

[0004] background Most small molecule drugs bind enzymes or receptors in tight, well-defined pockets. Protein-protein interactions, on the other hand, are very difficult to target with small molecules due to the large contact surfaces and shallow grooves or flat interfaces of proteins. E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination and are therefore more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Ligand development for E3 ligases has proven difficult, in part due to the fact that protein-protein interactions must be disrupted. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, additional compounds targeting E3 ligases have been reported, however the field is still developing.

[0005] One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor. VHL contains the substrate recognition subunit / E3 ligase complex VCB, which includes elongins B and C, as well as a complex containing cullin-2 and Rbx1. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the proangiogenic growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low oxygen levels. The inventors have demonstrated that VHL is a novel therapeutic target for cancer, chronic anemia, and ischemia. 2 We have generated the first small molecule von Hippel-Lindau (VHL) ligand for VCB, a substrate recognition subunit of E3 ligase that is a key target of VHL, and obtained a crystal structure that confirmed that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0006] Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologues are highly conserved from plants to humans, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), cullin-4A (CUL4A), and cullin regulatory factor 1 (ROC1). This complex ubiquitinates a number of other proteins. Although the mechanism is not yet fully understood, ubiquitination of target proteins by cereblon leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates a number of developmental processes, such as limb and auditory vesicle formation. The end result is that this ubiquitin ligase complex is important for limb outgrowth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage binding protein.

[0007] Thalidomide has been approved for the treatment of a number of immune conditions, but also for the treatment of certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogs are currently under investigation for use in the treatment of a variety of other types of cancer. Although the exact mechanism of thalidomide's antitumor activity is still being elucidated, it is known to inhibit angiogenesis. Recent publications discussing the biology of this imide compound include Lu et al. Science 343, 305 (2014) (Non-Patent Document 1) and Kronke et al. Science 343, 301 (2014) (Non-Patent Document 2).

[0008] Significantly, thalidomide and its analogs, such as pomalidomide and lenalidomide, are known to bind to cereblon. These agents bind to cereblon and alter the specificity of the complex, inducing the ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for multiple myeloma proliferation. In fact, higher cereblon expression has been associated with greater efficacy of imide drugs in the treatment of multiple myeloma.

[0009] There is a continuing need in the art for effective treatment of diseases, particularly hyperplasia and cancer, such as multiple myeloma.However, non-specific effects and the inability to target and regulate specific classes of proteins, such as transcription factors, ultimately remain barriers to the development of effective anti-cancer drugs.Therefore, small molecule therapeutics that exploit or enhance the substrate specificity of cereblon, while at the same time being "tunable" so that a wide range of protein classes can be specifically targeted and regulated, would be very useful as therapeutics. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Lu et al. Science 343, 305 (2014) [Non-Patent Document 2] Kronke et al. Science 343, 301 (2014) Summary of the Invention

[0011] The present disclosure relates to bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligase for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds as described herein. The advantage of the compounds provided herein is that they are capable of a broad range of pharmacological activity, consistent with selective degradation / inhibition of polypeptides from virtually any protein class or family. The present description also provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of disease conditions such as cancer, e.g., multiple myeloma.

[0012] Thus, in one aspect, the present disclosure provides novel imide-based compounds as described herein.

[0013] In a further aspect, the disclosure provides bifunctional or PROTAC compounds that include an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase ligand or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand or "PTM" group) such that the target protein / polypeptide is placed in close proximity to the ubiquitin ligase resulting in degradation (and inhibition) of the protein. In a preferred embodiment, the ULM is a cereblon E3 ubiquitin ligase binding moiety (i.e., a "CLM"). For example, the structure of a bifunctional compound is as follows: It can be displayed as TIFF2025020416000002.tif10128.

[0014] The respective arrangements of the PTM and CLM moieties as well as their numbers as shown herein are provided by way of example only and are not intended to limit the compounds in any manner. Those skilled in the art will appreciate that bifunctional compounds as described herein can be synthesized with varying numbers and arrangements of the respective functional moieties as desired.

[0015] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this case, the structure of the bifunctional compound is as follows: TIFF2025020416000003.tif10128, in which PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety.

[0016] In certain preferred embodiments, the E3 ubiquitin ligase is cereblon. Thus, in certain further embodiments, the CLM of the bifunctional compound comprises a chemical group such as an imide, amide, thioamide, or thioimide-derived moiety. In further embodiments, the CLM comprises a phthalimide group or an analog or derivative thereof. In yet further embodiments, the CLM comprises a phthalimide glutarimide group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0017] In certain embodiments, a compound as described herein comprises multiple CLMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0018] In a further aspect, the present description provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt thereof and a pharma- ceutically acceptable carrier. The therapeutic composition regulates protein degradation in a patient or subject, e.g., an animal, such as a human, and can be used to treat or ameliorate a disease state or condition that is regulated through degraded proteins. In certain embodiments, the therapeutic composition as described herein can be used to achieve the degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In yet another aspect, the present invention provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein, comprising a CLM and a PTM, preferably linked through a linker moiety, as otherwise described herein, where the CLM is coupled to the PTM, and the CLM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase, such as cereblon), and the PTM recognizes a target protein such that degradation of the target protein occurs when the target protein is placed in close proximity to the ubiquitin ligase, resulting in inhibition of degradation / effect of the target protein and control of protein levels. The control of protein levels afforded by the present invention provides for the treatment of a disease state or condition regulated through a target protein by reducing the level of that protein in the patient's cells.

[0019] In a further aspect, the description provides a method of assessing (i.e., determining and / or measuring) the binding affinity of a CLM. In certain embodiments, the method includes providing a test agent or compound of interest, e.g., an agent or compound having an imide moiety, e.g., a phthalimide group, a phthalimidoglutarimide group, a derivatized thalidomide, a derivatized lenalidomide, or a derivatized pomalidomide, and comparing the cereblon-binding affinity and / or inhibitory activity of the test agent or compound to an agent or compound known to bind to Revlon and / or inhibit the activity of cereblon.

[0020] In yet another aspect, the description provides a method of treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need of such a method a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein, or a salt thereof, together with a pharma- ceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease, disorder, or symptom thereof in the subject.

[0021] In another aspect, the description provides methods of using compounds according to the invention to identify the effect of degradation of a protein of interest in a biological system.

[0022] The above general areas of application are provided by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Further objects and advantages associated with the compositions, methods, and processes of the present invention will become apparent to those skilled in the art in light of the claims, description, and examples. For example, the various aspects and embodiments of the present invention may be utilized in numerous combinations, all of which are expressly contemplated by this description. Such further advantages, objects, and embodiments are expressly included within the scope of the present invention. Literature and other materials used herein are incorporated by reference to illustrate the background of the present invention and, in particular cases, to provide further details regarding the practice of the invention. [Brief description of the drawings]

[0023] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present invention and, together with the description, serve to explain the principles of the invention. The drawings are only for the purpose of illustrating embodiments of the present invention and are not to be construed as limiting the invention. Further objects, features and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings illustrating exemplary embodiments of the invention.

[0024] [Figure 1] Illustrative general principles of PROTAC function. (A) An exemplary PROTAC includes a protein targeting moiety (PTM; dark box), a ubiquitin ligase binding moiety (ULM; light triangle), and an optional linker moiety (L; black line) that couples or links the PTM to the ULM. (B) Illustrative functional use of PROTAC as described herein. Briefly, the ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein to the close proximity of the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin binding protein and catalyzes the attachment of ubiquitin (dark circle) to lysines via isopeptide bonds on the target protein, either alone or via the E2 protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasome machinery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description The following detailed description is provided to assist those skilled in the art in practicing the present invention. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All literature, patent applications, patents, drawings, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0026] Described herein are compositions and methods relating to the unexpected and surprising discovery that an E3 ubiquitin ligase protein, such as cereblon, ubiquitinates a target protein once the E3 ubiquitin ligase protein and the target protein are placed in close proximity by a bifunctional or chimeric construct linking the E3 ubiquitin ligase protein and the target protein. Accordingly, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein target binding moiety ("PTM"), which results in ubiquitination of a selected target protein, resulting in degradation of the target protein by the proteasome (see FIG. 1). The present invention also provides compositions libraries and uses thereof.

[0027] 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 this invention belongs. The terminology used in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0028] Where a range of values ​​is presented, it will be understood that unless the context clearly dictates otherwise (e.g., in the case of a group including a number of carbon atoms, in such cases each number of carbon atoms falling within the range is presented), each value between the upper and lower limit of that range and any other stated or existing value present in that range, to the nearest tenth of the lower limit, is also encompassed within the invention. The upper and lower limits of these narrower ranges may independently be included in the narrower ranges, and the narrower ranges are also encompassed within the invention, subject to any specifically excluded limit in the stated range. When the stated range includes one or both of the limits, ranges that do not include either or both of those included limits are also included in the invention.

[0029] The following terms are used to describe the present invention. If a term is not specifically defined herein, the term is given the art-recognized meaning that would be given to that term by one of ordinary skill in the art who would assign that meaning to the word in the context in which it is used in describing the present invention.

[0030] The articles "a" and "an" are used in this specification and the appended claims, unless the context clearly indicates otherwise, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0031] The phrase "and / or" as used herein and in the appended claims, should be understood to mean "either or both" of the elements so conjoined, i.e., the elements are conjunctive in some cases and disjunctive in other cases. When multiple elements are listed with "and / or," they should be considered in the same manner, i.e., "one or more" of the elements so conjoined. Other elements than the elements specifically identified by the "and / or" clause may optionally be present. That is, by way of example and not of limitation, a statement such as "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to only A (optionally including elements other than B); in another embodiment to only B (optionally including elements other than A); in yet another embodiment to both A and B (optionally including other elements), and so forth.

[0032] As used herein and in the appended claims, "or" should have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, i.e., including at least one of the plurality or recited elements and optionally additional unlisted items, but also including more than one. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of" or, when used in the claims, "consisting of," indicate the inclusion of exactly one element of the plurality or recited elements. In general, the term "or" as used herein should be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") only when preceded by terms of exclusivity, such as "either," "one of," "only one," or "exactly one," etc.

[0033] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are intended to be open-ended, i.e., meaning inclusive of, but not limited to, the object of the phrase. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0034] As used herein and in the appended claims, the phrase "at least one" in connection with a list of one or more elements will understandably refer to at least one element selected from any one or more of the elements in that list of elements, but does not necessarily include at least one of each and every element specifically listed within the list of elements, and does not exclude any combinations of elements in the list of elements. This definition also allows for the phrase "at least one" to optionally include elements other than those specifically identified within such list of elements, whether related or not to the specifically identified elements. That is, by way of example and not limitation, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer, in one embodiment, to at least one A, optionally in multiple instances, and where B is absent (and optionally including elements other than B); in another embodiment, to at least one B, optionally in multiple instances, and where A is absent (and optionally including elements other than A); in yet another embodiment, to at least one A, optionally in multiple instances, and at least one B, optionally in multiple instances (and optionally including other elements), and so forth.

[0035] It will be understood that in particular methods described herein that include multiple steps or acts, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are described, unless the context indicates otherwise.

[0036] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (co-administration of two or more therapeutic agents) and staggered administration (administration of one or more therapeutic agents at a different time than administration of an additional therapeutic agent or agent), so long as the therapeutic agents are present in the patient at the same time, to some extent, preferably in an effective amount. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly an agent including an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

[0037] The term "compound" as used herein, unless otherwise specified, refers to any of the specific chemical compounds disclosed herein, including its tautomers, positional isomers, geometric isomers, and stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), if applicable, as well as its pharma- ceutically acceptable salts and derivatives, including prodrug forms, if applicable in the context. Within the context in which it is used, the term "compound" generally refers to a single compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as mixtures biased toward a particular enantiomer or any enantiomer. The term also refers, in context, to prodrug forms of the compound that have been modified to facilitate administration and delivery of the compound to the site of action. It should be noted that in the description of the compounds, numerous substituents and variables associated therewith are specifically described. It will be appreciated by those of skill in the art that the molecules described herein are stable compounds, as generally described herein. Where bonds are shown, both double and single bonds are represented within the context of the compound shown.

[0038] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to the lysine of the target protein, thereby targeting the specific protein substrate for degradation by the proteasome. That is, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugating enzyme, are responsible for the transfer of ubiquitin to the target protein. In general, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin is attached to the first; a third is attached to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, where only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but instead may change their intracellular location or function, for example, through binding to other proteins that have domains that can bind ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is the lysine used to form polyubiquitin that is recognized by the proteasome.

[0039] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human, or a domestic animal, to which treatment, including prophylactic treatment, with the compositions according to the invention is provided. With respect to the treatment of an infection, condition, or disease state specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domesticated animals such as dogs or cats, or farm animals such as horses, cows, sheep, etc. In general, in the present invention, the term patient refers to a human patient, unless otherwise stated or indicated by the context in which the term is used.

[0040] The term "effective" is used to describe an amount of a compound, composition, or ingredient that, when used in the context of its intended use, produces an intended result. The term effective encompasses all other effective amount or effective concentration terms described or used in any way in this application.

[0041] Compounds and Compositions In one aspect, the present description provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM"), i.e., a cereblon E3 ubiquitin ligase binding moiety ("CLM"). In one embodiment, the CLM has the following structure: (I)L-CLM where L is a chemical linker group and CLM is a cereblon E3 ubiquitin ligase binding moiety. The number and / or relative arrangement of each moiety in the compounds shown herein is provided by way of example only. It will be appreciated by those skilled in the art that compounds as described herein can be synthesized with any number and / or arrangement of each functional moiety as desired.

[0042] The terms ULM and CLM are used in their inclusive sense unless otherwise indicated by the context. For example, the term ULM encompasses all ULMs, including those that bind cereblon (i.e., CLMs). Additionally, the term CLM encompasses all possible cereblon E3 ubiquitin ligase binding moieties.

[0043] In another aspect, the present invention provides bifunctional or multifunctional PROTAC compounds useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compounds include a CLM coupled, directly or indirectly, e.g., covalently, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the CLM and PTM are joined or coupled via a chemical linker (L). The CLM recognizes cereblon E3 ubiquitin ligase, the PTM recognizes the target protein, and the interaction of each moiety with the respective target promotes degradation of the target protein by placing the target protein in close proximity to the ubiquitin ligase protein. Exemplary bifunctional compounds include the following: (II) PTM-CLM It can be shown as follows.

[0044] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound may comprise the following: (III) PTM-L-CLM where PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ligase binding moiety.

[0045] In certain embodiments, a compound as described herein includes multiple PTMs (targeting the same or different proteins), multiple CLMs, one or more ULMs (i.e., moieties that specifically bind to different E3 ubiquitin ligases, e.g., VHL), or combinations thereof. In any of the aspects of the embodiments described herein, the PTMs, CLMs, and ULMs can be coupled directly, via one or more chemical linkers, or combinations thereof. In further embodiments, when a compound has multiple ULMs, the ULMs can be directed to the same E3 ubiquitin ligase, or each ULM can specifically bind to a different E3 ubiquitin ligase. In yet further embodiments, when a compound has multiple PTMs, the PTMs can be directed to the same target protein, or each PTM can specifically bind to a different target protein.

[0046] In another embodiment, the present description provides a compound comprising multiple CLMs coupled directly or via a chemical linker moiety (L). For example, a compound having two CLMs can be (IV) CLM-CLM or (V)CLM-L-CLM It can be shown as follows.

[0047] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are identical. In further embodiments, the compound comprising multiple CLMs further comprises at least one PTM coupled to the CLM directly or via a chemical linker (L) or both. In certain further embodiments, the compound comprising multiple CLMs further comprises multiple PTMs. In yet further embodiments, the PTMs are identical or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0048] In further embodiments, the present description provides compounds comprising at least two different CLMs coupled directly or via a chemical linker (L), or both. For example, such compounds comprising two different CLMs include the following: (VI) CLM-CLM' or (VII)CLM-L-CLM' where CLM' represents a cereblon E3 ubiquitin ligase binding moiety that is structurally distinct from the CLM. In certain embodiments, a compound may comprise multiple CLMs and / or multiple CLM's. In further embodiments, a compound comprising at least two different CLMs, multiple CLMs, and / or multiple CLM's further comprises at least one PTM coupled to the CLM or CLM', either directly or via a chemical linker (L), or both. In any of the embodiments described herein, a compound comprising at least two different CLMs may further comprise multiple PTMs. In still further embodiments, the PTMs are the same or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target. In still further embodiments, the PTM is itself a ULM or CLM (or a ULM' or CLM').

[0049] In preferred embodiments, the CLM comprises a moiety that is a ligand for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM comprises a species derived from the "imide" class of molecules. In certain further embodiments, the CLM comprises a phthalimide group or an analog or derivative thereof. In yet further embodiments, the CLM comprises a phthalimide glutarimide group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0050] In further embodiments, the present description provides compounds as described herein, including their enantiomers, diastereomers, solvates, and polymorphs, as well as their pharma- ceutically acceptable salts, e.g., acid and base salts, as polymorphs.

[0051] Neoimide Compounds In one aspect, the description provides compounds useful for binding to and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures: TIFF2025020416000004.tif129131In formula, W is independently selected from the group: CH2, CHR, C=O, SO2, NH, and N-alkyl; X is independently selected from the group: O, S, and H2; Y is independently selected from the group: NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is independently selected from the group: O and S, or H2, provided that X and Z cannot both be H2; G and G' are independently selected from the following group: H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1-Q4 represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SOR', -SONR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C- NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5, and -OCF3 R' and R'' are independently selected from a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; n is an integer from 1 to 4; TIFF2025020416000005.tif2128 represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains 1 to 4 independent functional groups or atoms.

[0052] Example CLM In any of the compounds described herein, the CLM has a chemical structure selected from the following group: TIFF2025020416000006.tif127128In formula, W is independently selected from the group: CH2, CHR, C=O, SO2, NH, and N-alkyl; X is independently selected from the group: O, S, and H2; Y is independently selected from the group: NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is independently selected from the group: O and S, or H2, provided that X and Z cannot both be H2; G and G' are independently selected from the following group: H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1-Q4 represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SOR', -SONR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C- NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5, and -OCF3 R' and R'' are independently selected from a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; n is an integer from 1 to 4; TIFF2025020416000007.tif2128 represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independent functional groups or atoms, and optionally, one of them is modified to covalently bond to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0053] The term "independently" is used herein to indicate that variables that can be independently assigned a meaning vary independently each time the meaning is assigned.

[0054] The term "alkyl" refers, within its context, to a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical, i.e., an alkyl group, preferably C1-C 10 , more preferably C1-C6, or C1-C3 alkyl groups, which may be substituted. Examples of alkyl groups include, among others, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl groups are terminally capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the invention may be used to covalently bond to dehalogenase enzymes. Such compounds generally have a side chain (often linked through a polyethylene glycol group) that terminates in an alkyl group with a halogen substituent (often chlorine or bromine) at the distal end, resulting in covalent bonding of the compound bearing such moiety to the protein.

[0055] The term "alkenyl" refers to a straight-chain, branched, or cyclic C-C alkyl group having at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radical.

[0056] The term "alkynyl" refers to a straight-chain, branched, or cyclic, C-C alkyl group having at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbon radical.

[0057] The term "alkylene", when used, refers to -(CH) n- group (n is generally an integer from 0 to 6), which may be substituted. When substituted, the alkylene group is preferably substituted at one or more methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain, if otherwise indicated herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (of 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with one halogen group, preferably a chlorine group (preferably, but not limited to, at the distal end of the polyethylene glycol chain). In yet other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as the side chain group of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0058] The term "unsubstituted" is intended to mean substituted with only hydrogen atoms. Where a range of carbon atoms includes C0, it means that the carbon is absent and replaced with H. That is, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, H is present in place of the carbon.

[0059] The term "substituted" or "optionally substituted" is intended to mean, independently (i.e., where multiple substitutions occur, each substituent is independent of another substituent), one or more substituents (up to a maximum of five substituents, preferably up to a maximum of three substituents, often one or two substituents, which may themselves include further substituted substituents, on a given moiety of a compound according to the invention, independently (i.e., where multiple substitutions occur, each substituent is independent of another substituent), at a carbon (or nitrogen) anywhere in a molecule, where the substituents include, for example, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably one, two or three halogens, e.g. trifluoromethyl, especially in alkyl, especially methyl groups), alkyl groups (preferably C1-C2 alkyl, ... 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioethers (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), esters or thioesters (preferably C1-C6 alkyl or aryl), including alkylene esters (wherein the attachment of the substituent is to the alkylene group rather than to the ester functionality, the ester functionality being preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amines (including five- or six-membered cyclic alkylene amines, further including C1-C6 alkyl or aryl, alkylamines or C1-C6 dialkylamines, where the alkyl groups may be substituted with one or two hydroxyl groups) or optionally substituted N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) groups, which may be substituted with a polyethylene glycol chain, which in turn is linked to an alkyl group having one halogen, preferably chlorine, substituent; hydrazines; amides, which are preferably substituted with one or two C1-C6 alkyl groups, where the amides include carboxamides, which may be substituted with one or two C1-C6 alkyl groups; alkanols, preferably C1-C6 alkyl or aryl; or alkanoic acids, preferably C1-C6 alkyl or aryl. Substituents according to the invention can include, for example, -SiR1R2R3 groups, where R1 and R2 are each as described elsewhere herein and R3 is H or a C1-C6 alkyl group, preferably R1, R2, R3 in this context are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly linked to the moiety to be substituted or the substituents may be substituted (CH2). m -, optionally substituted (OCH2) m -, -(OCH2CH2) m- or -(CH2CH2O) m The alkylene group -(CH2) as defined above may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through a - group (which may be substituted with one or more of the above-mentioned substituents). m -or-(CH2) n - groups or other chains such as ethylene glycol chains may be substituted at any position on the chain. Suitable substituents for the alkylene group include halogens, or C1-C6 (preferably C1-C3) alkyl groups, which may be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chain of an amino acid as described elsewhere herein, and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C0-C6 alkyl substituents, which may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, often methyl or O-methyl groups, or the side chain of an amino acid as described elsewhere herein. In the present invention, a moiety in a molecule may be substituted with up to 5 substituents, preferably up to 3. Often, in the present invention, a substituted moiety will be substituted with one or two substituents.

[0060] The term "substituted" (each substituent being independent of any other substituent) is intended to mean, within the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone (including sulfonamide), keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl-substituted amines, which may be substituted with one or two hydroxyl groups). Each of these groups, unless otherwise specified, within the context, has 1 to 6 carbon atoms. In certain embodiments, suitable substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) depending on the context of the use of the substituent. m - (wherein m and n are 1, 2, 3, 4, 5, or 6, in the present specification, in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-RS (R S is C1-C6 alkyl or -(CH2) m -NR1R2 radicals), NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl). R1 ​​and R2 are each, within the context, H or a C1-C6 alkyl radical, which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine. The term "substituted" is also intended to mean, within the chemical context of the compound defined and the substituents used, an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group as described anywhere herein. Alkylene groups may also be substituted as disclosed elsewhere herein, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl being preferred, thus providing a chiral center), the side chain of an amino acid group as described elsewhere herein, an amide group as described hereinabove, or a urethane group O-C(O)-NR1R2 group, where R1 and R2 are as described elsewhere herein, although many other groups can be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or less, preferably one or two. It should be noted that in the case of compounds where molecular substitution at a particular position is required (principally due to valence), but no substitution is indicated, the substitution is assumed or understood to be H, unless otherwise indicated in the context of the substitution.

[0061] The term "aryl" or "aromatic" refers, in context, to a substituted (as described elsewhere herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), which may be attached to a compound according to the invention at any available stable position on the ring, or as otherwise indicated in the presented chemical structure. Other examples of aryl groups, in context, include heteroaromatic ring systems having one or two nitrogen, oxygen, or sulfur atoms in the ring, "heteroaryl" groups, such as (as single rings) imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be substituted as described above.Heteroaryl groups that may be mentioned include nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazoline, sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridooxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be substituted.

[0062] The term "substituted aryl" refers to an aromatic carbocyclic group that consists of at least one aromatic ring or that consists of multiple fused rings, at least one of which is aromatic, and in which the rings are substituted with one or more substituents. For example, an aryl group can contain a substituent selected from the following: -(CH2) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n-C(O)(C0-C6)alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -(CH2) n-OC(O)(C0-C6)alkyl, amines, mono- or di-(C1-C6 alkyl)amines, the alkyl groups of which may be optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups, each of which may be substituted in the ortho-, meta- and / or para-positions of the phenyl ring, preferably in the para-position, optionally substituted phenyls; and / or at least one F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho-, meta- and / or para-positions of the phenyl ring, preferably the para-position), naphthyl group, which may be optionally substituted, optionally substituted heteroaryl, preferably optionally substituted isoxazole, including methyl substituted isoxazole, methyl substituted oxazole, and the like. optionally substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methylimidazole, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oxoimidazoles or methyloxoimidazoles, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl substituted triazole groups, optionally substituted pyridine groups including halo- (preferably F) or methyl substituted pyridine groups or oxapyridine groups (where the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines,and combinations thereof.

[0063] "Carboxyl" refers to the group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where the substituents of these generic names are the same as those defined for the corresponding groups herein.

[0064] The term "heteroaryl" or "hetaryl" refers to an optionally substituted quinoline (which may be attached to or substituted by the pharmacophore at any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted benzimidazole, a benzodiazole, a benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and / or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted (CH m -O-C1-C6 alkyl group or optionally substituted (CH2) m It can refer to, but is not limited in any way to, 1,2,3-triazole substituted with a -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (2-, 3-, or 4-pyridine), or a group depicted in the following chemical structure: TIFF2025020416000008.tif71128In formula, S c is CHR SS , N.R. URE , or O; R HETis H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group, -C≡CR a , where R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl), each of which may be substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which may be substituted, and Y C is N or CR YC where R YCis H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylene group, -C≡CR a , where R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl).

[0065] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both aryl or heteroaryl, respectively, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems in accordance with the definitions above.

[0066] The term "arylalkyl" as used herein refers to an aryl group, as defined above, attached to an alkyl group, as defined above. The arylalkyl group is attached to the parent moiety through the alkyl group, the alkyl group having from 1 to 6 carbon atoms. The aryl group of the arylalkyl group may be optionally substituted as defined above.

[0067] The term "heterocycle" refers to a cyclic group having at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. That is, heteroaryl moieties are included in the definition of heterocycle, depending on the context in which the term is used. Examples of heteroaryl groups are described herein above.

[0068] Examples of heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, among others. aryl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiane.

[0069] Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy nitrogen-containing heterocycles. The term "heterocycle" also includes bicyclic groups in which any of the heterocycles is fused to a benzene or cyclohexane ring or to another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0070] The term "cycloalkyl" can mean, but is not limited in any way to, a monocyclic or polycyclic alkyl group, as defined herein, i.e., a monovalent group derived from a cycloalkane, e.g., a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring, and cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can mean, but is not limited in any way to, a monocyclic or polycyclic alkyl group, substituted with one or more substituents, e.g., amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, etc., and these generic substituents have the same meaning as the definition of the group as defined in this description.

[0071] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, and which bears one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as in the definition of the group as defined in this Description.

[0072] The term "hydrocarbyl" is intended to mean a compound having carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0073] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A, and Rn can be independently covalently linked to a linker and / or a linker attached to one or more PTM, ULM, CLM, or CLM' groups.

[0074] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules resulting from a combination of one or more of the different features shown in the molecules below. TIFF2025020416000009.tif200148TIFF2025020416000010.tif149156TIFF20250204160 00011.tif209156TIFF2025020416000012.tif206155TIFF2025020416000013.tif114140

[0075] Linker Example In certain embodiments, compounds as described herein can be chemically linked or coupled via a chemical linker (L). In certain embodiments, the linker group L is a group that includes one or more covalently connected structural units A (e.g., -A...A q -), where A1 is a group coupled to at least one of a ULM, PTM, or combination thereof. In certain embodiments, A1 directly links a ULM, PTM, or combination thereof to another ULM, PTM, or combination thereof. In other embodiments, A1 links a ULM, PTM, or combination thereof to another ULM, PTM, or combination thereof via A q Indirectly connected through.

[0076] In a particular embodiment, A1 to A q are each independently a bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONRL3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl optionally substituted with a group; R L1 or R L2 can each independently be linked to other A groups to form a cycloalkyl and / or heterocyclyl moiety, which may include 0 to 4 R L5 groups; R L1 , R L2 , R L3 , R L4 , and R L5 are each independently H, halo, or C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 Alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 Alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0077] In certain embodiments, q is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0078] In certain embodiments, for example, when q is greater than 2, A q is a group connecting to a ULM or ULM' moiety, and A and A q are connected via structural unit A (the number of such structural units A is: q-2).

[0079] In certain embodiments, for example, when q is 2, A q is a group connecting A1 and the ULM or ULM′ moiety.

[0080] In certain embodiments, for example, when q is 1, the structure of the linker group, L, is -A1-, where A1 is a group connecting the ULM or ULM' moiety and the PTM moiety.

[0081] In further embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

[0082] In certain embodiments, the linker (L) is: TIFF2025020416000014.tif50128TIFF2025020416000015.tif230147.

[0083] In further embodiments, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, between 1 to about 8 ethylene glycol units and 1 to 6 ethylene glycol units, 2 to 4 ethylene glycol units, or an optionally substituted alkyl group with optionally substituted O, N, S, P, or Si atoms dispersed within the group. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl group. In certain embodiments, the linker may be asymmetric or symmetric.

[0084] In any of the embodiments of the compounds described herein, the linker group can be any suitable group as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0085] Although the CLM (or ULM) and PTM groups can be covalently attached to the linker group through any group that is suitable and stable for the linker chemistry, in preferred embodiments of the invention, the linker is independently covalently attached to the CLM and PTM groups, preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, which may be inserted at any position of the CLM and PTM groups to maximize binding of the CLM group to the ubiquitin ligase and the PTM group to the target protein to be degraded, respectively. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation may be the ubiquitin ligase itself.) In certain preferred embodiments, the linker may be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group of the CLM and / or PTM group.

[0086] Examples of PTMs In a preferred embodiment of the present invention, the PTM group is a group that binds to a target protein. The targets of the PTM group are numerous and are selected from proteins expressed in cells such that at least a portion of the sequence is found in the cell and may bind to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length that can be bound to a PTM group according to the present invention. As described elsewhere herein, any protein of a eukaryotic or microbial system, including a virus, a bacterium, or a fungus, is a target for ubiquitination mediated by the compounds according to the present invention. Preferably, the target protein is a eukaryotic protein. In a particular embodiment, the protein binding moiety is a haloalkane, preferably a C1-C substituted with at least one halo group. 10 The haloalkane is an alkyl group, preferably where the halo group is at the distal end of the alkyl group (i.e., away from the linker or CLM group), and the haloalkane is capable of being covalently attached to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.

[0087] PTM groups according to the present invention include, for example, any moiety that specifically binds to a protein (binds to a target protein), including, by way of example and not limitation, the following small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. The compositions described below exemplify some of the members of these nine classes of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties are linked, preferably through a linker, to a ubiquitin ligase binding moiety for the purpose of bringing the target protein (to which the protein targeting moiety binds) into close proximity to the ubiquitin ligase for ubiquitination and degradation.

[0088] Any protein that can be bound to a protein targeting moiety, i.e., a PTM group, and that can be acted upon or degraded by a ubiquitin ligase, is a target protein according to the present invention. In general, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral function of a cell, including proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolytic, biosynthetic, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipids, Proteins of interest may include proteins involved in the regulation of cell cycles, such as carbohydrates, receptor activity, cell motility, membrane fusion, cell-cell signaling, control of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins associated with cell death, proteins associated with transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity), virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, translation regulator activity. Proteins of interest may include proteins from eukaryotic and prokaryotic organisms, including humans, other animals, including domesticated animals, as targets for drug therapy, microorganisms for the determination of antibiotics and other antimicrobial agents, and plants, and even viruses, among many others.

[0089] In yet other embodiments, the PTM group is a haloalkyl group, which generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, frequently from about 2 to about 10 carbons in length, often from about 3 to about 8 carbons in length, and more often from about 4 to about 6 carbons in length. Haloalkyl groups are generally straight chain alkyl groups (although branched chain alkyl groups can also be used) that are end-capped with at least one halogen group, preferably a single halogen group, and often a single chloride group. Haloalkyl PT groups for use in the present invention preferably have the chemical structure -(CH2) v -halo, where v is any integer from 2 to about 12, often from about 3 to about 8, and more often from about 4 to about 6. Halo can be any halogen but is preferably Cl or Br, and more often is Cl.

[0090] In another embodiment, the present invention provides a library of compounds. The library comprises a plurality of compounds, where each composition has the formula AB, where A is a ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin ligase moiety as disclosed elsewhere herein) and B is a protein binding member of the molecular library, where A is coupled to B (preferably through a linker moiety), and the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein, in particular an E3 ubiquitin ligase, such as cereblon. In certain embodiments, the library contains a particular cereblon E3 ubiquitin ligase binding moiety coupled to a random set of target protein binding elements (e.g., a compound library). In such cases, the target protein is not predetermined, and the method can be used to determine the activity of the putative protein binding element and the pharmacological value of that element as a target for degradation by ubiquitin ligase.

[0091] The present invention may also be used to treat a number of disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and in which degradation of a protein would be beneficial to the patient.

[0092] In a further aspect, the present description provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt thereof, and a pharma- ceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal, such as a human, and treat or ameliorate a disease state or condition that is modulated through degraded proteins. In certain embodiments, the therapeutic composition as described herein can be used to effect degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain further embodiments, the disease is multiple myeloma.

[0093] In an alternative embodiment, the present invention relates to a method of treating or ameliorating a disease state or a symptom of a disease or condition in a subject in need thereof by degrading a protein or polypeptide that regulates the disease state or condition, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one of the compounds as described hereinabove, optionally in combination with a pharma- ceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent, the composition being effective to treat or ameliorate the disease or disorder or its symptom in the subject. The method according to the present invention can be used to treat a large number of disease states or conditions, including cancer, by administering an effective amount of at least one of the compounds described herein. The disease state or condition can be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus, bacteria, fungus, protozoa, or other microorganism, or a disease state caused by protein overexpression that leads to the disease state or condition.

[0094] In another aspect, the description provides methods for identifying the effect of degradation of a protein of interest in a biological system using compounds according to the invention.

[0095] The term "target protein" is used to describe a protein or polypeptide that is a target for binding to a compound according to the invention and degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties are linked to a CLM or ULM group through a linker group, L.

[0096] Target proteins that may be bound to a protein targeting moiety and degraded by a ligase bound to a ubiquitin ligase binding moiety can include any protein or peptide, including fragments, analogs, and / or congeners thereof. Target proteins include proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signaling functions or activities. In certain embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integrated function of a cell, including proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity, and the like. Proteins of interest may include proteins involved in synthesis activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell-cell signaling, control of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins associated with cell death, proteins associated with transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity), virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biosynthesis activity, translation regulator activity. Proteins of interest may include proteins from eukaryotic and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, including humans, microorganisms, viruses, fungi, and parasites, among others, as targets for drug therapy, including humans, other animals, including domesticated animals, microorganisms for the evaluation of antibiotics and other antimicrobial agents, and plants, and even viruses, among others, as targets for drug therapy.

[0097] More specifically, numerous proteins as drug targets for human therapeutics provide protein targets that may be conjugated with protein targeting moieties and incorporated into compounds according to the invention. These proteins include those that can be used to restore function in a number of polygenic diseases, such as B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV1 protease, HIV1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38MAP kinase, Ras1Raf1MEWERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha-reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide These include acetylcholinesterase and receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA or NGF receptor, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Still further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate phosphate synthase.

[0098] Haloalkane dehalogenase enzymes are another target for certain compounds according to the invention. Compounds according to the invention having a chloroalkane peptide binding moiety (C1-C12, often about C2-C10 alkyl halo group) can be used to inhibit and / or degrade haloalkane dehalogenase enzymes used in fusion proteins or related diagnostic proteins, as described in PCT / US2012 / 063401, filed December 6, 2011, and published June 14, 2012 as WO2012 / 078559, the contents of which are incorporated herein by reference.

[0099] These various protein targets can be used in screens to identify compound moieties that bind to the protein, and by incorporating such moieties into compounds according to the invention, the activity level of the protein can be altered for therapeutic end results.

[0100] "Protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein of interest or other protein or polypeptide, placing / bringing the protein or polypeptide in close proximity to a ubiquitin ligase so that protein or polypeptide degradation by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. The compositions described below exemplify some of the members of these nine classes of small molecule target proteins.

[0101] Examples of protein targeting moieties according to the present disclosure include haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0102] The compositions described below exemplify some of the members of these classes of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharma- ceutically acceptable salts, enantiomers, solvates, and polymorphs of the compositions, as well as other small molecules that may target proteins of interest. The references described herein below are incorporated herein by reference in their entirety.

[0103] I. Heat Shock Protein 90 (HSP90) Inhibitors: HSP90 inhibitors, as used herein, include, but are not limited to, the following:

[0104] 1. HSP90 inhibitors as defined in Vallee, et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone", (2011) J. Med. Chem. 54:7206, including YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide): TIFF2025020416000016.tif50128, where derivatization is performed such that a linker group L or -(L-CLM) group is attached, for example, via a terminal amide group.

[0105] 2. HSP90 inhibitor p54 (modified form) (8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine): TIFF2025020416000017.tif40128In this case the linker group L or -(L-CLM) group is attached, for example, via the terminal acetylene group.

[0106] 3. HSP90 inhibitors (modified forms) identified in Brough, et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J. MED. CHEM. vol:51, pag:196 (2008), including the compound 2GJ (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide) having the following structure: TIFF2025020416000018.tif53128 is included, where the derivatization involves a linker group L or -(L-CLM) group being attached, for example, via an amide group (at the amine or at the alkyl group of the amine).

[0107] 4. HSP90 inhibitors (modified forms) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the following structure: TIFF2025020416000019.tif37128 is included, where the linker group L or -(L-CLM) group is attached, for example, via a butyl group.

[0108] 5. The HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] (derivatives of) or any of its derivatives (e.g. 17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")) (derivatized where a linker group L or -(L-CLM) group is attached, for example, via an amide group).

[0109] II. Kinase and phosphatase inhibitors: Kinase inhibitors as used herein include, but are not limited to:

[0110] 1. Erlotinib derivative tyrosine kinase inhibitors: TIFF2025020416000020.tif31128 where R is, for example, a linker group L attached via an ether group or a -(L-CLM) group.

[0111] 2. Kinase inhibitor sunitinib (derivative): TIFF2025020416000021.tif32128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached via a pyrrole moiety).

[0112] 3. Kinase inhibitor sorafenib (derivatives): TIFF2025020416000022.tif24128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached via an amide moiety).

[0113] 4. Kinase inhibitor Dasatinib (derivative): TIFF2025020416000023.tif42128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached to a pyrimidine).

[0114] 5. Kinase inhibitor Lapatinib (derivative): TIFF2025020416000024.tif46128 (derivatized where a linker group L or -(L-CLM) group is attached, for example, via the terminal methyl of a sulfonylmethyl group).

[0115] 6. Kinase inhibitor U09-CX-5279 (derivative): In the TIFF2025020416000025.tif45128 derivatization, a linker group L or -(L-CLM) group is attached, for example, via an amine (aniline), a carboxylic acid, or an amine alpha to the cyclopropyl group, or a cyclopropyl group.

[0116] 7. Kinase inhibitors identified in Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease, J. MED. CHEM. vol:54, page:7797(2011), including kinase inhibitors Y1W and Y1X (derivatives thereof) having the following structures: TIFF2025020416000026.tif44128 contains YIX (1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea For derivatization, the linker group L or the -(L-CLM) group may be, for example: i Attached via a propyl group; TIFF2025020416000027.tif48128YIW 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea For derivatization, the linker group L or -(L-CLM) group is, for example, preferably attached via either an i-propyl group or a t-butyl group.

[0117] 8. Kinase inhibitors identified in Schenkel, et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibotors J. Med. Chem., 2011, 54(24), pp 8440-8450, including compounds 6TP and 0TP (derivatives) having the following structures: TIFF2025020416000028.tif351286TP 4-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide Thienopyridine Compound 19 In the derivatization, a linker group L or -(L-CLM) group is attached, for example, via a terminal methyl group attached to an amide moiety; TIFF2025020416000029.tif351280TP 4-Amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide Thienopyridine Compound 8 In the derivatization, a linker group L or a -(L-CLM) group is attached, for example, via a terminal methyl group attached to the amide moiety.

[0118] 9. Kinase inhibitors identified in Van Eis, et al., “2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes”, Biorg. Med. Chem. Lett. 2011 Dec 15;21(24):7367-72, including kinase inhibitor 07U having the following structure: TIFF2025020416000030.tif4212807U 2-Methyl-N~1~-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine where the linker group L or -(L-CLM) group is attached, for example, via a secondary amine or a terminal amino group.

[0119] 10. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J. STRUCT. BIOL. vol:176, pag:292 (2011), including the kinase inhibitor YCF having the following structure: TIFF2025020416000031.tif23128, where derivatization involves a linker group L or a -(L-CLM) group being attached, for example, via either of the terminal hydroxyl groups.

[0120] 11. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J. STRUCT. BIOL. vol:176, pag:292 (2011), including the kinase inhibitors XK9 and NXP (derivatives thereof) having the following structures: TIFF2025020416000032.tif28128XK9 N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide; TIFF2025020416000033.tif58128NXP N-{4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide where the derivatization involves a linker group L or a -(L-CLM) group being attached, for example, via either the terminal hydroxyl group (XK9) or hydrazone group (NXP).

[0121] 12. Kinase inhibitor afatinib (derivative of) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide) (derivatized where a linker group L or -(L-CLM) group is attached, for example, via an aliphatic amine group).

[0122] 13. Kinase inhibitor fostamatinib (derivative of) ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl dihydrogen phosphate hexahydrate) (derivatized in which a linker group L or a -(L-CLM) group is attached, for example, via a methoxy group).

[0123] 14. Kinase inhibitor gefitinib (derivative) (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine): TIFF2025020416000034.tif32128 (derivatized where the linker group L or -(L-CLM) group is attached, for example, via a methoxy or ether group).

[0124] 15. Kinase inhibitor lenvatinib (derivative of) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide) (derivatized in which the linker group L or the -(L-CLM) group is attached, for example, via the cyclopropyl group).

[0125] 16. Kinase inhibitor Vandetanib (derivative of) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized where a linker group L or -(L-CLM) group is attached, for example, via a methoxy or hydroxyl group).

[0126] 17. The kinase inhibitor Vemurafenib (derivative of) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide) (derivatized in which the linker group L or the -(L-CLM) group is attached, for example, via a sulfonylpropyl group).

[0127] 18. Kinase inhibitor Gleevec (derivative): TIFF2025020416000035.tif40128 (derivatized where R is attached as a linker group L or a -(L-CLM) group, for example, via an amide group or via an aniline amine group).

[0128] 19. Kinase inhibitor pazopanib (derivative) (VEGFR3 inhibitor): TIFF2025020416000036.tif37128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached to the phenyl moiety or via an aniline amine group).

[0129] 20. Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor TIFF2025020416000037.tif33128 (where R is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety).

[0130] 21. Kinase inhibitor TAE684 (derivative) ALK inhibitor TIFF2025020416000038.tif38128 (where R is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety).

[0131] 22. Kinase inhibitor Nilotinib (derivative) Abl inhibitor: TIFF2025020416000039.tif43128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached to the phenyl moiety or to the aniline amine group).

[0132] 23. Kinase inhibitor NVP-BSK805 (derivative) JAK2 inhibitor TIFF2025020416000040.tif48128 (derivatized where R is a linker group L or -(L-CLM) group, for example, attached to a phenyl moiety or a diazole group).

[0133] 24. Kinase inhibitors Crizotinib derivatives Alk inhibitors TIFF2025020416000041.tif53128 (derivatized where R is a linker group L or -(L-CLM) group, for example, attached to a phenyl moiety or a diazole group).

[0134] 25. Kinase inhibitors JNJ FMS (derivatives) inhibitors TIFF2025020416000042.tif39128 (derivatized where R is, for example, a linker group L or a -(L-CLM) group attached to the phenyl moiety).

[0135] 26. Kinase inhibitor Foretinib (derivative) Met inhibitor TIFF2025020416000043.tif36128 (derivatized where R is a linker group L or -(L-CLM) group, for example, attached to a hydroxyl or ether group of the phenyl or quinoline moiety).

[0136] 27. Allosteric protein tyrosine phosphatase inhibitors PTP1B (derivatives): In the TIFF2025020416000044.tif59128 derivatization, a linker group L or -(L-CLM) group is attached, for example, at R, as shown.

[0137] 28. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatives): In the TIFF2025020416000045.tif45128 derivatization, a linker group L or a -(L-CLM) group is attached, for example, at R.

[0138] 29. BRAF (BRAF V600E ) / MEK inhibitors (derivatives): In the TIFF2025020416000046.tif41128 derivatization, a linker group L or a -(L-CLM) group is attached, for example, at R.

[0139] 30. Inhibitors (or derivatives) of tyrosine kinase ABL In the TIFF2025020416000047.tif39128 derivatization, a linker group L or a -(L-CLM) group is attached, for example, at R.

[0140] 31. Kinase inhibitor OSI-027 (derivative) mTORC1 / 2 inhibitor In the TIFF2025020416000048.tif63128 derivatization, a linker group L or a -(L-CLM) group is attached, for example, at R.

[0141] 32. Kinase inhibitor OSI-930 (derivative) c-Kit / KDR inhibitor In the TIFF2025020416000049.tif72128 derivatization, a linker group L or a -(L-CLM) group is attached, for example, at R.

[0142] 33. Kinase inhibitor OSI-906 (derivative) IGF1R / IR inhibitor In the derivatization, a linker group L or -(L-CLM) group is attached, for example, at R; (in the derivatization, "R" designates the site of attachment of the linker group L or -(L-CLM) group on the piperazine moiety).

[0143] III.HDM2 / MDM2 inhibitors: HDM2 / MDM2 inhibitors, as used herein, include, but are not limited to, the following:

[0144] 1. HDM2 / MDM2 inhibitors as identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004), and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, which include (or are in addition to) the compounds nutlin-3, nutlin-2, and nutlin-1 (derivatives), and derivatives and analogs thereof, as set forth below: TIFF2025020416000051.tif52128 (derivatized where a linker group L or -(L-CLM) group is attached, for example, at a methoxy group or as a hydroxyl group); TIFF2025020416000052.tif46128 (derivatized where a linker group L or -(L-CLM) group is attached, for example, at a methoxy or hydroxyl group); TIFF2025020416000053.tif52128 (derivatized where a linker group L or -(L-CLM) group is attached, for example, via a methoxy group or as a hydroxyl group).

[0145] 2. Trans-4-Iodo-4'-boranyl-chalcone TIFF2025020416000054.tif27128 (derivatized where a linker group L or -(L-CLM) group is attached, for example, via a hydroxyl group).

[0146] IV. Compounds targeting human BET bromodomain-containing proteins: Compounds that target human BET bromodomain-containing proteins include, but are not limited to, compounds that relate to the target as described below, where "R" designates the attachment site for the linker group L or -(L-CLM) group.

[0147] 1.JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010). TIFF2025020416000055.tif33128

[0148] 2.I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains. J. Med Chem. (2011). TIFF2025020416000056.tif37128

[0149] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770. TIFF2025020416000057.tif34128

[0150] 4.I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion leukemia. Nature(2011): TIFF2025020416000058.tif53128 (wherein R designates in each case, for example, the attachment site of the linker group L or of the -(L-CLM) group).

[0151] V. HDAC Inhibitors: HDAC inhibitors (derivatives) include, but are not limited to:

[0152] 1.Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999). TIFF2025020416000059.tif35128 (wherein derivatization "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group).

[0153] 2. Compounds as defined in formula (I) of PCT WO0222577 ("DEACETYLASE INHIBITORS") (derivatized where a linker group L or -(L-CLM) group is attached, for example, via a hydroxyl group).

[0154] VI. Human Lysine Methyltransferase Inhibitors: Human lysine methyltransferase inhibitors include, but are not limited to:

[0155] 1.Chang et al. Structural Basis for G9a-Like protein Lysine Methyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16(3) 312. TIFF2025020416000060.tif41128 (wherein derivatization "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group).

[0156] 2.Liu, F. et al. Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Methyltransferase G9a. J. Med. Chem. (2009) 52(24) 7950. TIFF2025020416000061.tif39144 (wherein derivatization "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group).

[0157] 3. Azacitidine (derivatives of) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (derivatized where a linker group L or -(L-CLM) group is attached, for example, via the hydroxyl or amino group).

[0158] 4. Decitabine (derivatives of) (4-amino-1-(2-deoxy-bD-erythropentofuranosyl)-1,3,5-triazin-2(1H)-one) (derivatized where a linker group L or -(L-CLM) group is attached, for example, either via the hydroxyl group or at the amino group).

[0159] VII. Angiogenesis inhibitors: Angiogenesis inhibitors include, but are not limited to:

[0160] 1. GA-1 (derivatives) and their derivatives and analogs having the structure as described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec;2(12):1350-8, and linked to a linker.

[0161] 2. Estradiol (derivatives) which may be attached to a linker group L or a -(L-CLM) group, as generally described in Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211.

[0162] 3. Estradiol, testosterone (derivatives), and related derivatives, including but not limited to DHT and its derivatives and analogs, having a structure generally as described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12):1350-8, and attached to a linker group L or a -(L-CLM) group.

[0163] 4. Ovalicin, fumagillin (derivatives), and derivatives and analogs thereof having structures generally as described in Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and U.S. Pat. No. 7,208,157, and linked to a linker group L or -(L-CLM) group.

[0164] VIII. Immunosuppressive compounds: Immunosuppressant compounds include, but are not limited to:

[0165] 1. AP21998 (derivatives) having a structure generally as described in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754 and attached to a linker group L or a -(L-CLM) group.

[0166] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (derivatized with a linker group L or -(L-CLM) group, e.g., attached to either the hydroxyl) and beclomethasone dipropionate (derivatized with a linker group L or -(L-CLM) group, e.g., attached to the propionic acid group).

[0167] 3. Methotrexate (derivatized with a linker group L or -(L-CLM) group attached, for example, to either of the terminal hydroxyls).

[0168] 4. Cyclosporine (derivatized, either the linker group L or the -(L-CLM) group can be attached, for example, at the butyl group).

[0169] 5. Tacrolimus (FK-506) and rapamycin (derivatized, where a linker group L or -(L-CLM) group can be attached, for example, at one of the methoxy groups).

[0170] 6. Actinomycin (derivatized, the linker group L or the -(L-CLM) group can be attached, for example, at one of the isopropyl).

[0171] IX. Compounds targeting the aryl hydrocarbon receptor (AHR): Compounds that target the aryl hydrocarbon receptor (AHR) include, but are not limited to:

[0172] 1. Apigenin (derivatized with a linker group L or -(L-CLM) group in a manner generally as described in Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007).

[0173] 2. SR1 and LGC006 (derivatized to attach a linker group L or -(L-CLM)) as described in Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol. 329 no.5997 pp. 1345-1348.

[0174] X. Compounds that target the RAF receptor (kinase): TIFF2025020416000062.tif49128 (derivatized, e.g., where "R" designates the site of attachment of a linker group L or a -(L-CLM) group).

[0175] XI. Compounds targeting FKBP: TIFF2025020416000063.tif64128 (derivatized, e.g., where "R" designates the site of attachment of a linker group L or a -(L-CLM) group).

[0176] XII. Compounds targeting the androgen receptor (AR) 1. RU59063 Ligand (Derivative) of the Androgen Receptor TIFF2025020416000064.tif29128 (derivatized, e.g., where "R" designates the site of attachment of a linker group L or a -(L-CLM) group).

[0177] 2. Androgen receptor SARM ligands (or derivatives) TIFF2025020416000065.tif29128 (derivatized, e.g., where "R" designates the site of attachment of a linker group L or a -(L-CLM) group).

[0178] 3. Androgen receptor ligand DHT (and its derivatives) TIFF2025020416000066.tif35128 (derivatized, e.g., where "R" designates the site of attachment of a linker group L or a -(L-CLM) group).

[0179] 4. MDV3100 Ligand (Derivative) TIFF2025020416000067.tif22128

[0180] 5. ARN-509 Ligand (Derivatives) TIFF2025020416000068.tif22128

[0181] 6. Hexahydrobenzisoxazole TIFF2025020416000069.tif22128

[0182] 7. Tetramethylcyclobutane TIFF2025020416000070.tif28128

[0183] XIII. Compounds targeting the estrogen receptor (ER) ICI-182780 1. Estrogen receptor ligands TIFF2025020416000071.tif28128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group).

[0184] XIV. Compounds targeting the thyroid hormone receptor (TR) 1. Thyroid hormone receptor ligands (or derivatives) TIFF2025020416000072.tif62128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group, and MOMO denotes a methoxymethoxy group).

[0185] XV. Compounds that target the HIV protease 1. HIV protease inhibitors (derivatives) TIFF2025020416000073.tif24128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0186] 2. HIV protease inhibitors TIFF2025020416000074.tif34128 (derivatized where "R" designates the potential site of attachment of a linker group L or a -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0187] XVI. Compounds targeting HIV integrase 1. HIV integrase inhibitors (derivatives) TIFF2025020416000075.tif49128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0188] 2. HIV integrase inhibitors (derivatives) TIFF2025020416000076.tif47128

[0189] 3. HIV integrase inhibitor Isentress (derivative) TIFF2025020416000077.tif31128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0190] XVII. Compounds targeting HCV protease 1. HCV protease inhibitors (derivatives) TIFF2025020416000078.tif70128 (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group).

[0191] XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 and APT2) 1. APT1 and APT2 inhibitors (or derivatives) TIFF2025020416000079.tif52128 (derivatized, "R" designates the site of attachment of a linker group L or -(L-CLM) group). See Angew. Chem. Int. Ed. 2011, 50, 9838-9842, where L is a linker group as described anywhere herein and the CLM group is as described anywhere herein such that -(L-CLM) attaches the CLM group to a PTM group as described anywhere herein.

[0192] therapeutic composition A pharmaceutical composition comprising an effective amount of at least one bifunctional compound as described herein, and one or more compounds described anywhere herein, all in effective amounts, together with a pharma- ceutical effective amount of a carrier, excipient, or diluent is a further aspect of the present disclosure.

[0193] The present disclosure includes, where applicable, compositions comprising pharma- ceutically acceptable salts, particularly acid or base addition salts, of the compounds as described herein. The acids used to prepare the pharma- ceutically acceptable acid addition salts of the above-mentioned basic compounds useful according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)] salts, among many others.

[0194] Pharmaceutically acceptable base addition salts can also be used to generate pharma-ceutically acceptable salts of the compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents to prepare pharma-ceutically acceptable base salts of the compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine-(meglumine), and lower alkanolammonium and other base salts of pharma-ceutically acceptable organic amines.

[0195] The compounds as described herein can be administered in single or divided doses by oral, parenteral, or topical routes according to the present disclosure. Administration of the active compounds can range from continuous administration (intravenous drip) to multiple oral doses per day (e.g., QID), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include a penetration enhancer), buccal, sublingual, and suppository administration, among other routes of administration. Enteric coated oral tablets can also be used to improve the bioavailability of the compounds from oral routes of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected as well as the severity of the patient's disease. Administration of the compounds according to the present disclosure as sprays, mists, or aerosols for nasal, intratracheal, or pulmonary administration can also be used. Thus, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of the compounds as described herein, optionally in combination with a pharmacologic carrier, additive, or excipient. The compounds according to the present disclosure may be administered in immediate release, intermediate release, or sustained or controlled release dosage forms.Sustained or controlled release dosage forms are preferably administered orally, but also in suppositories and transdermal or other topical dosage forms.Intramuscular injection in liposomal form can also be used to control or sustain the release of the compound at the injection site.

[0196] The composition as described herein can be formulated in a conventional manner with one or more pharmacologic acceptable carriers, and can also be administered as controlled release formulations.The pharmacologic acceptable carriers that can be used in such pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid compounds, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0197] The compositions as described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an indwelling reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0198] Sterile injectable forms of the compositions as described herein may be aqueous or oleaginous suspensions. Such suspensions can be formulated by techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions using a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful for the preparation of injectables, as are natural pharma-ceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated variants. Such oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[0199] The pharmaceutical composition as described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or liquids.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically used.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When oral aqueous suspensions are required, active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavors or colorants can also be added.

[0200] Alternatively, the pharmaceutical composition as described herein may be administered in the form of a suppository for rectal administration. Suppositories can be prepared by mixing the active agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0201] The pharmaceutical composition as described herein may be administered externally.Suitable external formulations are easily prepared for each of these regions or organs.External administration for the lower intestinal tract can be achieved by rectal suppository formulation (see above) or by suitable enema formulation.Externally acceptable transdermal patches can also be used.

[0202] For external formulation, pharmaceutical composition can be formulated as suitable ointment, containing active ingredient suspended or dispersed in one or more carriers.External administration carrier of the compound of the present invention includes, but is not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In certain preferred embodiments of the present invention, the compound can be coated on the stent that is to be surgically implanted in a patient, to prevent or reduce the possibility of the stent causing blockage in the patient.

[0203] Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active component suspended or dispersed in one or more pharma- ceutically acceptable carriers, including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0204] For ophthalmic applications, the pharmaceutical compositions can be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, sterile saline, with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutical compositions can be formulated in an ointment, such as petrolatum.

[0205] Pharmaceutical compositions as described herein may also be administered by nasal aerosol, i.e., inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0206] Pharmaceutical compositions as described herein may be combined with carrier materials to produce a single dosage form, although the amount of compound in such compositions will vary depending on the host and the disease being treated, and the particular mode of administration. Preferably, the compositions will be formulated to contain about 0.05 milligrams to about 750 milligrams or more of active ingredient, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams, either alone or in combination with at least one other compound according to the present invention.

[0207] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, concomitant medications, as well as the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0208] A patient or subject in need of treatment using a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the invention, including a pharma- ceutically acceptable salt, solvate, or polymorph thereof, optionally in addition to a pharma- ceutically acceptable carrier or diluent, either alone or in combination with other known erythropoiesis stimulating agents as identified elsewhere herein.

[0209] These compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically (including transdermal routes in liquid, cream, gel, or solid form), or in aerosol form.

[0210] The active compound is included in a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing serious toxic effects in the patient being treated. Suitable doses of the active compound for all of the conditions described herein range from about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more typically 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical dosages will be in the range of 0.01 to 5% wt / wt in a suitable carrier.

[0211] The compounds may be conveniently administered in any suitable unit dosage form, including, but not limited to, those containing less than 1 mg, from 1 mg to 3000 mg, preferably from 5 to 500 mg, of active ingredient per unit dosage form. An oral dosage of about 25 to 250 mg is often convenient.

[0212] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable to provide an effective plasma concentration of the active ingredient.

[0213] The concentration of the active compound in the drug composition will depend on the absorption rate, distribution rate, inactivation rate, and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary with the severity of the symptoms to be alleviated. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once or divided into multiple smaller doses administered at various intervals.

[0214] Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivatives can be combined with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition.

[0215] Tablets, pills, capsules, troches, etc. may contain any of the following ingredients, or compounds of similar nature: binders, such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients, such as starch or lactose; dispersing agents, such as alginic acid, primogel, or corn starch; lubricants, such as magnesium stearate or sterote; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, the capsule may contain, in addition to materials of the above type, a liquid carrier, such as fatty oils. Dosage unit forms may also contain various other materials which modify the physical form of the dosage form, such as sugar coatings, shellac, or enteric agents.

[0216] The active compound or its pharma- ceutically acceptable salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent, and may also contain preservatives, dyes and colorings, and flavorings.

[0217] The active compounds or pharma- ceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as erythropoietin stimulating agents, including, among others, EPO and darbepoetin alfa.In certain preferred embodiments of the invention, one or more compounds according to the invention are co-administered with another bioactive agent, such as an erythropoietin stimulating agent, or a wound healing agent, including antibiotics, as described elsewhere herein.

[0218] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical administration can contain the following components: a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and agents for adjusting isotonicity, such as sodium chloride or glucose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0219] If administered intravenously, suitable carriers are physiological saline or phosphate buffered saline (PBS).

[0220] In one embodiment, the active compound is formulated with a carrier that protects the compound against rapid elimination from the body, such as a controlled release formulation, including implantable and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.

[0221] Liposomal suspensions can also be pharma- ceutically acceptable carriers. Liposomal suspensions can be prepared according to methods known to those skilled in the art, such as those described in US Pat. No. 4,522,811, which is incorporated herein by reference in its entirety. For example, liposomal formulations can be prepared by dissolving suitable lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidonoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, and then evaporating the inorganic solvent to leave the lipids as a thin film of dry lipids on the surface of the container. An aqueous solution of active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0222] Treatment method In a further aspect, the present description provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt thereof and a pharma- ceutically acceptable carrier, the therapeutic composition modulates protein degradation in a patient or subject, e.g., an animal, such as a human, and can thus be used to treat or ameliorate a disease or condition modulated through degraded proteins.

[0223] The terms "treat", "treating" and "treatment" as used herein refer to any action that benefits a patient to whom the compounds may be administered, including the treatment of any disease state or condition that is modulated through the protein to which the compounds bind. Disease states or conditions that can be treated using the compounds according to the invention are described herein above, including cancer.

[0224] The present description provides a therapeutic composition as described herein for effecting the degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain further embodiments, the disease is multiple myeloma. Thus, in another aspect, the present description provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, the bifunctional compound including, e.g., a CLM and a PTM, as described anywhere herein, linked, preferably through a linker moiety, in which the CLM is coupled to the PTM, such that degradation of the target protein occurs when the target protein is placed in close proximity to the ubiquitin ligase, resulting in degradation / inhibition of the effect of the target protein and control of the protein level, and the CLM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase, e.g., cereblon, etc.), and the PTM recognizes the target protein. The control of protein levels provided by the present invention provides for the treatment of disease states or conditions regulated through a target protein by lowering the target protein levels in a cell, e.g., in a patient's cells. In certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including a pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0225] In a further embodiment, the description provides a method of treating or ameliorating a disease, disorder, or a symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need of such a method a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein, or a salt thereof, and a pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder, or a symptom thereof, in the subject.

[0226] In another aspect, the description provides methods of using compounds according to the invention to identify effects of degradation of a protein of interest in a biological system.

[0227] In another embodiment, the invention relates to a method of treating a human patient in need of modulation of a disease state or condition through a protein, where degradation of the protein provides a therapeutic benefit to the patient, comprising administering to a patient in need thereof an effective amount of a compound according to the invention, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial pathogen or other exogenous pathogen, such as a virus, bacteria, fungus, protozoa, or other microorganism, or may be a disease state caused by overexpression of a protein leading to the disease state and / or condition.

[0228] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and in which degradation of one or more proteins in the patient may result in beneficial treatment or alleviation of the condition in a patient in need of such treatment or alleviation. In certain cases, the disease state or condition may be cured.

[0229] Disease states or conditions which may be treated using the compounds of the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0230] Further disease states or conditions treatable by the compounds according to the invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, diabetes mellitus type 1, diabetes mellitus type 2, epilepsy, Guillain-Barre syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, and vasculitis.

[0231] Still further disease states or conditions treatable with the compounds according to the invention include, inter alia, aceruloplasminemia, type II achondroplasia, achondroplasia, acral cephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitors, Emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary enamel imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple joint laxity (Ehlers-Danlos syndrome #joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyrus nematoid skin syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease) ), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-a-cat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypoparathyroidism, chondrodystrophy (achondroplasia), otospondylomegalyepphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal skeletal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(Familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagen diseases, conotruncal dysfacies syndrome, Cooley anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden's disease, craniofacial dysostosis (Cruzon's disease), Creutzfeldt-Jakob disease (prion disease), Cockayne's syndrome, Cowden's disease, Curschmann-Batten-Steinert syndrome (myotonic dystrophy) ), Beare-Stevenson gyrate cutis syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophies, neurodegenerative disorders including Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, deGrouchy syndrome and Dejerine-Sottas disease, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down's syndrome, short stature, erythropoietic proprotein Toporphyria, Erythrocyte 5-aminolevulinic acid synthase deficiency, Erythropoietic porphyria, Erythropoietic protoporphyria, Erythropoietic uroporphyria, Friedreich's ataxia, Familial paroxysmal polyserositis, Porphyria cutanea tarda, Familial neuropathy with liability to pressure palsies, Primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, Fragile X syndrome, Galactosemia, Hereditary encephalopathy, Giant cell hepatitis (neonatal hemochromatosis), Glenn-Blood-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria) , hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disorders including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia,Lacunar dementia, Langer-Sardino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, Polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Larbhardt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoelastosis) xanthomas), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, Sarcoma, Breast, Leukemia, and Adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis complex), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia, Strud wick type), Spondyloepiphyseal dysplasia congenita (SEDc) SEMD, Strudwick type (Spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), Infantile-onset ascending hereditary spastic paralysis, Speech and communication disorders, Sphingolipidosis, Tay-Sachs disease, Spinocerebellar ataxia, Stickler syndrome, Stroke, Androgen insensitivity syndrome, Tetrahydrobiopterin deficiency, Beta-thalassemia, Thyroid disease,These include sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo-X syndrome (Triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik's disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum.

[0232] The term "neoplasm" or "cancer" is used throughout this specification to refer to the pathological process that results in the formation and growth of cancerous or malignant neoplasms, i.e., abnormal tissue that grows by cellular proliferation, grows faster than normal, and continues to grow after stimuli that cause new growth cessation. Malignant neoplasms lack some or all structural organization and functional coordination with normal tissue, primarily invade surrounding tissues, metastasize to multiple sites, are likely to recur after attempted removal, and are likely to cause death to the patient if not treated appropriately. As used herein, the term neoplasm is used to describe all cancerous disease states and encompasses or includes the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Examples of cancers that may be treated with the present compounds, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, capsular sarcoma, and sarcomas of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach. Cancer types include, but are not limited to, sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, spinal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Further cancers treatable using the compounds according to the invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0233] The term "biologically active agent" is used to describe an agent, other than a compound according to the invention, that is used in combination with the present compounds as an agent having biological activity that assists in achieving the intended treatment, inhibition and / or prevention / prophylaxis for which the present compounds are used. Biologically active agents suitable for use herein include agents that have pharmacological activity similar to the activity for which the present compounds are used or administered, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, anti-microbial agents, anti-fungal agents, and the like.

[0234] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be used in combination with a compound according to the present invention for the treatment of cancer. Such agents include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, ba Talanib, AG-013736, AVE-0005, Goserelin acetate, Leuprolide acetate, Triptorelin pamoate, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Megestrol acetate, Raloxifene, Bicalutamide, Flutamide, Nilutamide, Megestrol acetate, CP-724714; TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Lonafarnib, BMS-214662, Tipifarnib ;Amifostine, NVP-LAQ824, Suberoylanilide hydroxamic acid, Valproic acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Amsacrine, Anagrelide, L-Asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, Adriamycin, Bleomycin, Buserelin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Clodronate, Cyproterone, Cytarabine, Dacarbazine, Dactinomycin, Daunorubicin, Diazepam, Ethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed,Rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, ibuprofen Interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor , zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,All-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, erwinia asparaginase, strontium-89, casopitant, netupitant, NK -1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0235] The term "anti-HIV agent" or "additional anti-HIV agent" includes, among others, e.g., nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., not representative of the present invention), protease inhibitors, fusion inhibitors, exemplary compounds of which include, among others, e.g., 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC, Fusion inhibitors such as (Reverset), D4T (stavudine), Rasivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), T20, fusions and mixtures thereof, and the term also includes anti-HIV compounds currently in clinical trials or development.

[0236] Other anti-HIV agents that can be used for co-administration with the compounds according to the invention include, for example, other NNRTIs (i.e., other than the NNRTIs according to the invention), including, inter alia, nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY097, DMP266, baicalin (TJN-151), ADAM-II (methyl), and the like. 3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-Diphenylhexenoate), Methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Capravirine (AG-1549, S-1153), Atevirdine (U-87201E), Aurintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inophyllum P, L-737,126, Mikellamine A (NSC650898), Mikellamine B (NSC649324), Mikellamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-Dimethylbenzyl)-1-(ethyloxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivatives), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497) , L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pyridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Robilid), R90385, S-2720, Suramin sodium, TBZ (thiazolbenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38, and UC-84.

[0237] The term "pharmaceutical acceptable salt" is used throughout the specification to describe, where applicable, a salt of one or more compounds described herein, which salt is made to increase the solubility of the compound in the gastric juices of the patient's gastrointestinal tract in order to facilitate the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutical acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium, magnesium, and ammonium salts, among many other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly suitable as neutral salts of the phosphate compounds according to the present invention.

[0238] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as esters, amides, other prodrug groups, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound.

[0239] General synthetic approach The synthesis realization and optimization of bifunctional molecules as described herein may be approached in a stepwise or modular manner. For example, the identification of compounds that bind to the target molecule may include high- or medium-throughput screening operations if suitable ligands are not readily available. Usually, the initial ligand will not require iterative design and optimization cycles to improve suboptimal aspects as identified by data obtained from suitable in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR operation will be to search for positions in the ligand that are tolerant to substitution and that may be suitable for attaching the linker chemical groups mentioned herein above. When crystal or NMR structural data are available, they can be used to focus such synthesis efforts.

[0240] In exactly the same manner, ligands for E3 ligases, i.e., ULM / CLM, can be identified and optimized.

[0241] With PTMs and ULMs (e.g., CLMs) at hand, one of skill in the art can use known synthetic methods to combine them with or without linker moieties. Linker moieties can be synthesized with a wide range of compositions, lengths, and flexibility and can be functionalized such that PTM and ULM groups are sequentially attached to the distal ends of the linker. Thus, a library of bifunctional molecules can be realized and characterized in in vitro and in vivo pharmacological and ADMET / PK experiments. With PTM and ULM groups, the final bifunctional molecules can be subject to iterative design and optimization cycles to identify molecules with desired properties.

[0242] Some non-limiting examples of methods for producing CLMs as described herein are summarized below. TIFF2025020416000080.tif188154TIFF2025020416000081.tif214152TIFF20250204160 00082.tif120154TIFF2025020416000083.tif205155TIFF2025020416000084.tif149155

[0243] As shown in Representative Reaction Example 1, dimethyl phthalate derivatives can be condensed with glutamine (racemic or enantiomeric) or glutamine analogs and then further reacted with an agent such as carbonyldiimidazole to form 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives.

[0244] Alternatively, the intermediate phthalimide resulting from the first condensation above may be prepared separately and / or isolated and then reacted with a dehydrating agent such as trifluoroacetamide, POCl3, or acetic anhydride to form the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative as shown in Representative Reaction 2. The same intermediate phthalimide may also be reacted with Lawesson's reagent followed by a dehydration step to provide the thio analogues such as those shown in Representative Reactions 8 and 9.

[0245] Representative Example 3 shows N 1 An example of a protected form of a 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative, such as a -BOC species, can be deprotected, in this example, by using a reagent such as TFA or silica, to give the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0246] Phthalic anhydrides, such as that shown in Representative Example 4, can be ring-opened by reaction with amines, such as 3-aminopiperidine-2,6-dione, to form intermediate carboxylate species which, upon treatment with carbonyldiimidazole and benzotriazole, will form the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives. Alternatively, the two components may be combined together in the presence of acetic acid to give the desired product, as shown in Representative Reaction Example 13.

[0247] In an analogous reaction, an anhydride derivative such as that shown in Representative Reaction Example 5 may be reacted with an amine (ammonia in the example shown) and then with carbonyldiimidazole to form the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0248] If phthaloyl chloride is available, it can be directly condensed with glutamine (racemic or enantiomeric) or glutamine analogs as shown in Representative Reaction Example 6, followed by further reaction with an agent such as carbonyldiimidazole to form the 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0249] The o-bromobenzamide can be reacted with a CO source, such as an acid chloride, in the presence of a palladium catalyst and a phosphine reagent to produce the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative as shown in Representative Reaction Example 7. Alternatively, CO gas itself can be used in conjunction with a rhodium(II) catalyst and silver carbonate to produce the desired product.

[0250] 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives and 5-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1,3-diazinan-2,4,6-trione derivatives can be prepared by means similar to some of the methods described above for 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives. In representative reactions 20 and 21, phthalic anhydride can be reacted with 5-amino-1,2,3,4-tetrahydropyrimidin-2,4-dione derivatives or 5-amino-1,3-diazinan-2,4,6-trione derivatives, respectively, in the presence of acetic acid to form the desired products.

[0251] Alternatively, 5-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1,3-diazinan-2,4,6-trione derivatives can be prepared by reacting 5-amino-1,3-diazinan-2,4,6-trione derivatives with phthalic acid mono-tert-butyl ester in the presence of Hunig's base, carbodiimide, and benzotriazole, as shown in Representative Reaction Example 12. Similar conditions can be employed to prepare 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives from phthalic acid mono-tert-butyl ester, as shown in Representative Reaction Example 14.

[0252] Compounds such as 3-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinazoline-2,4-dione can be prepared from anthranilic acid derivatives by reaction of 3-aminopiperidine-2,6-dione with a carbodiimide, as shown in Representative Reaction Example 16. The intermediate benzamide product may be isolated (or separately prepared) and further reacted with a carbodiimide to produce the 3-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinazoline-2,4-dione derivative, as shown in Representative Reaction Example 15.

[0253] 3-(2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione analogs can be prepared by activating salicylic acid with chloroformate and then condensing with 3-aminopiperidine-2,6-dione as shown in Representative Reaction Example 17.

[0254] 3,3-Dichloro-2,1λ 6 2-Benzoxathiol-1,1-diones can be prepared by reacting 2-sulfobenzoic acid with POCl3 and PCl5 as shown in Representative Reaction Example 18. These compounds can be reacted with amino derivatives to give, for example, the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ 6,2-benzothiazole-1,1,3-trione derivatives can be produced.

[0255] As shown in Representative Reaction Example 19, the anion of a saccharin derivative is alkylated with an electrophile such as 3-bromo-3-methylpiperidin-2-one to give the desired 2-(3-methyl-2-oxopiperidin-3-yl)-2,3-dihydro-1λ 6 ,2-benzothiazole-1,1,3-trione derivatives can be produced.

[0256] 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ 6 Analogs of ,2-benzothiazole-1,1,3-trione can also be prepared by reaction of methyl 2-[(2,6-dioxopiperidin-3-yl)sulfamoyl]benzoate with a strong base such as sodium hydride (see Representative Reaction 20).

[0257] As shown in Representative Reaction Example 21, the 2-methyl-2,3-dihydro-1H-indene-1,3-dione derivative is deprotonated with sodium ethoxide and then reacted with an electrophile such as 3-bromopiperidine-2,6-dione to give 3-(2-methyl-1,3-dioxo-1H-inden-2-yl)piperidine-2,6-dione.

[0258] 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione and other N 1 Preparation of -substituted compounds (Representative Reaction 22) can be achieved by reacting 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)pentanedioic acid with N-benzylhydroxylamine and with trifluoroacetic anhydride.

[0259] Molecules such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (Representative Reaction Example 23) can then be converted to N-alkyl groups such as 2-(1-hydroxy-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione by removing the benzyl under hydrogenation conditions. 1 -hydroxy analogues may also be used.

[0260] In representative reaction example 24, methyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (and analogs) is reacted with 3-aminopiperidin-2-one to give 2-(2-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0261] The same amines can also be reacted with phthalic anhydride derivatives in the presence of a Lewis acid, such as zinc bromide, and a trimethylsilyl ether to give the same type of product, as shown in Representative Reaction 25. The intermediate products of this reaction, if isolated or prepared elsewhere (Representative Reaction 26), can be fully cyclized using a dehydrating agent.

[0262] Isomeric derivatives such as 2-(6-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, shown in Representative Reaction Example 27, can be obtained through the reaction of phthalic acid with 5-aminopiperidin-2-one.

[0263] 2-(1-benzyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,4-dione and other N 1Preparation of -substituted compounds (Representative Reactions 28 and 29) can be accomplished by several routes. For example, anhydride (2-(2,6-dioxooxan-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione) can be condensed with 3-aminopiperidine-2,6-dione in the presence of DMAP and carbonyldiimidazole (Representative Reaction 28), or 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives can be alkylated with electrophiles such as benzyl bromide in the presence of base as shown in Representative Reaction 29.

[0264] In some cases, protecting group strategies and / or functional group transformations (FGI) may be required to facilitate preparation of the desired materials. Such chemical processes are well known to synthetic organic chemists, and many of them can be found in textbooks such as "Greene's Protective Groups in Organic Synthesis" Peter GM Wuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley).

[0265] Regulation of protein levels The present description also provides a method of controlling protein levels in a cell, which is based on the use of compounds as described herein that are known to interact with specific target proteins such that degradation of the target protein in vivo results in controlling the amount of the protein in a biological system, preferably providing a specific therapeutic effect.

[0266] The following examples are used to help illustrate the invention and are not to be construed as limiting the invention in any manner.

[0267] Specific Embodiments of the Disclosure The present disclosure encompasses the following specific embodiments. These following embodiments may include all of the features recited in the embodiments described below, as written. Where applicable, the following embodiments may also include features recited in any of the embodiments described below inclusively or in alternative embodiments thereof (e.g., embodiment (8) may include the features recited in embodiment (1) as recited and / or any of embodiments (2)-(7)). (1) A chemical structure containing: L-CLM wherein L is a linker group; and CLM is cereblon E3 ubiquitin ligase binding moiety; the linker group is chemically linked to the CLM; A compound, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof. (2) A chemical structure containing: PTM-L-CLM wherein the PTM is a protein targeting moiety that binds to a target protein or polypeptide; the PTM is chemically linked to the CLM through the linker group; Compound (1). (3) The compound according to (1), wherein the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. (4) The compound according to (1), wherein the chemical group is a phthalimide group or an analog or derivative thereof. (5) The compound according to (1), wherein the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof. (6) The compound further comprises a ULM, a second CLM, a CLM', or a multiple or combination thereof; ULM is an E3 ubiquitin ligase binding moiety; the second CLM has the same chemical structure as the CLM; CLM' is a cereblon E3 ubiquitin ligase binding moiety that is structurally different from the CLM; the ULM, the second CLM, the CLM', or a plurality or combination thereof, is optionally coupled to an additional linker group; The compound according to (1). (7) The CLM has the chemical structure represented by: TIFF2025020416000085.tif127132In formula, W is selected from the group consisting of CH2, CHR, C=O, SO2, NH, and N-alkyl; each X is independently selected from the group consisting of O, S, and H2; Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is selected from the group consisting of O, S, and H2; G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SOR', -SONR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SONR' R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO2)NR' Contains R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5, and -OCF3; R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; TIFF2025020416000086.tif2128 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains a functional group or atom, In the formula, n is an integer from 1 to 4, and If n is 1, R n is modified to be covalently attached to said linker group (L); and If n is 2, 3, or 4, then one R n is modified so as to be covalently bonded to the linker group (L), and other R n is optionally modified to be covalently attached to a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof; The compound according to (1). (8) The compound according to (1), wherein the CLM is selected from the group consisting of: 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodecan-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodecan-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatetradecan-14-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy)phenyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)acetamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; 4-(4-{[(5Z)-3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)propyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propyl)acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{2-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)phenyl]pyrimidin-5-yl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]-3-fluorophenyl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-2-fluorophenyl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-3-fluorophenyl}acetamide; and 2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]acetamide. (9) The linker group (L) has the following formula: -A q - The compound includes a chemical structural unit represented by the formula: q is an integer greater than 1; and A is independently a bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 , SONR L3 ,CONR L3 , N.R. L3CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl, optionally substituted with a group; R L1 , R L2 , R L3 , R L4 , and R L5 are independently H, halo, and C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclyl, OC 1-8 Cycloalkyl, SC 1-8 Cycloalkyl, NHC 1-8 Cycloalkyl, N(C 1-8 Cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 Alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 Alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 Alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 Alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 Alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, and NHSO2NH2; and If q is greater than 1, R L1 or R L2 each independently linking to another A group, L5 can form cycloalkyl and / or heterocyclyl moieties which can be further substituted with groups, The compound according to (1). (10) The compound according to (2), wherein the PTM is a protein targeting moiety that binds to a target protein, a target polypeptide, or a fragment thereof, and the target protein, the target polypeptide, or a fragment thereof has a biological function selected from the group consisting of structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. (11) The PTM group is a moiety that binds to a target protein, the target protein being selected from the group consisting of B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners of the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, transforming growth factor beta-activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha-reductase inhibitor, angiotensin 11, glycerol The compound according to (2), which is selected from the group consisting of lysine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen-related receptor, focal adhesion kinase, Src, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptor (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA or NGF receptor, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, ion channel of GABA-gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Still further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase. (12) The compound according to (2), wherein the PTM group is an Hsp90 inhibitor; a kinase inhibitor, a phosphatase inhibitor, an HDM2 / MDM2 inhibitor, a compound targeting a human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting a RAF receptor, a compound targeting an FKBP, an angiogenesis inhibitor, an immunosuppressant compound, a compound targeting an aryl hydrocarbon receptor, a compound targeting an androgen receptor, a compound targeting an estrogen receptor, a compound targeting an estrogen-related receptor, a compound targeting a thyroid hormone receptor, a compound targeting an HIV protease, a compound targeting an HIV integrase, a compound targeting an HCV protease, or a compound targeting an acyl protein thioesterase 1 and / or 2. (13) The compound according to (2), wherein the PTM group is selected from the group consisting of TANK-binding kinase 1 (TBK1), estrogen receptor alpha (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc. (14) A composition comprising the compound according to (2). (15) A pharmaceutical composition comprising the compound according to (2) and a pharma- ceutically acceptable carrier, additive, and / or excipient. (16) The pharmaceutical composition according to (15), further comprising a bioactive agent. (17) The pharmaceutical composition according to (16), wherein the bioactive agent is an antiviral agent. (18) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HIV agent. (19) The pharmaceutical composition according to (18), wherein the anti-HIV agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, or a mixture thereof. (20) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HCV agent. (21) The pharmaceutical composition according to (16), wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, immune agents, cardiovascular agents, and neuroactive agents. (22) The pharmaceutical composition according to (16), wherein the bioactive agent is an anticancer agent. (23) The anticancer drug is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, butabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly 10] acetate (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) X, where x=1-2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP- LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol , epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, strepto Zosyn, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Diftitox, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Cremophor, Docetaxel, Epothilone B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-aspartate Paraginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, erwinia-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,The composition according to (22), wherein the active ingredient is selected from the group consisting of lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alpha, darbepoetin alpha, and mixtures thereof. (24) A method for inducing degradation of a target protein in a cell, comprising: The method comprises the step of administering to the cell an effective amount of the compound described in (2). (25) A method for inducing degradation of a target protein in a cell, comprising: The method, comprising the step of administering to the cell an effective amount of the compound according to (10). (26) A method for inducing degradation of a target protein in a cell, comprising: The method, comprising the step of administering to the cell an effective amount of the compound according to (11). (27) A method for inducing degradation of a target protein in a patient, comprising: The method comprises the step of administering to the patient an effective amount of the compound described in (2). (28) A method for treating a disease state or condition in a patient caused by dysregulated protein activity, comprising administering an effective amount of a compound according to (2). (29) The method according to (28), wherein the disease state or symptom is asthma, multiple sclerosis, cancer, cilia-related disease, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome. (30) The method according to (28), wherein the disease state or symptom is Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, diabetes mellitus type 1, diabetes mellitus type 2, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, or vasculitis. (31) The disease state or symptom is aceruloplasminemia, type II achondroplasia, achondroplasia, cephalic malformation, type II Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ochronosis, alpha-1-antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, or Alström's disease. syndrome, Alexander disease, hereditary amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple joint laxity (Ehlers-Danlos syndrome #multiple joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyrate cutis syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome Lipoprotein lipase deficiency, CGD chronic granulomatous disease, cuneus limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-a-cat syndrome, CAVD (congenital absence of vas deferens), Caylor cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypoparathyroidism, chondrodystrophy (achondroplasia), otospondylomegalyepphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal skeletal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis),Congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagen diseases, conotruncal dysfacies syndrome, Cooley anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden's disease, craniofacial dysostosis (Cruzon's disease), Creutzfeldt-Jakob disease (prion disease), Cockayne's syndrome, Cowden's disease, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson gyrate cutis syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophies, Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Neurodegenerative disorders including Grouchy syndrome and Dejerine-Sottas disease, Developmental disorders, Distal spinal muscular atrophy, Type V, Androgen insensitivity syndrome, Diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, Dihydrotestosterone receptor deficiency, Androgen insensitivity syndrome, Down syndrome, Dwarf stature, Erythropoietic protoporphyria, Erythropoietic 5-aminolevulinic acid synthase deficiency, Erythropoietic porphyria, Erythropoietic protoporphyria, Erythropoietic uroporphyria, Friedreich's ataxia, Familial paroxysmal polyserositis, Porphyria cutanea tarda, Familial neuropathy with liability to pressure palsies, Primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, Fragile X syndrome, Galactosemia, Hereditary encephalopathy, Giant cells Hepatitis (neonatal hemochromatosis), Glenn-Blood-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disorders including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia,Langer-Sardino achondrogenesis, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrosis fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Larbhardt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoelastosis elastosis) xanthomas), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, Sarcoma, Breast, Leukemia, and Adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis complex), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia, Str Strudwick type), SEDc (Spondyloepiphyseal dysplasia congenita), SEMD, Strudwick type (Spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, Skin pigmentation disorder, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), Infantile-onset ascending hereditary spastic paralysis, Speech and communication disorder, Sphingolipidosis, Tay-Sachs disease, Spinocerebellar ataxia, Stickler syndrome, Stroke, Androgen insensitivity syndrome, Tetrahydrobiopterin deficiency, Beta-thalassemia,The method according to (28), wherein the disease is thyroid disease, sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo-X syndrome (triple-X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik's disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum. (32) The method according to (28), wherein the disease state or condition is cancer. (33) The cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; multiple myeloma; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, glioma, and glioma. 32. The method of claim 31, wherein the cancer is selected from the group consisting of membranous sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, spinal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, and melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. (34) The method according to (32), wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, or Philadelphia chromosome positive CML. (35) A compound library comprising more than one compound according to (1). (36) A method for identifying a compound containing an E3 ubiquitin ligase binding moiety that recognizes cereblon (CRBN), comprising: incubating a test compound with a CRBN protein; determining the amount of said test compound bound to said CRBN protein. The method comprising: (37) The chemical structure represented by: TIFF2025020416000087.tif127132, W is selected from the group consisting of CH2, CHR, C=O, SO2, NH, and N-alkyl; each X is independently selected from the group consisting of O, S, and H2; Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is selected from the group consisting of O, S, and H2; G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3, and Q4 represent a carbon C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SOR', -SONR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SONR' R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO2)NR' Contains R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5, and -OCF3; R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; TIFF2025020416000088.tif2128 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains a functional group or atom, In the formula, n is an integer of 1 to 4. Cereblon E3 ubiquitin ligase binding moiety (CLM). (38) The above R n comprises a functional group or atom covalently linked to a linker group (L), a protein targeting moiety (PTM), an E3 ubiquitin ligase binding moiety (ULM), or any multiple or combination thereof. (39) The ULM is a second CLM, a CLM', or any multiple or combination thereof; the second CLM has the same chemical structure as the CLM; and The CLM according to (38), wherein the CLM' is structurally different from the CLM. EXAMPLES

[0268] A. Assay 1. CRBN Assay - Cloning, Expression, and Purification of Human CRBN and DDB1 This procedure is standard for those skilled in the art and is exemplified by the description in Lopez-Girona et al. (Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide, A Lopez-Girona, D Mendy, T Ito, K Miller, AK Gandhi, J Kang, S Karasawa, G Carmel, P Jackson, M Abbasian, A Mahmoudi, B Cathers, E Rychak, S Gaidarova, R Chen, PH Schafer, H Handa, TO Daniel, JF Evans and R Chopra, Leukemia 26: 2326-2335, 2012).

[0269] The cDNA of the CRBN and DDB1 genes can be amplified by PCR using Pfusion (NEB) as the polymerase and the following primer sequences: TIFF2025020416000089.tif44160

[0270] Using ligation-independent cloning methods26, CRBN can be cloned into pBV-ZZ-HT-LIC, pBV-GST-LIC, and pMA-HT-LIC, and DDB1 can be cloned into pBV-notag-LIC. When cloned into the mammalian vector pMA-HT-LIC, the CRBN-Flag-Reverse oligo carries a C-terminal FLAG tag for immunodetection. DDB1-Rev carries a StrepTag27. The ZZ-tag28 is required to achieve high expression of soluble CRBN; without it, His-CRBN is expressed at low levels, while GST-CRBN results in aggregated protein. Recombinant baculoviruses of ZZ-His-CRBN and DDB1-StrepTag (ST) are generated and amplified in Sf9 insect cells using the Bac-to-Bac baculovirus expression system from Invitrogen. ZZ-His-CRBN and DDB1-ST are co-expressed in High Five (Tni) insects in 10 L wave bags using unsupplemented ESF921 medium from Expression Systems at 27° C. Forty-eight hours post-infection, cells are harvested by centrifugation and the paste is resuspended in PBS + 5× protease inhibitor cocktail (Roche, Indianapolis, IN).

[0271] All subsequent protein purification steps are performed at 4°C. Frozen cells are thawed and resuspended in 5 volumes of cell lysis solution (50 mM Tris·HCl (pH 8.0), 0.5 M NaCl, 10% glycerol, 2 mM DTT) supplemented with 20 mM imidazole and protease inhibitors, lysed, and centrifuged to obtain a clear supernatant. CRBN-DDB1 is purified on an AKTA-xpress system (GE Healthcare) using nickel-sepharose and S200 Sephacryl chromatography. The complex is then further purified by anion exchange chromatography on an 8 ml MonoQ column and a second pass through S-200 gel filtration. CRBN-DDB1 was identified by SDS-PAGE, and CRBN-DDB1-containing fractions were pooled and stored at -70°C.

[0272] 2. Binding measurement of compounds to recombinant CRBN by fluorescent heat lysis assay This assay is standard to those skilled in the art and is exemplified by the description in Lopez-Girona et al. (Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide, A Lopez-Girona, D Mendy, T Ito, K Miller, AK Gandhi, J Kang, S Karasawa, G Carmel, P Jackson, M Abbasian, A Mahmoudi, B Cathers, E Rychak, S Gaidarova, R Chen, PH Schafer, H Handa, TO Daniel, JF Evans and R Chopra, Leukemia 26: 2326-2335, 2012).

[0273] According to Pantoliano et al. (Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E et al. High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 2001;6:429-440), the thermal stability of CRBN-DDB1 in the presence or absence of test compounds is examined in a microplate format in the presence of Cypro Orange. 2 mg of protein is added to 20 ml of assay buffer (25 mM Tris-HCl (pH 8.0), 150 mM NaCl, 2 uM Cypro Orange) and subjected to a temperature step increase from 20°C to 70°C, and the fluorescence is measured every 1°C on an ABI Prism 7900HT (Applied Biosystems, Carlsbad, CA, USA). Compounds are dissolved in DMSO (final concentration in assay is 1%) and tested in quadruplicate at concentrations ranging from 30 nM to 1000 uM; controls contained 1% DMSO only.

[0274] 3.LCMS method The analysis is carried out on a Poroshell 120 EC C18 column (50 mm x 3.0 mm inner diameter, packing diameter 2.7 μm) at 45°C.

[0275] The solvents used were: A = 0.1% v / v formic acid in water. B = 0.1% v / v formic acid in acetonitrile.

[0276] The solvent gradient used was as follows: TIFF2025020416000090.tif52128

[0277] UV detection is by averaging the signal from wavelengths 210 nm to 350 nm, and mass spectra are recorded on a mass spectrometer using positive mode electrospray ionization.

[0278] Below are shown the mobile phases and solvent gradients used when compounds were purified by preparative HPLC.

[0279] 4.Preparative HPLC (formic acid modification) HPLC analysis is carried out on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0280] The solvents used were: A = 0.1% v / v formic acid in water. B=acetonitrile.

[0281] 5. Preparative HPLC (Ammonium Bicarbonate Modification) HPLC analysis is carried out on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0282] The solvents used were: A = 10 mM ammonium bicarbonate in water. B=acetonitrile.

[0283] For each preparative purification, regardless of the mobile phase used, the solvent gradient employed was dependent on the retention time as recorded by analytical LCMS of the particular compound being purified. The flow rate was 20 mL / min.

[0284] UV detection is at a wavelength of 254 nm or 220 nm.

[0285] While preferred embodiments of the present invention have been shown and described herein, it is to be understood that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the spirit of the invention. It is therefore intended by the appended claims to cover all such modifications which fall within the spirit and scope of the invention.

[0286] B. Synthesis: The synthetic details for the examples included below are representative of general procedures that provide information for the synthesis of a more extensive set of examples.

[0287] 1. 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione TIFF2025020416000091.tif18128 Step 1: 4-Fluoroisobenzofuran-1,3-dione A mixture of 3-fluorophthalic acid (50 g, 271.7 mmol) in acetic anhydride (400 mL) was refluxed for 2 h. The volatiles were removed under reduced pressure and the residue was crystallized in acetic anhydride to give 4-fluoroisobenzofuran-1,3-dione (40 g, crude) as a brown solid. TIFF2025020416000093.tif13147 Step 2: 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid TIFF2025020416000094.tif19128 A mixture of the above 4-fluoroisobenzofuran-1,3-dione (40 g, crude) and L-glutamine (35 g, 239 mmol) in dry DMF (200 mL) was stirred at 90° C. for 8 h. The solvent was removed under reduced pressure. The residue was redissolved in 4N HCl (200 mL) and stirred for an additional 8 h. The resulting precipitate was collected by filtration, washed with water, and dried to give 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, crude) as an off-white solid. TIFF2025020416000095.tif20153 Step 3: 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione TIFF2025020416000096.tif15128 A mixture of the above 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, crude), 1,1'-carbonyldiimidazole (CDI) (24.2 g, 149.4 mmol), and 4-dimethylaminopyridine (DMAP) (1.3 g, 11.5 mmol) in acetonitrile (80 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration and washed with acetonitrile (100 mL) to give the crude product, which was purified by silica gel chromatography using 1-10% MeOH in DCM as eluent to give 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (9.0 g, 12% yield over three steps) as a pale yellow solid. TIFF2025020416000097.tif20148

[0288] 2. N-(3-(5-bromo-2-chloropyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide TIFF2025020416000098.tif14128 Step 1: tert-Butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate TIFF2025020416000099.tif16128 A mixture of tert-butyl N-(3-aminopropyl)-N-methylcarbamate (826 mg, 4.40 mmol) and 5-bromo-2,4-dichloropyrimidine (400 mg, 1.76 mmol) in MeOH (10 mL) was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by Teledyne ISCO chromatography [0→35% EtOAc / heptane] to give tert-butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate (615 mg, 92% yield). LC-MS (ES) + ):m / z=381.05 / 383.05[MH + ], tR =2.55 minutes. Step 2: {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine TIFF2025020416000100.tif15128 To a solution of tert-butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate (615 mg, 1.62 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.54 mL, 6.5 mmol) at room temperature. After stirring for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by Teledyne ISCO chromatography [0→15% methanol in DCM] to give {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 82% yield). LC-MS (ES + ):m / z=280.99 / 282.99[MH + ], t R =1.13 minutes. Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide TIFF2025020416000101.tif16128To a solution of {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutanecarbonyl chloride (188 mg, 1.60 mmol) in DCM (10 mL) at room temperature was added triethylamine (0.41 mL, 2.92 mmol). The reaction mixture was left stirring at room temperature for 16 h and then concentrated in vacuo. The residue was purified by Teledyne ISCO chromatography [0→100% EtOAc / heptane] to give N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide (268 mg, 56%). LC-MS (ES + ):m / z=363.04 / 365.04[MH + ], t R =2.18 minutes.

[0289] 3. (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid TIFF2025020416000102.tif36128 The title compound was prepared according to the procedures described in WO2011 / 143660.

[0290] 4. (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile TIFF2025020416000103.tif23128 The title compound was prepared according to the procedure described in Patch, RJ et al. J. Med. Chem. 2011, 54, 788-808.

[0291] 5. 4-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile TIFF2025020416000104.tif28128 The title compound was prepared according to the procedure described in Jung, ME et al. J. Med. Chem. 2010, 53, 2779-2796.

[0292] 6. 2-Chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile hydrochloride TIFF2025020416000105.tif21128 The title compound was prepared according to the procedure described in Guo, C. et al. J. Med. Chem. 2011, 54, 7693-7704.

[0293] 7. [N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide] TIFF2025020416000106.tif25128 (Compound structure #17 shown in Table 1) Step 1: 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate TIFF2025020416000107.tif9128A mixture of 2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) (3 g, 5.96 mmol), 4-nitrophenol (813 mg, 5.84 mmol), and potassium carbonate (1.65 g, 11.94 mmol) in dry N,N-dimethylformamide (20 mL) was stirred at 50° C. overnight. The mixture was cooled to room temperature, poured into water (60 mL), and then extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 10-20% ethyl acetate in hexane) to give 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.65 g, 95% yield) as a yellow oil. LC-MS (ES + ): m / z 470.2[MH + ](t R =2.83 minutes). Step 2: [1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene] TIFF2025020416000108.tif10128 A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.65 g, 5.64 mmol) and sodium azide (734 mg, 11.29 mmol) in ethanol (30 mL) was refluxed for 16 h. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with water (50 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 1-(2-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene (865 mg) as a yellow oil. Step 3: [2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine] A mixture of 1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene (865 mg, 2.54 mmol), triphenylphosphine (999 mg, 3.81 mmol), and water (69 mg, 3.83 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature under nitrogen for 14 hours. The volatiles were removed under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluting with 3-5% methanol in dichloromethane) to give 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine (661 mg, 83% yield) as a yellow oil. TIFF2025020416000110.tif20148 Step 4: tert-Butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate TIFF2025020416000111.tif10128A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine (661 mg, 2.1 mmol), triethylamine (449 mg, 4.43 mmol), and di-tert-butyl dicarbonate (505 mg, 2.31 mmol) in dichloromethane (25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 mL), washed with water (30 mL x 2) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20-40% ethyl acetate in hexane) to give tert-butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (818 mg, 94% yield) as a yellow oil. TIFF2025020416000112.tif20147 Step 5: tert-Butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate TIFF2025020416000113.tif10128 A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl carbamate (818 mg, 1.97 mmol), iron powder (1.1 g, 0.65 mmol), and ammonium chloride (528 mg, 9.87 mmol) in ethanol (20 mL) and water (5 mL) was stirred at 80 °C for 1 h. The mixture was cooled to room temperature and the solid precipitate was filtered off and washed with ethyl acetate (20 mL x 2). The filtrate was partitioned between ethyl acetate (120 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 30-40% ethyl acetate in hexanes) to give tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (512 mg, 67% yield) as a yellow oil. Step 6: tert-Butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate TIFF2025020416000114.tif13128 A mixture of tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (130 mg, 0.34 mmol), N-(3-(5-bromo-2-chloropyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (24 mg, 0.06 mmol), and p-toluenesulfonic acid (11.6 mg, 0.07 mmol) in dioxane (1.5 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous sodium bicarbonate (1.0 N, 30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 50% ethyl acetate in hexanes) to give tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, 17% yield) as a yellow oil. Step 7: N-(3-(2-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide TIFF2025020416000115.tif13128 A mixture of tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, 0.06 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (1 mL) was stirred at room temperature for 2 hours. Volatiles were removed in vacuo. The residue was partitioned between dichloromethane (60 mL) and aqueous sodium bicarbonate (2.0 N, 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N-(3-(2-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (18 mg, 52% yield) as a yellow oil. Step 8: N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide A mixture of N-(3-(2-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (130 mg, 0.03 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (8.2 mg, 0.03 mmol), and N-ethyl-N-isopropylpropan-2-amine (7.6 mg, 0.06 mmol) in dry N,N-dimethylformamide (1 mL) was stirred at 90° C. for 12 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to give N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (10.2 mg, 40% yield) as a yellow solid. LC-MS (ES + ):m / z=865.27 / 867.27(1:1)[MH] + .t R =2.06 minutes. TIFF2025020416000117.tif27150

[0294] 8. 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide TIFF2025020416000118.tif34128 (Compound structure #14 shown in Table 1) Step 1: (2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione TIFF2025020416000119.tif24128 A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine (128 mg, 0.41 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (112.5 mg, 0.41 mmol), and N-ethyl-N-isopropylpropan-2-amine (105 mg, 0.81 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at 90° C. for 12 hours. The mixture was cooled to room temperature, poured into water (20 mL), and extracted with ethyl acetate (35 mL×2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione (73 mg, 31% yield) as a yellow solid. LC-MS (ES + ):m / z571.3[MH + ], t R =2.46 minutes. Step 2: (4-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) TIFF2025020416000120.tif251282-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione (73 mg, 0.128 mmol) and iron powder (71.6 mg, 1.28 mmol) in ethanol (2 mL) were added to a solution of ammonium chloride (68 mg, 1.26 mmol) in water (0.5 mL) at room temperature, and the resulting mixture was stirred at 80 °C for 1 h. After the mixture was cooled to room temperature, the solid precipitate was filtered and washed with ethyl acetate (10 mL × 2). The filtrate was partitioned between ethyl acetate (60 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(2-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (66.5 mg, crude) as a yellow oil. LC-MS (ES + ):m / z541.5[MH + ], t R =1.593 minutes. Step 3: 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide TIFF2025020416000121.tif341284-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58.4 mg, 0.11 mmol), (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1, 4] Diazepin-6-yl) acetic acid (43.3 mg, 0.11 mmol) and N-ethyl-N-isopropylpropan-2-amine (41.8 mg, 0.32 mmol) were dissolved in dry N,N-dimethylformamide (1 mL) and stirred at 0° C. to which was added (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (82 mg, 0.21 mmol). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 minutes. The mixture was poured into water (25 mL) and extracted with ethyl acetate (35 ml×2). The combined organic phase was washed with water (20 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide (52 mg, 52% yield) as a yellow solid. LC-MS (ES + ):m / z923.29 / 925.29(3:1)[MH + ], t R =2.689 minutes. TIFF2025020416000122.tif34154

[0295] 9. (Z)-4-(4-((3-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile TIFF2025020416000123.tif24128 (Compound structure #22 shown in Table 1) Step 1: (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate) TIFF2025020416000124.tif17128A mixture of (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (1.0 g, 2.3 mmol), potassium carbonate (1.0 g, 6.9 mmol), and 2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)=bis(4-methylbenzenesulfonate) (1.3 g, 2.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (40 mL×3). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, and evaporated in vacuo. The crude residue was purified by silica gel flash column chromatography (eluted with 10-30% ethyl acetate in hexanes) to give (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.0 g, 61% yield) as a pale yellow solid. Step 2: (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile TIFF2025020416000125.tif17128A mixture of (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.0 g, 1.4 mmol) and sodium azide (185 mg, 2.8 mmol) in ethanol (20 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature and partitioned with ethyl acetate (100 mL) and water (20 mL). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (130 mg, crude) as a light yellow oil, which was used in the next step without further purification. Step 3: (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile TIFF2025020416000126.tif17128 A mixture of the above (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (130 mg, crude), triphenylphosphine (100 mg, 0.34 mmol) in water (0.2 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluting with 3-5% methanol in dichloromethane) to give (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (60 mg, 8% yield over two steps) as a yellow oil. LC-MS (ES + ):m / z552.1[MH + ], t R =2.15 minutes. Step 4: (Z)-4-(4-((3-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile A mixture of (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (60 mg, 0.10 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (30 mg, 0.13 mmol), and N-ethyl-N-isopropylpropan-2-amine (50 mg, 0.39 mmol) in 1-methylpyrrolidin-2-one (1 mL) was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (5 mL) and extracted with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give (Z)-4-(4-((3-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (9.5 mg, 11.8% yield) as a yellow solid. LC-MS (ES) + ):m / z808.19[MH + ], t R =3.022 minutes. TIFF2025020416000128.tif26152

[0296] 10. 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile TIFF2025020416000129.tif18128 (Compound structure #1 shown in Table 1) Step 1: 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane TIFF2025020416000130.tif4128To a solution of 2-(2-(2-(trityloxy)ethoxy)ethoxy)ethanol (7 g, 17.7 mmol) in N,N-dimethylformamide (50 mL) was slowly added sodium hydride (60% in mineral oil, 707 mg, 17.7 mmol) at 0 °C. The mixture was stirred at room temperature for 30 min, then 3-(benzyloxy)propyl 4-methylbenzenesulfonate (5.8 g, 18.0 mmol) was added in one portion at 0 °C, and the resulting mixture was left to stir at 70 °C overnight. After cooling to room temperature, the mixture was carefully quenched with water (40 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phase was washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluting with 5-10% ethyl acetate in hexanes) to give 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g, 50% yield) as a colorless oil. TIFF2025020416000131.tif20146 Step 2: 1-Phenyl-2,6,9,12-tetraoxatetradecan-14-ol TIFF2025020416000132.tif41281,1,1,16-Tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g, 8.8 mmol) was dissolved in methylene chloride (10 mL) and methanol (10 mL) and aqueous hydrochloric acid (37%, 2.5 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with aqueous sodium bicarbonate (1N, 50 mL), water (30 mL), brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 20-40% ethyl acetate in hexanes) to give 1-phenyl-2,6,9,12-tetraoxatetradecan-14-ol (1.9 g, 73% yield) as a colorless oil. Step 3: 1-Phenyl-2,6,9,12-tetraoxatetradecan-14-yl 4-methylbenzenesulfonate TIFF2025020416000133.tif4128 A mixture of 1-phenyl-2,7,10,13-tetraoxapentadecan-15-ol (1.9 g, 6.3 mmol), triethylamine (1.3 mL, 9.5 mmol), N,N-dimethylpyridin-4-amine (75 mg, 0.63 mmol), and 4-methylbenzene-1-sulfonyl chloride (1.45 g, 7.65 mmol) in dichloromethane (20 mL) was stirred at room temperature for 3 h. The reaction was quenched by the addition of water (20 mL) and the product was extracted with dichloromethane (40 mL x 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 10-30% ethyl acetate in hexanes) to give 1-phenyl-2,6,9,12-tetraoxatetradecan-14-yl 4-methylbenzenesulfonate (2.2 g, 78% yield) as a colorless oil. TIFF2025020416000134.tif20148 Step 4: 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane TIFF2025020416000135.tif4128 A mixture of 1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate (2.2 g, 4.9 mmol) and sodium azide (420 mg, 6.3 mmol) in ethanol (10 mL) was refluxed for 5 h. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane (1.4 g, crude) as a colorless oil, which was used in the next step without further purification. Step 5: tert-Butyl (1-phenyl-2,6,9,12-tetraoxatetradecan-14-yl)carbamate TIFF2025020416000136.tif4128 A mixture of the above 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane (1.4 g, crude) and triphenylphosphine (1.7 g, 6.5 mmol) in tetrahydrofuran (15 mL) and water (0.5 mL) was stirred overnight at room temperature under nitrogen atmosphere. Triethylamine (0.9 mL, 6.5 mmol) and di-tert-butyl dicarbonate (1.1 g, 5.2 mmol) were added to the reaction mixture at 0° C. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 mL) and water (50 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluted with 30-50% ethyl acetate in hexanes) to give tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecan-14-yl)carbamate (1.2 g, 50% yield over two steps) as a colorless oil. Step 6: tert-Butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate TIFF2025020416000137.tif4128A mixture of tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecan-14-yl)carbamate (1.2 g, 3 mmol) and palladium on carbon (10%, 200 mg) in ethanol (50 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon). The palladium on carbon was removed by filtration and washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate (900 mg, crude) as a colorless oil, which was used in the next step without further purification. Step 7: 2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate TIFF2025020416000138.tif4128A mixture of the above tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate (900 mg, crude), triethylamine (0.6 mL, 4.35 mmol), N,N-dimethylpyridin-4-amine (16 mg, 0.14 mmol), and 4-methylbenzene-1-sulfonyl chloride (660 mg, 3.5 mmol) in anhydrous dichloromethane (15 mL) was stirred at room temperature for 3 h. Water (20 mL) was added to quench the reaction, and the product was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 20-30% ethyl acetate in hexanes) to give 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate (650 mg, 77% yield) as a light yellow oil. TIFF2025020416000139.tif20147 Step 8: tert-butyl (2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethyl)carbamate TIFF2025020416000140.tif151282,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate (115 mg, 0.25 mmol), potassium carbonate (69 mg, 0.50 mmol), and 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.25 mmol) in acetonitrile (5 mL) were stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 10-30% ethyl acetate in hexane) to give tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethylcarbamate (150 mg, 82% yield) as a yellow oil. LC-MS (ES) + ):m / z695.40[MH + ], t R =2.79 minutes. Step 9: 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile TIFF2025020416000141.tif15128 A mixture of tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethyl carbamate (150 mg, 0.21 mmol) in anhydrous dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure and the residue was poured into aqueous sodium bicarbonate (1N, 20 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, crude) as a brown oil, which was used in the next step without further purification. Step 10: 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile TIFF2025020416000142.tif18128 The above 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, crude), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (41 mg, 0.15 mmol), and N-ethyl-N-isopropylpropan-2-amine (58 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (3 mL) and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with water (30 mL×2) and brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (34.5 mg, 27% yield) as a yellow solid. LC-MS (ES) + ):m / z851.25[MH + ], t R =2.652 minutes. TIFF2025020416000143.tif27135

[0297] 11. 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide TIFF2025020416000144.tif30128 Step 1: 3-[(5-hydroxypentyl)oxy]propanenitrile TIFF2025020416000145.tif7128To a suspension of sodium hydride (60% dispersion in mineral oil, 820 mg, 34.2 mmol) in THF (50 mL) was added pentane-1,5-diol (2.98 g, 28.6 mmol). After stirring at room temperature for 20 min, the mixture was cooled to 0 °C and acrylonitrile (1.20 g, 22.8 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 10 h. Some of the solvent was removed under reduced pressure and the residue was poured into water. The mixture was extracted with DCM (3x). The organic layer was filtered through a Biotage Universal Phase Separator and concentrated under reduced pressure. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with MeOH / DCM (0:100 to 3:97) to give 3-[(5-hydroxypentyl)oxy]propanenitrile (635 mg, 18% yield). TIFF2025020416000146.tif20151 Step 2: tert-Butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate TIFF2025020416000147.tif12128 To a solution of 3-[(5-hydroxypentyl)oxy]propanenitrile (400 mg, 2.54 mmol) in MeOH (12 mL) and HO (2.0 mL) was added nickel(II) chloride (393 mg, 3.04 mmol) followed by sodium borohydride (360 mg, 9.52 mmol) in portions. The mixture was stirred at room temperature for 3 h and then quenched with MeOH (12 mL). The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure. To a solution of the above crude product in THF (5 mL) was added 6 M aqueous NaOH (0.5 mL) and di-tert-butyl dicarbonate (831 mg, 3.81 mmol), and the resulting mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with MeOH / DCM (0:100 to 4:96) to give tert-butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate (366 mg, 55% yield). TIFF2025020416000148.tif19146 Step 3: tert-Butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate TIFF2025020416000149.tif13128 To a solution of tert-butyl (3-((5-hydroxypentyl)oxy)propyl)carbamate (300 mg, 3.88 mmol) in DCM (10 mL) was added DIPEA (599.3 μL, 3.44 mmol), tosyl chloride (262.3 mg, 1.38 mmol), and 4-dimethylaminopyridine (14.0 mg, 0.115 mmol). The resulting mixture was stirred at room temperature for 20 h. The reaction was quenched with half-saturated sodium bicarbonate, extracted with DCM (2×), filtered through a Biotage Universal Phase Separator, and concentrated in vacuo. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with EtOAc / heptane (0:100 to 30:70) to give tert-butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate (914 mg, 26% yield). TIFF2025020416000150.tif27152 Step 4: Methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate TIFF2025020416000151.tif16128A mixture of tert-butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate (340 mg, 0.82 mmol), methyl 4-hydroxybenzoate (117 mg, 0.77 mmol), potassium carbonate (203 mg, 1.47 mmol) in MeCN (10 mL) was stirred at 80° C. for 24 h. The reaction mixture was diluted with EtOAc and washed with half-saturated sodium bicarbonate solution (1×), water (2×), brine (1×), and then filtered through a Biotage Universal Phase Separator. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with EtOAc / heptane (0:100 to 50:50) to give methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (300 mg, 93% yield). LC-MS (ES + ): m / z 418.21 [MNa + ], t R =2.74 minutes. Step 5: 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid TIFF2025020416000152.tif161284-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (150 mg, 0.38 mmol) in 1:1:1 THF / water / MeOH (6.0 mL, v / v / v) was added with lithium hydroxide (81.6 mg, 3.41 mmol). The resulting mixture was stirred at room temperature overnight and then acidified to pH 2-3 with 6N aqueous HCl. The mixture was concentrated under reduced pressure to remove most of the solvent, then diluted with EtOAc, washed with water (2x), brine (2x), filtered through a Biotage Universal Phase Separator, and concentrated under reduced pressure. The crude product was used in the next step without further purification (123 mg). LC-MS (ES + ): m / z 404.20 [MNa + ], tR =2.40 minutes. Step 6: tert-Butyl N-(3-{[5-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxy}propyl)carbamate TIFF2025020416000153.tif191284-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid (124 mg, 0.322 mmol), 2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (89.8 mg, 0.322 mmol) in DMF (5 mL) was added DIPEA (112 μL, 0.65 mmol) and TBTU (155 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 1 h, then diluted with EtOAc, washed with water (3×), brine (1×), filtered through a Biotage Universal Phase Separator, and concentrated in vacuo. The residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with MeOH / DCM (0:100 to 5:95) to give tert-butyl N-(3-{[5-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxy}propyl)carbamate (169 mg, 82% yield). LC-MS (ES + ):m / z643.32 / 645.31(3:1)[MH + ], t R =3.04 minutes.

[0298] 12. 4-{[5-(3-aminopropoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide TIFF2025020416000154.tif17128 To a solution of tert-butyl N-(3-{[5-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxy}propyl)carbamate (124 mg, 0.192 mmol) in DCM (5 mL) was added trifluoroacetic acid (372 μL, 4.86 mmol) and heated at 45° C. for 1 h until the reaction was complete. The reaction was then concentrated in vacuo to a solid and used in the next step without further purification (104 mg, 99% yield). LC-MS (ES + ):m / z543.27 / 545.26(3:1)[MH + ], t R =2.26 minutes.

[0299] 13. 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide TIFF2025020416000155.tif30128 (Compound structure #11 shown in Table 1) To a solution of 4-{[5-(3-aminopropoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (30.0 mg, 0.0553 mmol) in 1,4-dioxane (2 mL) was added diisopropylethylamine (384 μL, 2.21 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (18.3 mg, 0.0664 mmol). The resulting mixture was refluxed for 16 h, then diluted with EtOAc, washed with half-saturated brine solution (2×), filtered through a Biotage Universal Phase Separator, and concentrated in vacuo. The residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO column eluting with MeOH / DCM (0:100 to 7:93) to give 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (12 mg, 28% yield). LC-MS (ES + ):m / z799.31 / 801.31(3:1)[MH + ], t R =2.97 minutes. TIFF2025020416000156.tif54151

[0300] C. Proteolysis Bioassay: The following bioassays were performed to assess the level of protein degradation observed in various cell types using representative compounds disclosed herein.

[0301] In each bioassay, cells were treated with various amounts of compounds encompassed by the present disclosure as shown in Table 1. The studies assessed the degradation of the following proteins: TANK-binding kinase 1 (TBK1), estrogen receptor alpha (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc.

[0302] 1.TBK1 Western Blot Protocol Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco) supplemented with 15% FBS (ATCC) and 10 Units / mL human recombinant insulin (Gibco). DMSO control and compound treatments (0.1 μM, 0.3 μM, and 1 μM) were performed in 12-well plates for 16 hours. The TLR3 agonist PolyI:C (Invivogen; tlrl-pic) was added for the last 3 hours. Cells were harvested and lysed in RIPA buffer (50 mM Tris (pH 8), 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified by centrifugation at 16,000 g for 10 minutes and supernatants were resolved by SDS-PAGE. Immunoblotting was performed using standard protocols. Antibodies used were TBK1 (Cell Signaling #3504), pIRF3 (abcam #ab76493), and GAPDH (Cell Signaling #5174). Bands were quantified using a Biorad ChemiDoc MP imaging system.

[0303] 2. ERRα Western Blot Protocol NAMALWA cells (ATCC) were cultured in RPMI-1640 (Life Technologies) supplemented with 15% FBS (Life Technologies). DMSO control and compound incubations (0.1 μM, 0.3 μM, and 1 μM) were performed in 24-well plates for 16 hours. Cells were harvested and lysed in cell lysis solution (Cell Signaling Technologies) containing protease inhibitors (Thermo Scientific). Lysates were clarified by centrifugation at 16,000g for 10 minutes, and supernatants were resolved by SDS-PAGE. Immunoblotting was performed using standard protocols. Antibodies used were ERRα (Cell Signaling #8644) and GAPDH (Cell Signaling #5174). Bands were quantified using a Bio-Rad ChemiDoc MP imaging system.

[0304] 3. BRD4 Western Blot Protocol VCaP cells were purchased from ATCC and cultured in Dulbecco's modified Eagle's medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatments (0.003 μM, 0.01 μM, 0.03 μM, and 0.1 μM) were performed in 12-well plates for 16 h. Cells were harvested and lysed in RIPA buffer (50 mM Tris (pH 8), 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified by centrifugation at 16,000 g for 10 min, and protein concentrations were measured. Equal amounts of protein (20 μg) were subjected to SDS-PAGE analysis, followed by immunoblotting according to standard protocols. The antibodies used were BRD4 (Cell Signaling #13440) and Actin (Sigma #5441). The detection reagent was Clarity Western ECL Substrate (Bio-rad #170-5060).

[0305] 4. AR ELISA Protocol VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle Medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatments (0.0001μM to 1μM) were performed in 96-well plates for 16 hours. Cells were harvested and lysed in cell lysis solution (Catalog#9803) (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM Na2EDTA, 1mM EGTA, 1% Triton, 2.5mM sodium pyrophosphate, 1mM B-glycerophosphate, 1mM Na3VO4, 1ug / ml leupeptin). Lysates were clarified by centrifugation at 16,000g for 10 minutes and analyzed by PathScan AR ELISA (Cell Signaling The PathScan® Total Androgen Receptor Sandwich ELISA Kit is a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) that detects endogenous levels of total androgen receptor protein. Androgen receptor rabbit mAb is coated onto microwells. Upon incubation with cell lysate, the coated antibody captures the androgen receptor protein. After extensive washing, androgen receptor mouse detection mAb is added to detect the captured androgen receptor protein. Anti-mouse IgG, HRP-conjugated antibody is then used to recognize the bound detection antibody. HRP substrate TMB is added to develop color. The absorbance of the color is proportional to the amount of total androgen receptor protein.

[0306] The antibodies included in the kit are custom formulated specific to the kit.

[0307] 5. c-Myc ELISA Assay Protocol 22RV-1 cells were purchased from ATCC and cultured in RPMI+10%FBS medium. Cells were harvested using trypsin (Gibco#25200-114), counted, and seeded in 96-well plates at 30,000 cells / well in a volume of 75 μL / well in RPMI+10%FBS medium. Cells were dosed with compounds diluted in 0.1% DMSO and incubated for 18 hours, then washed and lysed in 50 uL of RIPA buffer (50 mM Tris (pH 8), 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease inhibitors and phosphatase inhibitors. Lysates were clarified by centrifugation at 4000 rpm for 10 minutes at 4°C, then aliquots were added to a 96-well ELISA plate from the Novex Human c-myc ELISA kit, Life Technologies Catalog #KHO2041. 50ul of c-Myc detection antibody was added to each well, the plate was incubated at room temperature for 3 hours, then washed with ELISA wash buffer. 100uL of anti-rabbit IgG-HRP secondary antibody was added to each well and incubated at room temperature for 30 minutes. The plate was washed with ELISA wash buffer, 100uL of TMB was added to each well, then observed for color change every 5 minutes. 100uL of stop solution was added and the plate was read at 450nm.

[0308] D. Results Table 1 presents the results of experimental data obtained with several representative compounds encompassed by the present disclosure. In particular, various cell types were treated with the compounds listed in Table 1. These compounds are identified by chemical structure, mass spectrometry characterization, and compound name.

[0309] Table 1 shows that (A) 10-30% degradation was achieved in cells treated with 1 uM of compounds 1, 6-9, 12, and 17; (B) 31-50% degradation was achieved in cells treated with 1 uM of compounds 2-5, 10, and 20; and (C) >50% degradation was achieved in cells treated with 1 uM of compounds 11, 13-16, 18-19, 21, and 22. Table 1 also shows that (D) compounds 24 and 26-35 achieved IC50 <50 nM, whereas (E) compounds 23 and 25 have IC 50 It indicates that it has.

[0310] The contents of all references, patents, pending patent applications and published patents mentioned throughout this application are hereby expressly incorporated by reference.

[0311] Those skilled in the art will know or can ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. It should be understood that the detailed examples and embodiments described herein are given by way of illustration only and are not to be considered as limiting the invention in any manner. Various modifications and alterations will be suggested to those skilled in the art in light thereof, and such modifications and alterations are deemed to be within the spirit and scope of this application and within the scope of the appended claims. For example, the relative amounts of the components may be changed to optimize the desired effect, additional components may be added, and / or one or more of the components described may be replaced with similar components. Further advantages, features, and functions associated with the systems, methods, and processes of the invention will be apparent from the appended claims. Moreover, those skilled in the art will know or can ascertain many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

[0312] [Table 1] TIFF2025020416000158.tif209141TIFF2025020416000159.tif208144TIFF2025020416000160.tif208128TIFF2025020416000161.tif208142TIFF2025020416000162.tif208128TIFF2025020416000163.tif208131TIFF2025020416000164.tif208132Categories of degradative activity: A = 10-30% decomposition at 1uM 31-50% decomposition at B=1uM >50% decomposition at C=1uM D=IC 50 <50nM E=IC 50 >50nM Cells used in bioassays: 1 VCaP cells 2 Panc02.13 cells 3 Namalwa cells 4 22RV-1 cells

[0313] Sequence information SEQUENCE LISTING <110> ARVINAS OPERATIONS, INC. <120> IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE <150> US 61 / 979,351 <151> 2014-04-14 <160> 5 <170> PatentIn version 3.5 <210> 1 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Primer Sequence <400> 1 gtgccgcgtg gctccatggc cggcgaagga gatcagcagg a 41 <210> 2 <211> 41 <212> DNA <213> Artificial Sequence <220> <223> Primer Sequence <400> 2 gcttcctttc gggcttatta caagcaaagt attactttgt c 41 <210> 3 <211> 50 <212> DNA <213> Artificial Sequence <220> <223> Primer Sequence <400> 3 tcgggcgcgg ctctcggtcc gaaaaggatg tcgtacaact acgtggtaac 50 <210> 4 <211> 61 <212> DNA <213> Artificial Sequence <220> <223> Primer Sequence <400> 4 gcttcctttc gggcttattt ttcgaactgc gggtggctcc aatggatccg agttagctcc 60 t 61 <210> 5 <211> 61 <212> DNA <213> Artificial Sequence <220> <223> Primer Sequence <400> 5 gcttcctttc gggcttactt atcgtcatcg tccttgtagt ccaagcaaag tattactttg 60 t 61

Claims

1. Chemical structure including: L-CLM wherein L is a linker group; and CLM is cereblon E3 ubiquitin ligase binding moiety; The linker group is chemically linked to the CLM. A compound, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

2. Chemical structure including: PTM-L-CLM wherein PTM is a protein targeting moiety that binds to a target protein or polypeptide; The compound of claim 1 , wherein the PTM is chemically linked to the CLM through the linker group.

3. 2. The compound of claim 1, wherein the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide.

4. The compound of claim 3 , wherein the chemical group is a phthalimido group or an analog or derivative thereof.

5. 2. The compound of claim 1, wherein the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

6. the compound further comprises a ULM, a second CLM, a CLM', or a multiple or combination thereof; ULM is an E3 ubiquitin ligase binding moiety; the second CLM has the same chemical structure as the CLM; CLM' is a cereblon E3 ubiquitin ligase binding moiety having a structure different from that of the CLM; 2. The compound of claim 1, wherein the ULM, the second CLM, the CLM', or a plurality or combination thereof, is optionally coupled to an additional linker group.

7. The CLM has the chemical structure represented below: During the ceremony, W is CH ２ , CHR, C=O, SO ２ , NH, and N-alkyl; Each X is independently O, S, or H. ２ selected from the group consisting of: Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is O, S, or H ２ selected from the group consisting of: G and G' are independently H, alkyl, OH, CH optionally substituted with R' ２ -heterocyclyl, and benzyl optionally substituted by R'; Q １ , Q ２ , Q ３ , and Q ４ represents a carbon C substituted with a group independently selected from R′, N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SO ２ R', -SO ２ NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ３ , -CN, -NR'SO ２ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ２ ) NR'R'', -SO ２ NR'COR'', -NO ２ , -CO ２ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ５ , and -OCF ３ Including; R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R ｎ contains a functional group or atom, wherein n is an integer from 1 to 4, and When n is 1, R ｎ is modified to be covalently attached to said linker group (L); and When n is 2, 3, or 4, one R ｎ is modified so as to be covalently bonded to the linker group (L), and other R ｎ is optionally modified to be covalently attached to a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

8. 2. The compound of claim 1, wherein the CLM is selected from the group consisting of: 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodecan-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodecan-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatetradecan-14-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy)phenyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)acetamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecan-18-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy)phenyl]amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; 4-(4-{[(5Z)-3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)propyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propyl)acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)phenyl]ethyl]acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{2-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)phenyl]pyrimidin-5-yl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]-3-fluorophenyl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-2-fluorophenyl}acetamide; 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-3-fluorophenyl}acetamide; and 2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 ２ , ６ ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecan-12-yl}oxy)phenyl]acetamide.

9. The linker group (L) has the following formula: -A ｑ - The compound includes a chemical structural unit represented by the formula: q is an integer greater than 1; and A is independently a bond, CR Ｌ１ R Ｌ２ ,O,S,SO,SO ２ , N.R. Ｌ３ , S.O. ２ N.R. Ｌ３ , SONR Ｌ３ , C.O.R. Ｌ３ , N.R. Ｌ３ C.O.N.R. Ｌ４ , N.R. Ｌ３ SO ２ N.R. Ｌ４ , C.O., C.R. Ｌ１ =CR Ｌ２ , C≡C, SiR Ｌ１ R Ｌ２ , P(O)R Ｌ１ , P(O)OR Ｌ１ , N.R. Ｌ３ C(=NCN)NR Ｌ４ , N.R. Ｌ３ C (=NCN), NR Ｌ３ C(=CNO ２ ) N.R. Ｌ４ , 0 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ cycloalkyl, 0 to 6 R Ｌ１ and / or R Ｌ２ C optionally substituted with a group ３－１１ heterocyclyl, 0 to 6 R Ｌ１ and / or R Ｌ２ aryl optionally substituted with a group, 0 to 6 R Ｌ１ and / or R Ｌ２ heteroaryl, optionally substituted with a group; R Ｌ１ , R Ｌ２ , R Ｌ３ , R Ｌ４ , and R Ｌ５ are each independently H, halo, C １－８ Alkyl, O.C. １－８ Alkyl, SC １－８ Alkyl, NHC １－８ Alkyl, N(C １－８ Alkyl) ２ , C ３－１１ Cycloalkyl, aryl, heteroaryl, C ３－１１ Heterocyclyl, O.C. １－８ Cycloalkyl, SC １－８ Cycloalkyl, NHC １－８ Cycloalkyl, N(C １－８ Cycloalkyl) ２ , N(C １－８ Cycloalkyl) (C １－８ alkyl), OH, NH ２ , S.H., S.O. ２ C １－８ Alkyl, P(O)(OC １－８ Alkyl) (C １－８ alkyl), P(O)(OC １－８ Alkyl) ２ , C.C.-C. １－８ Alkyl, CCH, CH=CH(C １－８ alkyl), C(C １－８ alkyl)=CH(C １－８ alkyl), C(C １－８ alkyl)=C(C １－８ Alkyl) ２ , Si(OH) ３ , Si(C １－８ Alkyl) ３ , Si(OH)(C １－８ Alkyl) ２ , C.O.C. １－８ Alkyl, CO ２ H, halogen, CN, CF ３ , C.H.F. ２ , C.H. ２ F. NO ２ , S.F. ５ , S.O. ２ N.H.C. １－８ Alkyl, SO ２ N (C １－８ Alkyl) ２ , SONHC １－８ Alkyl, SON(C １－８ Alkyl) ２ , CONHC １－８ Alkyl, CON(C １－８ Alkyl) ２ , N(C １－８ alkyl)CONH(C １－８ Alkyl), N(C １－８ alkyl)CON(C １－８ Alkyl) ２ , NHCONH(C １－８ alkyl), NHCON(C １－８ Alkyl) ２ , N.H.C.O.N. ２ , N(C １－８ Alkyl)SO ２ NH (C １－８ Alkyl), N(C １－８ Alkyl)SO ２ N (C １－８ Alkyl) ２ , N.H.S.O. ２ NH (C １－８ alkyl), NHSO ２ N (C １－８ Alkyl) ２ , and N.H.S.O. ２ N.H. ２ and When q is greater than 1, R Ｌ１ Or R Ｌ２ each independently linking to another A group, Ｌ５ 2. The compound of claim 1, which can form a cycloalkyl and / or heterocyclyl moiety which can be further substituted with groups.

10. 3. The compound of claim 2, wherein the PTM is a protein targeting moiety that binds to a target protein, target polypeptide, or fragment thereof, the target protein, target polypeptide, or fragment thereof having a biological function selected from the group consisting of structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction.

11. The PTM group is a moiety that binds to a target protein, and the target protein may be any of B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGFβ-activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitors, bile acid transport inhibitors, 5-alpha reductase inhibitors, angiotensin 11, Glycine 3. The compound of claim 2, selected from the group consisting of lysine receptors, noradrenaline reuptake receptors, estrogen receptors, estrogen related receptors, focal adhesion kinase, Src, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA or NGF receptor, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Still additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

12. 3. The compound of claim 2, wherein the PTM group is an Hsp90 inhibitor; a kinase inhibitor, a phosphatase inhibitor, a HDM2 / MDM2 inhibitor, a compound targeting human BET bromodomain containing protein, a HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting the RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressant compound, a compound targeting the aryl hydrocarbon receptor, a compound targeting the androgen receptor, a compound targeting the estrogen receptor, a compound targeting an estrogen related receptor, a compound targeting the thyroid hormone receptor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease, or a compound targeting acyl protein thioesterase 1 and / or 2.

13. 3. The compound of claim 2, wherein the PTM group is selected from the group consisting of TANK-binding kinase 1 (TBK1), estrogen receptor alpha (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc.

14. A composition comprising the compound of claim 2.

15. A pharmaceutical composition comprising a compound according to claim 2 and a pharma- ceutically acceptable carrier, additive and / or excipient.

16. 16. The pharmaceutical composition of claim 15, further comprising a bioactive agent.

17. 17. The pharmaceutical composition of claim 16, wherein the bioactive agent is an antiviral agent.

18. The pharmaceutical composition of claim 17, wherein the antiviral agent is an anti-HIV agent.

19. 19. The pharmaceutical composition of claim 18, wherein the anti-HIV agent is a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a fusion inhibitor, or a mixture thereof.

20. 18. The pharmaceutical composition of claim 17, wherein the antiviral agent is an anti-HCV agent.

21. 17. The pharmaceutical composition of claim 16, wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, immune agents, cardiovascular agents, and neuroactive agents.

22. 17. The pharmaceutical composition of claim 16, wherein the bioactive agent is an anti-cancer agent.

23. The anticancer drug is everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910. Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR １ KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl [D-Ser(But)6,Azgly]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, acetate salt of [D-Ser(But)6,Azgly]-, (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH ２ Acetate [C ５９ H ８４ N １８ Oi ４ - (C ２ H ４ O ２ ) Ｘ , where x=1-2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP -LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol , epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, strepto Zosyn, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-aspartate Paraginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, erwinia-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,23. The composition of claim 22, wherein the active ingredient is selected from the group consisting of lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

24. 1. A method for inducing degradation of a target protein in a cell, comprising: The method comprising the step of administering to said cell an effective amount of a compound of claim 2.

25. 1. A method for inducing degradation of a target protein in a cell, comprising: The method comprising the step of administering to said cell an effective amount of a compound according to claim 10.

26. 1. A method for inducing degradation of a target protein in a cell, comprising: The method comprising the step of administering to said cell an effective amount of a compound according to claim 11.

27. 1. A method for inducing degradation of a target protein in a patient, comprising: The method comprising the step of administering to said patient an effective amount of a compound according to claim 2.

28. 11. A method for treating a disease state or condition in a patient where the disease state or condition is caused by dysregulated protein activity, the method comprising administering an effective amount of a compound described in claim 2.

29. 29. The method of claim 28, wherein the disease state or condition is asthma, multiple sclerosis, cancer, cilia-related disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

30. 29. The method of claim 28, wherein the disease state or condition is Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, diabetes mellitus type 1, diabetes mellitus type 2, epilepsy, Guillain-Barre syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, vasculitis.

31. The disease state or condition is selected from the group consisting of aceruloplasminemia, type II achondroplasia, achondroplasia, acral cephaly, type II Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple joint laxity (Ehlers-Danlos syndrome #multiple joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyrate cutis syndrome, Mediterranean fever, familial, Ben Jamin syndrome, beta-thalassemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevy-Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dube syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome group (lipoprotein lipase deficiency), CGD chronic granulomatous disease, cuneus limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-a-cat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypoparathyroidism, chondrodystrophy (achondroplasia), otospondylomegalyepphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis),Congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagen disease, conotruncal dysfacial syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden's disease, craniofacial dysostosis (Cruzon's disease), Creutzfeldt-Jakob disease (prion disease), Cockayne's syndrome, Cowden's disease, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson gyrate cutis syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), muscular dystrophies, Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Neurodegenerative disorders including Grouchy syndrome and Dejerine-Sottas disease, Developmental disorders, Distal spinal muscular atrophy, Type V, Androgen insensitivity syndrome, Diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, Dihydrotestosterone receptor deficiency, Androgen insensitivity syndrome, Down's syndrome, Dwarf stature, Erythropoietic protoporphyria, Erythrocytic 5-aminolevulinic acid synthase deficiency, Erythropoietic porphyria, Erythropoietic protoporphyria, Erythropoietic uroporphyria, Friedreich's ataxia, Familial paroxysmal polyserositis, Porphyria cutanea tarda, Familial neuropathy with liability to pressure palsies, Primary pulmonary hypertension (PPH), Fibrocystic disease of the pancreas, Fragile X syndrome, Galactosemia, Hereditary encephalopathy, Giant cells Hepatitis (neonatal hemochromatosis), Glenn-Blood-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disorders including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia,Langer-Sardino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrosis fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Larbhardt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudoelastosis elastosis) xanthomas), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent multiple serositis, retinal disorder, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis complex), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia, Strudwick type SED) spondyloepiphyseal dysplasia congenita, SEMD, spondyloepiphyseal dysplasia, sproutwick type, Shprintzen syndrome, skin pigmentation disorder, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, speech and communication disorder, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia,29. The method according to claim 28, which is selected from the group consisting of thyroid disease, sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo-X syndrome (Triple-X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik's disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum.

32. 29. The method of claim 28, wherein the disease state or condition is cancer.

33. The cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; multiple myeloma, sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, and sarcomas.

33. The method of claim 32, wherein the cancer is selected from the group consisting of tumors, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, spinal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratocarcinoma.

34. 33. The method of claim 32, wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

35. A compound library comprising more than one compound according to claim 1.

36. 1. A method for identifying a compound containing an E3 ubiquitin ligase binding moiety that recognizes cereblon (CRBN), comprising: incubating a test compound with a CRBN protein; determining the amount of said test compound bound to said CRBN protein; The method comprising:

37. The chemical structure represented by: wherein W is CH ２ , CHR, C=O, SO ２ , NH, and N-alkyl; Each X is independently O, S, or H. ２ selected from the group consisting of: Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is O, S, or H ２ selected from the group consisting of: G and G' are independently H, alkyl, OH, CH optionally substituted with R' ２ -heterocyclyl, and benzyl optionally substituted by R'; Q １ , Q ２ , Q ３ , and Q ４ represents a carbon C substituted with a group independently selected from R′, N, or N-oxide; A is independently selected from the group: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SO ２ R', -SO ２ NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetaryl, -alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF ３ , -CN, -NR'SO ２ NR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -NR'C(=N-CN)R'', -NR'C(=C-NO ２ ) NR'R'', -SO ２ NR'COR'', -NO ２ , -CO ２ R', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF ５ , and -OCF ３ Including; R' and R'' are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, hetaryl, and heterocyclyl; represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R ｎ contains a functional group or atom, In the formula, n is an integer from 1 to 4. Cereblon E3 ubiquitin ligase binding moiety (CLM).

38. The R ｎ comprises a functional group or atom covalently linked to a linker group (L), a protein targeting moiety (PTM), an E3 ubiquitin ligase binding moiety (ULM), or any multiple or combination thereof.

39. the ULM is a second CLM, a CLM', or any multiple or combination thereof; The second CLM has the same chemical structure as the CLM; and The CLM of claim 2 , wherein the CLM' is structurally distinct from the CLM.

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