Imide-based protein degradation modulators and related methods of use

Abstract

To provide compounds useful as modulators of targeted ubiquitination and as inhibitors of various polypeptides and other proteins. [Solution] A compound, or a pharmaceutically acceptable salt thereof, enantiomer, stereoisomer, solvate, or polymorph thereof, having the following chemical structure: L-CLM, where L is a linker group and CLM is a cereblon E3 ubiquitin ligase binding site, the linker group being chemically linked to CLM.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is an international PCT application claiming the benefits and priority of U.S. Provisional Application No. 61 / 979,351, filed April 14, 2014, titled "IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE," the prior application which is incorporated herein by reference in its entirety.

[0002] Reference In accordance with Section 1.52(e) of Federal Regulation 37, sequence listing information in a computer-readable format is submitted with this specification using PatentIn-3.5 in .txt format, with filename: Sequence_Listing_ST25.txt; size: 2KB; creation date: April 14, 2015, and this sequence listing information is incorporated herein by reference in its entirety.

[0003] Field of Invention This description provides imide compounds, bifunctional compounds containing them, 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 present invention. [Background technology]

[0004] background Most small molecule drugs bind to enzymes or receptors in tight, clearly defined pockets. Protein-protein interactions, on the other hand, are extremely difficult to target with small molecules due to the large contact surface and shallow grooves or flat interfaces of proteins. E3 ubiquitin ligases (hundreds of which are known in humans) provide substrate specificity for ubiquitination and, therefore, due to their specificity to their particular protein substrates, are more attractive therapeutic targets than general proteasome inhibitors. The development of ligands for E3 ligases has proven difficult, partly because it inevitably disrupts protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of Nutrin, the first small molecule E3 ligase inhibitor, further compounds targeting E3 ligases have been reported, although this field is still developing.

[0005] One type of E3 ligase with potential therapeutic properties is the von Hippel-Lindau (VHL) tumor suppressor. VHL contains a substrate recognition subunit / E3 ligase complex VCB (which includes elongin B and C), as well as a complex containing karin-2 and Rbx1. The main substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as pro-angiogenic growth factor VEGF and erythropoietin in response to hypoxic levels. The inventors believe VHL may be used in cancer, chronic anemia, and ischemia. 2 We created the first von Hippel-Lindau (VHL) small molecule ligand for VCB, the substrate recognition subunit of E3 ligase, a key target of VHL, and obtained its crystal structure, confirming that the compound mimics the binding mode of the transcription factor HIF-1α, the main substrate of VHL.

[0006] Cereblon is a protein encoded by the CRBN gene in humans. CRBN homologous species are highly conserved from plants to humans, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with DNA damage binding protein 1 (DDB1), karin-4A (CUL4A), and karin regulator 1 (ROC1). This complex ubiquitinates numerous other proteins. While 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 numerous developmental processes, such as limb and auditory vesicle formation. The ultimate consequence is that this ubiquitin ligase complex is crucial for limb elongation 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 numerous immunological conditions, and is also approved for the treatment of certain neoplastic diseases, including multiple myeloma. Thalidomide and several of its analogues are currently being studied for use in the treatment of various other types of cancer in addition to multiple myeloma. Although the exact mechanism of thalidomide's antitumor activity is still being elucidated, it is known to inhibit angiogenesis. Recent literature considering the biology of this imide compound includes Lu et al., Science 343, 305 (2014) (Non-patent Literature 1) and Kronke et al., Science 343, 301 (2014) (Non-patent Literature 2).

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

[0009] There is a continuing demand for effective treatments of diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, nonspecific effects and the inability to target and modulate specific classes of proteins, such as transcription factors, remain barriers to the development of effective anticancer drugs. Therefore, small molecule therapeutics that leverage or enhance the substrate specificity of cereblon, while simultaneously being "modulatory" to specifically target and modulate a wide range of protein classes, would be extremely useful as therapeutic agents. [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) [Overview of the Initiative]

[0011] This disclosure relates to a bifunctional compound that functions to recruit and degrade endogenous proteins into E3 ubiquitin ligases, and to methods of using the same. More specifically, this disclosure provides a bifunctional, or proteolytically targeted, chimeric (PROTAC) compound, which, as described herein, finds useful as a modulator of targeted ubiquitination of various polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compound. The advantage of the compounds provided herein is that they enable a broad range of pharmacological activity, consistent with selective polypeptide degradation / inhibition from virtually any protein class or family. This disclosure also provides methods of using the compounds as described herein in effective amounts for the treatment or remission of disease conditions such as cancer, e.g., multiple myeloma.

[0012] Accordingly, in one embodiment, the present disclosure provides novel imide compounds as described herein.

[0013] In a further embodiment, the present disclosure provides a bifunctional, or PROTAC, compound comprising an E3 ubiquitin ligase-binding moiety (i.e., an E3 ubiquitin ligase ligand or "ULM" group) and a target protein-binding moiety (i.e., a protein / polypeptide target-directed ligand or "PTM" group) such that the target protein / polypeptide is positioned in close proximity to the ubiquitin ligase, resulting in the degradation (and inhibition) of that protein. In a preferred embodiment, the ULM is a cerebron E3 ubiquitin ligase-binding moiety (i.e., "CLM"). For example, the structure of a bifunctional compound is as follows: This can be shown as in TIFF2026094376000002.tif10128.

[0014] The arrangements and numbers of the PTM and CLM portions as shown herein are provided for illustrative purposes only and are not intended to limit the compounds in any way. As will be obvious to those skilled in the art, the bifunctional compounds described herein can be synthesized by changing the number and arrangement of each functional portion 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: As shown in TIFF2026094376000003.tif10128, in the figure, PTM is the protein / polypeptide target-directed portion, L is the linker, and CLM is the cerebron E3 ubiquitin ligase binding portion.

[0016] In certain preferred embodiments, the E3 ubiquitin ligase is cereblon. Therefore, in certain further embodiments, the bifunctional compound CLM comprises chemical groups such as imide, amide, thioamide, and thioimide-derived moieties. In further embodiments, CLM comprises a phthalimide group or its analogues or derivatives. In yet another embodiment, CLM comprises a phthalimidoglutarimide group or its analogues or derivatives. In yet another embodiment, CLM comprises members of the group consisting of thalidomide, lenalidomide, pomalidomide, and their analogues or derivatives.

[0017] In certain embodiments, the compounds described herein include multiple CLMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0018] In further embodiments, this description provides therapeutic compositions comprising an effective amount of the compound or a salt thereof as described herein and a pharmaceutically acceptable carrier. The therapeutic compositions modulate proteolysis in patients or subjects, such as animals such as humans, and can therefore be used to treat or induce remission of disease conditions or symptoms regulated through proteolytic proteins. In certain embodiments, the therapeutic compositions as described herein may be used to achieve the degradation of a target protein for the treatment or remission of a disease, such as cancer. In yet another embodiment, the present invention provides a method for ubiquitination / degradation of a target protein in cells. In a particular embodiment, the method comprises administering a bifunctional compound as described herein, comprising CLM and PTM, preferably linked via a linker moiety, as described herein, wherein the CLM is coupled with PTM such that degradation of the target protein occurs when the target protein is located in close proximity to the ubiquitin ligase, resulting in inhibition of the degradation / effect of the target protein and control of protein levels; the CLM recognizes a ubiquitin pathway protein (e.g., ubiquitin ligase, preferably E3 ubiquitin ligase, e.g., cereblon); and the PTM recognizes the target protein. The control of protein levels provided by the present invention offers treatment of a disease condition or symptom regulated through the target protein by reducing its level in the patient's cells.

[0019] In a further embodiment, this description provides a method for assessing (i.e., determining and / or measuring) the binding affinity of CLM. In a particular embodiment, the method includes providing a test agent or compound of interest, e.g., 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 with an agent or compound known to bind to and / or inhibit the activity of cereblon.

[0020] In yet another embodiment, this description provides a method for treating or relieving a disease, disorder, or symptom thereof in a subject or patient, such as an animal such as a human, the method comprising administering to a subject in need of such a method a composition comprising a compound or salt thereof as described herein in an effective amount, for example, a therapeutically effective amount, together with a pharmaceutically acceptable carrier, the composition being effective in treating or relieving a disease, disorder, or symptom thereof in the subject.

[0021] In another embodiment, this description provides a method for identifying the effect of compounds according to the present invention on the degradation of a target protein in a biological system.

[0022] The general scope of application described above is illustrative only and is not intended to limit the scope of this disclosure and the appended claims. Further objectives and advantages relating to the compositions, methods, and processes of the present invention will be apparent to those skilled in the art in light of this claim, description, and examples. For example, various aspects and embodiments of the present invention may be used in numerous combinations, all of which are clearly considered in this description. Such further advantages, objectives, and embodiments are clearly included within the scope of the present invention. To illustrate the background of the present invention and, in special cases, to provide further details relating to the implementation of the invention, the documents and other materials used herein are incorporated by reference. [Brief explanation of the drawing]

[0023] The accompanying drawings, incorporated herein and forming part thereof, illustrate several embodiments of the present invention and, together with the description, serve to illustrate the principles of the present invention. The drawings are for illustrative purposes only of embodiments of the present invention and should not be construed as limiting the invention. Further objects, features, and advantages of the present invention will become apparent from the following detailed description in conjunction with the accompanying drawings illustrating exemplary embodiments of the present invention.

[0024] [Figure 1] Examples of the general principles of PROTAC function. (A) The example PROTAC includes a protein targeting moiety (PTM; dark square), a ubiquitin ligase binding moiety (ULM; light triangle), and an optional linker moiety (L; black line) that couples or links the PTM with the ULM. (B) Examples of the functional use of PROTAC as described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds to a target protein and recruits it to the immediate vicinity of the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes ubiquitin (dark circle) binding to lysine via isopeptide bonds on the target protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasome mechanism. [Modes for carrying out the invention]

[0025] Detailed explanation The following detailed description will assist those skilled in the art in carrying out the invention. Those skilled in the art can modify and alter the embodiments described herein without departing from the spirit or scope of this disclosure. All references, patent applications, patents, drawings, and other references made herein are expressed herein by reference in their entirety.

[0026] This specification describes compositions and methods relating to the unexpected and surprising discovery that an E3 ubiquitin ligase protein, such as cereblon, and a target protein are positioned in close proximity by a bifunctional, i.e., chimeric construct that links the E3 ubiquitin ligase protein and the target protein, and that the E3 ubiquitin ligase protein then ubiquitinates 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"), such compounds and compositions result in ubiquitination of a selected target protein, resulting in the degradation of the target protein by the proteasome (see Figure 1). The present invention also provides a library of compositions and their uses.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. The terminology used in this description is for the purpose of describing specific embodiments and is not intended to limit the present invention.

[0028] When a range of values ​​is presented, naturally, unless explicitly specified in the context (for example, in the case of a group containing the number of carbon atoms, in such a case the number of carbon atoms within that range is presented), each value between the upper and lower limits of that range and any other specified or existing values ​​within that range is included in the present invention, up to a unit of one-tenth of the lower limit. These upper and lower limits of narrower ranges may independently be included in narrower ranges, and these narrower ranges are also included in the present invention and are subject to any limit values ​​that are specifically excluded in the specified range. If the specified range includes one or both of the limit values, ranges that do not include one or both of those limit values ​​are also included in the present invention.

[0029] The following terms will be used to describe the present invention. If a term is not specifically defined herein, it will be given the meaning that is recognized in the art to those skilled in the art in the context in which it is used in the description of the present invention.

[0030] The articles “a” and “an,” when used herein and in the appended claims, indicate that the grammatical object of the article is one or more (i.e., at least one), unless otherwise explicitly stated in the context. For example, “an element” means one or more elements.

[0031] When used in this specification and in the appended claims, the phrase "and / or" naturally means "one or both" of the elements that are thus connected; that is, the elements may be contiguous in some cases and separate in others. Similarly, when multiple elements are listed with "and / or," they should be considered as "one or more" of the elements that are thus connected. Other elements other than those specifically identified by the "and / or" clause may be present at their discretion. For example, and not as an exclusionary statement, when used in conjunction with non-restrictive terms such as "comprising," one embodiment may indicate only A (including elements other than B at their discretion); another embodiment may indicate only B (including elements other than A at their discretion); and yet another embodiment may indicate both A and B (including other elements at their discretion).

[0032] Where used herein and in the appended claims, “or” naturally has the same meaning as “and / or” as defined above. For example, when items are separated in an enumeration, “or” or “and / or” should be interpreted as inclusive, that is, including at least one of the multiple or enumerated elements and any additional items not enumerated by choice, but including more than one. Only terms explicitly indicated to the contrary, such as “only one of” or “exactly one of” or “consisting of” when used in a claim, indicate that it includes exactly one of the multiple or enumerated elements. In general, where used herein, the term “or” should be interpreted as indicating an exclusive choice (i.e., “one or the other, but not both”) only when preceded by terms of exclusivity, such as “either,” “one of,” “only,” or “exactly one.”

[0033] In the claims and in the above specification, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” are, naturally, non-restrictive, meaning they include but are not limited to the object. Only the transitional phrases “consisting of” and “consisting essentially of” are supposed to be restrictive or semi-restrictive, respectively, as specified 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 relation to an enumeration of one or more elements naturally refers to at least one element selected from any one or more elements in that enumeration, but does not necessarily include at least one of each individual element specifically enumerated in the enumeration, nor does it exclude any combination of elements in the enumeration. This definition also allows for the optional presence of elements other than those specifically identified in the enumeration of elements to which the phrase “at least one” refers, whether or not they are related to the specifically identified elements. In other words, it is not limiting, but for example, “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”) could, in one embodiment, indicate at least one A, including optionally multiple cases, but without B (and optionally include elements other than B); in another embodiment, indicate at least one B, including optionally multiple cases, but without A (and optionally include elements other than A); and in yet another embodiment, indicate at least one A, including optionally multiple cases, and at least one B, including optionally multiple cases (and optionally include other elements).

[0035] Naturally, in any particular method described herein that includes multiple steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are described, unless otherwise specified in the context.

[0036] The terms “co-administration,” “co-administering,” and “combination therapy” refer to both simultaneous administration (simultaneous administration of two or more therapeutic agents) and administration at different times (administering one or more therapeutic agents at different times than the administration of further therapeutic agents or agonists), insofar as the therapeutic agents are present in the patient at the same time, to some extent, preferably in effective amounts. In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one further bioactive agonist, particularly an anticancer agent. In particularly preferred embodiments, the co-administration of the compounds results in synergistic activity and / or therapeutic effect, including anticancer activity.

[0037] Where used herein, the term “compound” refers, unless otherwise specified, 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) where applicable, as well as its pharmaceutically acceptable salts and derivatives (including prodrug forms) where applicable in context. Where 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 compound, as well as mixtures biased toward a particular enantiomer or any of the enantiomers. Where applicable in context, the term also refers to prodrug forms of compounds modified to facilitate the administration and delivery of the compound to the site of action. In the description of the compound, numerous substituents and variables associated therewith are specifically described. As is obvious to those skilled in the art, the molecules described herein are stable compounds, as is generally described herein. When bonds are shown, both double and single bonds are represented within the context of the compound being shown.

[0038] The term "ubiquitin ligase" refers to a family of proteins that target specific substrate proteins for degradation by promoting ubiquitin transfer to those substrate proteins. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with E2 ubiquitin-conjugating enzymes, binds ubiquitin to the lysine of target proteins, thereby targeting specific protein substrates for degradation by the proteasome. In other words, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-conjugating enzymes, are responsible for ubiquitin transfer to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin molecule binds to the first, and a third binds to the second. Polyubiquitination labels proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which case only one ubiquitin molecule is attached to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome; instead, their intracellular positioning or function may be altered, for example, through binding to other proteins that have domains capable of binding to ubiquitin. Further complicating matters, different lysines of ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 of the ubiquitin chain, which is used to form polyubiquitin recognized by the proteasome.

[0039] The terms “patient” or “subject” are used throughout this specification to describe animals, preferably humans or domestic animals, to which treatment, including prophylactic treatment, is provided with the compositions according to the present invention. With respect to the treatment of infections, symptoms, or disease conditions specific to certain animals, such as human patients, the term patient refers to certain animals, including domesticated animals such as dogs or cats, or livestock animals such as horses, cattle, or sheep. In general, in the present invention, the term patient refers to human patients unless otherwise specified or indicated by the context in which the term is used.

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

[0041] Compounds and compositions In one embodiment, this description provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM"), namely a cereblon E3 ubiquitin ligase binding moiety ("CLM"). In one embodiment, the CLM has the following structure: (I) L-CLM The compounds are coupled with a chemical linker (L), where L is a chemical linker group and CLM is the cereblon E3 ubiquitin ligase binding site. The number and / or relative arrangement of each part in the compounds described herein are illustrative only. As will be obvious to those skilled in the art, the compounds described herein can be synthesized in any desired number and / or arrangement of each functional part.

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

[0043] In another embodiment, the present invention provides bifunctional or multifunctional PROTAC compounds useful for controlling protein activity by inducing the degradation of target proteins. In certain embodiments, the compound comprises a portion that binds to a target protein (i.e., a protein targeting portion or "PTM") and a CLM that is directly or indirectly coupled, for example, covalently. 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 a target protein, and the interaction between each portion and its respective target promotes the degradation of the target protein by positioning the target protein very close to the ubiquitin ligase protein. Exemplary bifunctional compounds are as follows: (II) PTM-CLM This can be shown as follows.

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

[0045] In certain embodiments, the compounds described herein include multiple PTMs (targeting the same or different proteins), multiple CLMs, one or more ULMs (i.e., moieties that specifically bind to another E3 ubiquitin ligase, e.g., VHL), or a combination thereof. In any aspect of the embodiments described herein, the PTMs, CLMs, and ULMs can be coupled directly, via one or more chemical linkers, or in combination thereof. In further embodiments, if the compound has multiple ULMs, the ULMs may be for the same E3 ubiquitin ligase, or each ULM may specifically bind to a different E3 ubiquitin ligase. In further embodiments, if the compound has multiple PTMs, the PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

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

[0047] In certain embodiments, if the compound contains multiple CLMs, the CLMs are identical. In further embodiments, the compound containing multiple CLMs further includes at least one PTM coupled to the CLMs directly, via a chemical linker (L), or both. In certain further embodiments, the compound containing multiple CLMs further includes multiple PTMs. In further embodiments, the PTMs are identical or optionally different. In further embodiments, if the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0048] In further embodiments, this description provides compounds comprising at least two different CLMs coupled directly, via a chemical linker (L), or both. For example, such compounds comprising two different CLMs are: (VI) CLM-CLM' or (VII)CLM-L-CLM' This can be shown as follows. In the formula, CLM' represents a cereblon E3 ubiquitin ligase binding site which is structurally different from CLM. In certain embodiments, the compound may contain a plurality of CLMs and / or a plurality of CLM'. In further embodiments, a compound containing at least two different CLMs, a plurality of CLMs, and / or a plurality of CLM' further contains at least one PTM coupled to a CLM or CLM' directly, via a chemical linker (L), or both. In any of the embodiments described herein, a compound containing at least two different CLMs may further contain a plurality of PTMs. In further embodiments, the PTMs may be identical or optionally different. In further embodiments, if the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets. In further embodiments, the PTM itself is a ULM or CLM (or a ULM' or CLM').

[0049] In preferred embodiments, CLM comprises a moiety that is a ligand for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, CLM comprises a chemical species derived from a molecule of the "imide" class. In certain further embodiments, CLM comprises a phthalimide group or its analogues or derivatives. In even further embodiments, CLM comprises a phthalimidoglutarimide group or its analogues or derivatives. In yet another embodiment, CLM comprises members of the group consisting of thalidomide, lenalidomide, pomalidomide, and their analogues or derivatives.

[0050] In further embodiments, this description provides compounds as described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salts, such as acid salts and base salts, as polymorphs.

[0051] neoimide compounds In one embodiment, this description provides compounds useful for binding to and / or inhibiting cereblon. In a particular embodiment, the compounds are selected from the group consisting of the following chemical structures: TIFF2026094376000004.tif129131In formula, W is independently selected from the following groups: CH2, CHR, C=O, SO2, NH, and N-alkyl; X is independently selected from the following groups: O, S, and H2; Y is independently selected from the following groups: NH, N-alkyl, N-aryl, N-hetalyl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is independently selected from the following groups, O and S, or H2, however, X and Z cannot both be H2; G and G' are independently selected from the following groups: H, alkyl, OH, optionally substituted CH2-heterocyclyl, and optionally substituted benzyl; Q1-Q4 represent carbon atoms C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the following groups: alkyl, cycloalkyl, Cl, and F; R includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetalil, -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 bond, H, alkyl, cycloalkyl, aryl, hetalyl, and heterocyclyl. n is an integer between 1 and 4; TIFF2026094376000005.tif2128 represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and, R n It contains 1 to 4 independent functional groups or atoms.

[0052] Example CLM Any compound described herein has a chemical structure selected from the following group: TIFF2026094376000006.tif127128In formula, W is independently selected from the following groups: CH2, CHR, C=O, SO2, NH, and N-alkyl; X is independently selected from the following groups: O, S, and H2; Y is independently selected from the following groups: NH, N-alkyl, N-aryl, N-hetalyl, N-cycloalkyl, N-heterocyclyl, O, and S; Z is independently selected from the following groups, O and S, or H2, however, X and Z cannot both be H2; G and G' are independently selected from the following groups: H, alkyl, OH, optionally substituted CH2-heterocyclyl, and optionally substituted benzyl; Q1-Q4 represent carbon atoms C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the following groups: alkyl, cycloalkyl, Cl, and F; R includes, but is not limited to, -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetalil, -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 bond, H, alkyl, cycloalkyl, aryl, hetalyl, and heterocyclyl. n is an integer between 1 and 4; TIFF2026094376000007.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 be covalently bonded with a PTM, a chemical linker group (L), ULM, CLM (or CLM'), or a combination thereof.

[0053] The term "independently" is used herein to indicate that a variable item to which an independent meaning can be applied changes independently each time that meaning is applied.

[0054] The term "alkyl" in this context refers to a linear, branched, or cyclic, fully saturated hydrocarbon radical, i.e., an alkyl group, preferably C1-C1. 10 , more preferably C1-C6 or C1-C3 alkyl groups, where the alkyl group may be substituted. Examples of alkyl groups include, in particular, 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 group is capped at the terminus with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the present invention may be used to covalently bond with a dehalogenase enzyme. Such compounds generally have a side chain ending with an alkyl group having a halogen substituent (often chlorine or bromine) at the distal end (often linked via a polyethylene glycol group), resulting in a covalent bond between the compound having such a portion and the protein.

[0055] The term "alkenyl" refers to a linear, branched, or cyclic C2-C bond containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radicals are exhibited.

[0056] The term "alkynyl" refers to a linear, branched, or cyclic C2-C bond having at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbon radicals are exhibited.

[0057] The term "alkylene" is used, when applicable, as -(CH2) n- indicates a group (where n is generally an integer from 0 to 6), and this group may be substituted. If substituted, the alkylene group is preferably substituted with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group) at one or more methylene groups, 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, as otherwise described herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), the urethane or alkoxy group may be further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), and the polyethylene glycol chain may be substituted with an alkyl chain substituted with one halogen group, preferably a chlorine group (preferably at the distal end of the polyethylene glycol chain, but not limited thereto). In further embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as 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" means that substitution is only by hydrogen atoms. If a certain number of carbon atoms include C0, it means that carbon is absent and replaced by H. That is, carbon atoms in the range C0-C6 include cases with 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, H is present instead of carbon.

[0059] The terms “substituted” or “may be substituted” mean, within the context of the given context, one or more independent substituents (i.e., if multiple substitutions occur, each substituent is independent of other substituents) at carbon (or nitrogen) at any position in the molecule (i.e., each substituent is independent of other substituents) (in some parts of the compound according to the present invention, independently of up to five substituents, preferably up to three substituents, often one or two substituents, which themselves may be further substituted), and substituents include hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (particularly alkyl, particularly methyl, preferably one, two, or three halogens, e.g., trifluoromethyl), alkyl (particularly C1-C) 10, more preferably, C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl, etc.), alkoxy group (preferably C1-C6 alkyl or aryl, which includes phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl), which also includes alkylene ester (where the bond of the substituent is in the alkylene group rather than the ester functional group, and the ester functional group is preferably substituted by a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkyleneamine, and further including C1-C6 alkylamine or C1-C6 dialkylamine, and these alkyl groups may be substituted by one or two hydroxyl groups) or optionally substituted N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (this group may be substituted by a polyethylene glycol chain, and the polyethylene glycol chain is further bonded to an alkyl group having one halogen, preferably chlorine substituent), hydrazine, amide, which is preferably substituted by one or two C1-C6 alkyl groups (amide includes carboxamide, and carboxamide may be substituted by one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl). Examples of the substituents according to the present invention include, for example, -SiR1R2R3 group, wherein R1 and R2 are each as described anywhere in this specification, and R3 is H or a C1-C6 alkyl group, and preferably R1, R2, R3 are, in this context, C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly linked to the substituted part, or alternatively, the substituent may be (CH2) m - through, or optionally substituted (OCH2) m -, -(OCH2CH2) m-, or -(CH2CH2O) m -The alkylene group-(CH2) may be linked to the substituted moiety through the group (which may be substituted with one or more of the substituents described above) (preferably in the case of an aryl or heteroaryl moiety). m -or-(CH2) n - The group or other chains, such as an ethylene glycol chain, may be substituted at any position on the chain. Preferred 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 amino acid side chains as described herein, and may be substituted amides (preferably substituted carboxamides as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which alkyl substituents may be further substituted). In certain embodiments, the alkylene group (often a monomethylene group) is substituted with one or two may be substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, often methyl or O-methyl groups, or amino acid side chains as described herein. In the present invention, a portion of the molecule may be substituted with up to five substituents, preferably up to three substituents. In many cases, the substituted portion in the present invention is substituted with one or two substituents.

[0060] The term "substituted" (where each substituent is independent of any other substituent) means, within the scope of the context in which it is used, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone (including sulfonamide), keto, carboxy, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (in particular C1-C6 alkylene-NR1R2, mono or di-C1-C6 alkylsubstituted amines, which may be substituted with one or two hydroxyl groups). Each of these groups has 1 to 6 carbon atoms, within the scope of the context, unless otherwise specified. In certain embodiments, preferred substituents, depending on the context of use of the substituent, are, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m -(In this specification, m and n are 1, 2, 3, 4, 5, or 6 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, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl),-(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S ,-S(O)-RS (R S C1-C6 alkyl or -(CH2) m Examples include the -NR1R2 group), NO2, CN, or halogens (F, Cl, Br, I, preferably F or Cl). R1 ​​and R2 are, in this context, H or C1-C6 alkyl groups (which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term “substituted” also means, within the chemical context of the defined compound and the substituents used, an aryl or heteroaryl group that may be substituted, or an aryl heterocyclic group that may be substituted, as described elsewhere herein. The alkylene group may also be substituted as disclosed in any of the foregoing, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), an amino acid side chain as described in any of the foregoing, an amide group as described above in the foregoing, or a urethane group OC(O)-NR1R2, where R1 and R2 are as described in any of the foregoing, however, many other groups can be used as substituents. Various optionally substituted portions may be substituted with three or more substituents, preferably three or fewer substituents, preferably one or two substituents. Note that molecular substitution at a specific position is required (in principle, for valence reasons), but in the case of compounds where substitution is not shown, the substitution is considered or understood to be H unless specifically suggested in the context of substitution.

[0061] The terms “aryl” or “aromatic” in context refer to substituted (as described herein) or unsubstituted monovalent aromatic radicals having a monocyclic (e.g., benzene, phenyl, benzyl) or fused ring (e.g., naphthyl, anthracenyl, phenantrenyl, etc.) and can be bonded to the compounds according to the present invention at any available stable position on the ring or as shown in either 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, in particular, for example (as monocyclics) imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or as fused ring systems, indole, quinoline, indidine, azaindridine, benzofurazan, etc., which may be substituted as described above.Examples of heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indidine, azaindidine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinoridine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimida This includes zoles, pyrrolopyridines, pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles, such as thiophenes and benzothiophenes; oxygen-containing aromatic heterocycles, such as furans, pyrans, cyclopentapyrans, benzofurans, and isobenzofurans; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazoles, thiadiazoles, isothiazoles, benzoxazoles, benzothiadiazoles, benzothiadiazoles, phenothiazines, isoxazoles, furazans, phenoxazines, pyrazoloxazoles, imidazothiazoles, thienofurans, phlopyrroles, pyridoxazines, phlopyridines, phlopyrimidines, thienofyrimidines, and oxazoles, all of which may be substituted.

[0062] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring, or multiple fused rings, of which at least one is aromatic, where the rings in the group are substituted with one or more substituents. For example, an aryl group may contain substituents selected from: -(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, amine, mono or di-(C1-C6 alkyl)amine, the alkyl group of the amine may be 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 group (each substituted at the ortho-, meta-, and / or para- positions of the phenyl ring, preferably at the para- position), may be substituted phenyl A phenyl group (this phenyl group itself is preferably substituted with a linker group bonded to a PTM group containing ULM), 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), a naphthyl group, which may be substituted, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole including a methyl-substituted isoxazole, including a methyl-substituted oxazole substituted or alternatively substituted oxazoles, substituted or alternatively substituted thiazoles including methyl-substituted thiazoles, substituted or alternatively substituted isothiazoles including methyl-substituted isothiazoles, substituted or alternatively substituted pyrroles including methyl-substituted pyrroles, substituted or alternatively substituted imidazoles including methylimidazoles, substituted or alternatively substituted benzimidazoles or methoxybenzylimidazoles, substituted or alternatively substituted oxoimidazoles or methyloxoimidazoles, substituted or alternatively substituted diazole groups including methyl-substituted diazole groups, substituted or alternatively substituted pyridine groups including halo-(preferably F) or methyl-substituted pyridine groups or oxapyridine groups (in this case, the pyridine group is linked to the phenyl group by oxygen), substituted or alternatively substituted furans, substituted or alternatively substituted benzofurans, substituted or alternatively substituted dihydrobenzofurans, substituted or alternatively substituted indoles, indolindine or azaindidine (2, 3, or 4-azaidinidine), substituted or alternatively substituted quinolines,and combinations thereof.

[0063] "Carboxyl" represents the group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, but the substituents of these common names are the same as the definitions of the corresponding group as defined herein.

[0064] The term "heteroaryl" or "hetaryl" refers to optionally substituted quinoline (any carbon atom in the quinoline ring that can be bonded to or substituted with a pharmacophore), optionally substituted indole (including dihydroindole), optionally substituted indidine, optionally substituted azaindidine (2, 3, or 4-azaidinidine), optionally substituted benzimidazole, benzodiazole, benzooxofran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol-substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted (CH2)). m -O-C1-C6 alkyl group, or possibly substituted (CH2) m -C(O)-O-C1-C6 alkyl group substituted 1,2,3-triazole, optionally substituted pyridine (2-, 3-, or 4-pyridine), or the group described in the following chemical structures, but not limited thereto: TIFF2026094376000008.tif71128In formula, S c CHR SS , NR URE , or O; R HETThis can be H, CN, NO2, a halo (preferably Cl or F), an optionally substituted C1-C6 alkyl group (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), an 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 a C1-C3 alkyl group); R SS is H, CN, NO2, 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 These are 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 halogens, preferably fluorine groups, or may be substituted heterocycles, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which may be substituted, and Y C is N or CR YC And in the formula, R YCThis can be 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 optionally substituted acetylene group-C≡CR a , where R a This is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group).

[0065] The terms "aralkyl" and "heteroarylalkyl" refer to groups that include both aryl or heteroaryl, as well as alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems, respectively, according to the definitions above.

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

[0067] The term "heterocyclic ring" refers to a cyclic group having at least one heteroatom, e.g., N, O, or S, which may be aromatic (heteroaryl) or non-aromatic. That is, the heteroaryl portion is included in the definition of a heterocyclic ring, depending on the context in which the term is used. Examples of heteroaryl groups are given above in this specification.

[0068] Examples of heterocyclic compounds include, in particular, 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, isothiazolidinyl Ryl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthilidinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranil, tetrahydropyranil, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanil, oxathiolanil, thian.

[0069] The heterocyclic group can be optionally substituted with members selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, 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, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl. Such a heterocyclic group may have a monocyclic ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carborin, phenantholidine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranil, and N-alkoxy nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which one of the heterocyclic rings is fused with a benzene ring, a cyclohexane ring, or another heterocyclic ring (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0070] The term "cycloalkyl" can mean, but is not limited to, a monovalent group derived from a monocyclic or polycyclic alkyl group, i.e., a cycloalkane, as defined herein, such as a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "substituted cycloalkyl" can mean, but is not limited to, a monocyclic or polycyclic alkyl group substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo. The substituents in these common names have the same meaning as the definitions of the group as defined in this explanation.

[0071] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P. "Substitutive heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is substituted with a heteroatom selected from the group consisting of N, O, S, or P, and which has one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto, or sulfo, where the substituents in these common names have the same meaning as the definition of the group as defined in this explanation.

[0072] The term "hydrocarbyl" means a compound having carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and may contain 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 independently be covalently bonded to a linker and / or a linker bonded to one or more PTM, ULM, CLM, or CLM' groups.

[0074] More specifically, examples of CLMs, not limiting ones, are those listed below, as well as "hybrid" molecules resulting from one or more combinations of the different characteristics shown in the molecules listed below. TIFF2026094376000009.tif200148TIFF2026094376000010.tif149156TIFF20260943760 00011.tif209156TIFF2026094376000012.tif206155TIFF2026094376000013.tif114140

[0075] Linker example In certain embodiments, the compounds described herein can be chemically linked or coupled via a chemical linker (L). In certain embodiments, the linker group L is a group comprising structural units A connected by one or more covalent bonds (e.g., -A1...A q -), where A1 is a group coupled with at least one of ULM, PTM, or a combination thereof. In a particular embodiment, A1 directly couples a ULM, PTM, or a combination thereof with another ULM, PTM, or a combination thereof. In another embodiment, A1 couples a ULM, PTM, or a combination thereof with another ULM, PTM, or a combination thereof. q They are indirectly connected through [this].

[0076] In certain embodiments, A1~A q Each is independent, combined, and CR. L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 , SONRL3 , CONR L3 , NR L3 CONR L4 , NR L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 groups, optionally substituted C 3-11 cycloalkyl, 0 to 6 R L1 and / or R L2 groups, optionally substituted C 3-11 heterocyclyl, 0 to 6 R L1 and / or R L2 groups, optionally substituted aryl, 0 to 6 R L1 and / or R L2 groups, optionally substituted heteroaryl, where R L1 or R L2 may each independently link with other A groups to form a cycloalkyl and / or heterocyclyl moiety, and the formed moiety may be further substituted with 0 to 4 R L5 groups; wherein, R L1 , R L2 , R L3 , R L4 , and R L5 are each independently H, halo, 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 a particular embodiment, q is a non-negative integer. In a particular embodiment, q is a non-negative integer.

[0078] In a particular embodiment, for example, if q is greater than 2, A q This is a base that connects to the ULM or ULM' portion, and A1 and A q They are connected via structural unit A (number of such structural unit A: q-2).

[0079] In a particular embodiment, for example, if q is 2, A q This is a base that connects to A1 and to the ULM or ULM' portion.

[0080] In a particular embodiment, for example, when q is 1, the structure of the linker group L is -A1-, where A1 is a group that connects to the ULM or ULM' portion and the PTM portion.

[0081] In a further embodiment, q is an integer between 1 and 100, 1 and 90, 1 and 80, 1 and 70, 1 and 60, 1 and 50, 1 and 40, 1 and 30, 1 and 20, or 1 and 10.

[0082] In a particular embodiment, the linker (L) is as follows: Selected from the group consisting of TIFF2026094376000014.tif50128 and TIFF2026094376000015.tif230147.

[0083] In further embodiments, the linker group is a 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, and 2 to 4 ethylene glycol units, or a substituted alkyl group having 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 embodiment of the compounds described herein, the linker group may be any suitable group as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group having a size in the range of about 1 to about 12 ethylene glycol units, 1 to about 10 ethylene glycol units, about 2 to 6 ethylene glycol units, about 2 to 5 ethylene glycol units, or about 2 to 4 ethylene glycol units.

[0085] Although the CLM (or ULM) group and the PTM group can be covalently bonded to the linker group through any group suitable and stable for the chemical properties of the linker, in a preferred embodiment of the present invention, the linker is independently covalently bonded to the CLM group and the PTM group, preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, and these groups may be inserted at any position on the CLM group and the PTM group to maximize the binding of the CLM group to the ubiquitin ligase and the binding of the PTM group to the target protein to be degraded. (In a particular embodiment where the PTM group is a ULM group, the target protein to be degraded may be the ubiquitin ligase itself.) In a particular preferred embodiment, the linker may be linked to the CLM and / or PTM group to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group.

[0086] Examples of PTM In a preferred embodiment of the present invention, the PTM group is a group that binds to a target protein. The target of the PTM group is selected from proteins expressed in cells, of which there are many types, and at least a portion of the sequence is found in cells and is capable of binding to the PTM group. The term "protein" includes oligopeptide sequences and polypeptide sequences of sufficient length that can bind to the PTM group according to the present invention. Any protein of the eukaryotic or microbial system, including viruses, bacteria, or fungi, as described in any part of this specification, is a target of ubiquitination mediated by the compound according to the present invention. Preferably, the target protein is a eukaryotic protein. In a particular embodiment, the protein-binding moiety is a C1-C substituted with a haloalkane, preferably at least one halo group. 10 The haloalkane is an alkyl group, preferably with the halo group located at the distal end of the alkyl group (i.e., away from the linker or CLM group), and this haloalkane can covalently bind to a dehalogenase enzyme in a patient or subject, or in a diagnostic assay.

[0087] Examples of PTM groups according to the present invention include any moiety that specifically binds to a protein (bounds to a target protein), and the following small molecule target protein moieties are listed as examples, not limitations: among many, 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 aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some of the members of these nine types of small molecule target protein binding moieties. Examples of such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding moieties are linked to a ubiquitin ligase binding moiety, preferably via a linker, for the purpose of bringing the target protein (to which the protein target-directing moiety binds) to the vicinity of the ubiquitin ligase for ubiquitination and degradation.

[0088] Any protein that can bind to a protein targeting moiety, i.e., a PTM group, and is acted upon or degraded by a ubiquitin ligase, can be considered a target protein according to the present invention. Generally, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integrated function of cells, including proteins with catalytic activity, aromatase activity, kinetic activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolytic activity, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signaling factor activity, structural molecule activity, and binding activity (proteins, lipids, etc.). Proteins related to carbohydrates, receptor activity, cell motility, membrane fusion, intercellular signaling, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins related to cell death, transport-related proteins (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, and electron transporter activity), pathogenicity, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular organization and biosynthesis activity, and translation regulatory activity can be cited. Target proteins can be derived from eukaryotes and prokaryotes, and among the many such organisms, humans as targets of drug therapy, other animals including domesticated animals, microorganisms for the evaluation of antibiotics and other antimicrobial agents, as well as plants and even viruses.

[0089] In further embodiments, the PTM group is a haloalkyl group, which generally has a length ranging from about 1 or 2 to about 12 carbon atoms, often about 2 to 10 carbon atoms, often about 3 to about 8 carbon atoms, and more often about 4 to about 6 carbon atoms. The haloalkyl group is generally a linear alkyl group (although segmented alkyl groups can also be used), with at least one halogen group, preferably a single halogen group, often a single chloride group, capped at the ends. The haloalkyl PT group for use in the present invention is preferably of the chemical structure -(CH2) v - Represented by a halo, where v is any integer between 2 and approximately 12, often between approximately 3 and approximately 8, and more often between approximately 4 and approximately 6. The halo can be any halogen, but is preferably Cl or Br, and more often Cl.

[0090] In another embodiment, the present invention provides a library of compounds comprising several compounds, each composition having formula AB, where A is a ubiquitin pathway protein-binding moiety (preferably an E3 ubiquitin ligase moiety as disclosed herein), B is a protein-binding member of the molecular library, A is coupled to B (preferably through a linker moiety), and the ubiquitin pathway protein-binding moiety recognizes a ubiquitin pathway protein, particularly an E3 ubiquitin ligase, such as cereblon. In a particular embodiment, the library contains a specific cereblon E3 ubiquitin ligase-binding moiety bound to a random set of target protein-binding elements (e.g., a compound library). In such a case, 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 ligases.

[0091] The present invention can also be used to treat a number of disease conditions and / or symptoms, including any disease conditions and / or symptoms in which proteins are dysregulated and any disease conditions and / or symptoms in which the breakdown of proteins is beneficial to the patient.

[0092] In a further embodiment, this description provides therapeutic compositions comprising an effective amount of the compound or a salt thereof as described herein, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally additional bioactive agents. The therapeutic compositions can be used to modulate proteolysis in a patient or subject, such as an animal such as a human, and to treat or induce remission of a disease condition or symptom modulated through the degraded protein. In a particular embodiment, the therapeutic compositions as described herein can be used to bring about the degradation of a protein of interest for the treatment or remission of a disease, such as cancer. In a particular further embodiment, the disease is multiple myeloma.

[0093] In an alternative embodiment, the present invention relates to a method for treating or achieving remission of a disease condition or symptoms in a subject requiring treatment of a disease condition or remission of symptoms of a disease or symptom, by degrading proteins or polypeptides that modulate the disease condition or symptoms, the method comprising administering to the patient or subject at least one of the compounds described herein above in an effective amount, e.g., a therapeutically effective amount, in combination with optionally pharmaceutically acceptable carriers, additives, or excipients, and optionally additional physiologically active agents, the composition being effective in treating or achieving remission of the disease or disorder or symptoms in the subject. The method according to the present invention can be used to treat a very large number of disease conditions or symptoms, including cancer, by administering at least one of the compounds described herein in an effective amount. The disease condition or symptoms may be caused by microbial pathogens or other exogenous pathogens, e.g., viruses, bacteria, fungi, protozoa, or other microorganisms, or they may be caused by protein overexpression that leads to the disease condition or symptoms.

[0094] In another embodiment, this description provides a method for identifying the effect of compounds according to the present invention on the degradation of a target protein in a biological system.

[0095] The term "target protein" is used to describe a protein or polypeptide that is targeted for binding with the compounds according to the present invention and for degradation by ubiquitin ligases. Such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of their compositions, as well as other small molecules that can target the protein of interest. These binding moieties are linked to a CLM or ULM group via a linker group L.

[0096] Any protein or peptide, including its fragments, analogues, and / or homologues, can be listed as target proteins that may bind to a protein targeting moiety and may be degraded by a ligase bound to a ubiquitin ligase binding moiety. Target proteins include any protein and peptide having any biological function or activity, such as structural, regulatory, hormonal, enzymatic, gene, immune, contractile, storage, transport, and signaling functions or activities. In certain embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, and proteins associated with the integrated function of cells, such as proteins with catalytic activity, aromatase activity, kinetic activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolytic activity, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signaling factor activity, structural molecular activity, etc. Proteins involved in synthetic activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, intercellular signaling, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins related to cell death, transport-related proteins (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, and electron transporter activity), pathogenicity, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular organization and biosynthesis activity, and translation regulatory activity can be listed. Target proteins can include proteins derived from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites. Among the many such organisms, humans, microorganisms, viruses, fungi, and parasites are particularly noteworthy as targets for drug therapy. Among the many such organisms, humans, microorganisms, viruses, fungi, and parasites are particularly noteworthy as targets for drug therapy, as are other animals including domesticated animals, microorganisms for evaluating antibiotics and other antimicrobial agents, plants, and even viruses.

[0097] More specifically, numerous proteins, which serve as drug targets for human therapeutics, become protein targets that can potentially bind to the protein targeting moiety and are incorporated into the compound according to the present invention. Examples of such proteins include those that can be used to restore function in numerous polygenic diseases, such as B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners of the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, 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 receptor, and JAW. STAT, RXR and similar, HIV1 protease, HIV1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channels, multidrug resistance (MDR), protein P glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptors, inosine monophosphate dehydrogenase, p38MAP kinase, Ras1Raf1MEWERK pathway, interleukin-1 converting enzyme, caspase, 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 transport protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin-11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Examples of target proteins include EGF receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, TrkA (i.e., NGF receptors), beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21neu, telomerase inhibitors, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, GABAergic chloride channel ion channels, acetylcholinesterases, voltage-sensitive sodium channel proteins, calcium-releasing channels, and chloride channels. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvir shikimate phosphate synthase.

[0098] Haloalkane dehalogenase enzymes are another target of the specific compounds according to the present invention. Compounds according to the present invention having a chloroalkane peptide bond moiety (C1-C12, often about C2-C10 alkylhalo 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 for screening to identify compound moieties that bind to proteins, and by incorporating such moieties into the compounds according to the present invention, the activity level of the protein can be modified for the ultimate therapeutic outcome.

[0100] A "protein targeting moiety," or PTM, is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest, placing / bringing that protein or polypeptide close to the ubiquitin ligase so that ubiquitin ligase degradation of that protein or polypeptide may occur. Examples, though not limiting, of small molecule target protein-binding moieties include, among many others, 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 aryl hydrocarbon receptors (AHRs). The compositions described below exemplify some of these nine types of small molecule target proteins.

[0101] Examples of protein targeting moieties in this disclosure include haloalkanehalogenase 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 aryl hydrocarbon receptors (AHRs).

[0102] The compositions described below exemplify some of the members of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of those compositions, as well as other small molecules that may target the protein of interest. References made herein below shall be 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, include YKB(N-[4-(3H-imidazo[4,5-C]pyridine-2-yl)-9H-fluoren-9-yl]-succinamide): TIFF2026094376000016.tif50128 is included, and in derivatization, the linker group L or -(L-CLM) group is bonded, for example, via a terminal amide group.

[0105] 2. HSP90 inhibitor p54 (modified form) (8-[(2,4-dimethylphenyl)sulfanyl]-3]penta-4-in-1-yl-3H-purine-6-amine): In this case, the linker group L or -(L-CLM) group is bonded, for example, via a terminal acetylene group.

[0106] 3. HSP90 inhibitors (or modified versions thereof) 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), include the compound 2GJ(5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholine-4-ylmethyl)phenyl]isoxazole-3-carboxamide), which has the following structure: TIFF2026094376000018.tif53128 is included, and in derivatization, the linker group L or -(L-CLM) group is bonded, for example, via an amide group (in the amine or in the alkyl group of the amine).

[0107] 4. HSP90 inhibitors (modified forms thereof) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, include the HSP90 inhibitor PU3 having the following structure: TIFF2026094376000019.tif37128 is included, in which case the linker group L or -(L-CLM) group is bonded, for example, via a butyl group.

[0108] 5. 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 this) or any of its derivatives (e.g., 17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")) (in derivatization, the linker group L or -(L-CLM) is linked, for example, via an amide group).

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

[0110] 1. Erlotinib derivative tyrosine kinase inhibitors: In formula TIFF2026094376000020.tif31128, R is, for example, a linker group L or -(L-CLM) group bonded via an ether group.

[0111] 2. Kinase inhibitor sunitinib (or its derivatives): TIFF2026094376000021.tif32128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded via a pyrrole moiety).

[0112] 3. Kinase inhibitor sorafenib (or its derivatives): TIFF2026094376000022.tif24128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded via an amide moiety).

[0113] 4. Kinase inhibitor dasatinib (or its derivatives): TIFF2026094376000023.tif42128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to a pyrimidine).

[0114] 5. Kinase inhibitors lapatinib (and its derivatives): TIFF2026094376000024.tif46128 (In derivatization, the linker group L or -(L-CLM) group is bonded, for example, via a terminal methyl group of a sulfonylmethyl group).

[0115] 6. Kinase inhibitor U09-CX-5279 (or its derivatives): In derivatization, the linker group L or -(L-CLM) is bonded to, for example, an amine (aniline), a carboxylic acid, or a cyclopropyl group via an alpha-position amine or 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), include kinase inhibitors Y1W and Y1X (derivatives thereof) having the following structures: TIFF2026094376000026.tif44128 contains YIX(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea In derivatization, the linker group L or -(L-CLM) group is, for example, i Bonded via a propyl group; TIFF2026094376000027.tif48128YIW 1-(3-tert-butyl-1-phenyl-1H-pyrazole-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea In derivatization, the linker group L or -(L-CLM) group is bonded, for example, preferably 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, include compounds 6TP and 0TP (derivatives thereof) having the following structures: TIFF2026094376000028.tif351286TP 4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide Thienopyridine compound 19 In derivatization, the linker group L or -(L-CLM) is attached, for example, via a terminal methyl group bonded to the amide moiety; TIFF2026094376000029.tif351280TP 4-amino-N-methyl-2-[4-(morpholine-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide Thienopyridine compound 8 In derivatization, the linker group L or -(L-CLM) is attached, for example, via a terminal methyl group bonded to the amide moiety.

[0118] 9. Kinase inhibitors identified in VanEis, 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, include the kinase inhibitor 07U having the following structure: TIFF2026094376000030.tif4212807U 2-Methyl-N~1~-[3-(pyridine-4-yl)-2,6-naphthyridine-1-yl]propan-1,2-diamine In derivatization, the linker group L or -(L-CLM) is bonded via, for example, 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), include the kinase inhibitor YCF having the following structure: TIFF2026094376000031.tif23128 is included, and in derivatization, the linker group L or -(L-CLM) group is bonded via, for example, one 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), include the kinase inhibitors XK9 and NXP (derivatives thereof) having the following structures: TIFF2026094376000032.tif28128XK9 N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide; TIFF2026094376000033.tif58128NXP N-{4-[(1E)-N-carbamimidoleethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide In derivatization, the linker group L or -(L-CLM) is bonded via, for example, a terminal hydroxyl group (XK9) or a hydrazone group (NXP).

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

[0122] 13. Kinase inhibitor fostamatinib (or its derivatives) (dihydrogen phosphate [6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidine-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazine-4-yl]methyl hexahydrate) (In derivatization, the linker group L or -(L-CLM) is attached, for example, via a methoxy group).

[0123] 14. Kinase inhibitor gefitinib (or its derivatives) (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-ylpropoxy)quinazoline-4-amine): TIFF2026094376000034.tif32128 (In derivatization, the linker group L or -(L-CLM) group is bonded via, for example, a methoxy or ether group).

[0124] 15. Kinase inhibitor lenvatinib (or its derivatives) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide) (in derivatization, the linker group L or -(L-CLM) is linked, for example, via a cyclopropyl group).

[0125] 16. Kinase inhibitor vandetanib (or its derivatives) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidine-4-yl)methoxy]quinazoline-4-amine) (in derivatization, the linker group L or -(L-CLM) is attached via, for example, a methoxy or hydroxyl group).

[0126] 17. Kinase inhibitor vemurafenib (or its derivatives) (propan-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl}amide) (In derivatization, the linker group L or -(L-CLM) is attached via, for example, a sulfonylpropyl group).

[0127] 18. Kinase inhibitor Gleebec (and its derivatives): TIFF2026094376000035.tif40128 (In derivatization, R is linked as a linker group L or -(L-CLM) group, for example, via an amide group or an anilineamine group).

[0128] 19. Kinase inhibitors: Pazopanib (or its derivatives) (VEGFR3 inhibitors): TIFF2026094376000036.tif37128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to the phenyl moiety or via an anilineamine group).

[0129] 20. Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor TIFF2026094376000037.tif33128 (In this case, R is, for example, a linker group L or -(L-CLM) group bonded to the phenyl portion).

[0130] 21. Kinase inhibitor TAE684 (derivative) ALK inhibitor TIFF2026094376000038.tif38128 (In this case, R is, for example, a linker group L or -(L-CLM) group bonded to the phenyl portion).

[0131] 22. Kinase inhibitors: Nilotinib (and its derivatives), Abl inhibitors: TIFF2026094376000039.tif43128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to the phenyl moiety or to the anilineamine group).

[0132] 23. Kinase inhibitor NVP-BSK805 (derivative) JAK2 inhibitor TIFF2026094376000040.tif48128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to a phenyl moiety or diazole group).

[0133] 24. Kinase inhibitors, crizotinib derivatives, Alk inhibitors TIFF2026094376000041.tif53128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to a phenyl moiety or diazole group).

[0134] 25. Kinase inhibitors JNJ FMS (derivatives) inhibitors TIFF2026094376000042.tif39128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to the phenyl portion).

[0135] 26. Kinase inhibitors: Foretinib (and its derivatives), Met inhibitors TIFF2026094376000043.tif36128 (In derivatization, R is, for example, a linker group L or -(L-CLM) group bonded to the hydroxyl or ether group of the phenyl or quinoline moiety).

[0136] 27. Allosteric protein tyrosine phosphatase inhibitor PTP1B (or its derivatives): In derivatization, the linker group L or -(L-CLM) group is bonded, for example, at R, as shown.

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

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

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

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

[0141] 32. Kinase inhibitor OSI-930 (derivative) c-Kit / KDR inhibitor In the case of TIFF2026094376000049.tif72128 derivatization, the linker group L or the -(L-CLM) group binds, for example, at R.

[0142] 33. Kinase inhibitor OSI-906 (derivatives) IGF1R / IR inhibitor In the case of TIFF2026094376000050.tif58128 derivatization, the linker group L or the -(L-CLM) group binds, for example, at R; (in derivatization, "R" designates the binding site of the linker group L or the -(L-CLM) group in 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 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 the compounds, Nutlin-3, Nutlin-2, and Nutlin-1 (derivatives) as described below, as well as their derivatives and analogs (or are added): TIFF2026094376000051.tif52128 (in derivatization, the linker group L or the -(L-CLM) group binds, for example, at the methoxy group or as a hydroxyl group); TIFF2026094376000052.tif46128(In derivatization, the linker group L or the -(L-CLM) group binds, for example, at a methoxy group or a hydroxyl group); TIFF2026094376000053.tif52128(In derivatization, the linker group L or the -(L-CLM) group binds, for example, via a methoxy group or as a hydroxyl group).

[0145] 2.Trans-4-Iodo-4'-Boranil-Chalcone TIFF2026094376000054.tif27128(In derivatization, the linker group L or the -(L-CLM) group binds, for example, via a hydroxyl group).

[0146] IV. Compounds Targeting Human BET Bromodomain-Containing Proteins: Examples of compounds targeting human BET bromodomain-containing proteins include, but are not limited to, compounds related to the targets as described below, where "R" designates the binding site of the linker group L or the -(L-CLM) group.

[0147] 1. JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010). TIFF2026094376000055.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). TIFF2026094376000056.tif37128

[0149] 3. Compounds described by Hewings et al., 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770. TIFF2026094376000057.tif34128

[0150] 4.I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion leukemia. Nature(2011): TIFF2026094376000058.tif53128 (wherein R specifies, in each case, for example, the linker group L or the -(L-CLM) group bonding site).

[0151] V.HDAC inhibitors: Examples of HDAC inhibitors (or derivatives thereof) include, but are not limited to, the following:

[0152] 1.Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999). TIFF2026094376000059.tif35128 (In derivatization, "R" specifies, for example, the linker group L or -(L-CLM) group binding site).

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

[0154] VI. Human lysine methyltransferase inhibitors: Examples of human lysine methyltransferase inhibitors include, but are not limited to, the following.

[0155] 1.Chang et al. Structural Basis for G9a-Like protein Lysine Methyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16(3) 312. TIFF2026094376000060.tif41128 (In derivatization, "R" specifies, for example, the linker group L or -(L-CLM) group binding site).

[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. TIFF2026094376000061.tif39144 (In derivatization, "R" specifies, for example, the linker group L or -(L-CLM) group binding site).

[0157] 3. Azacitidine (or its derivatives) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazine-2(1H)-one) (In derivatization, the linker group L or -(L-CLM) is linked, for example, via a hydroxyl or amino group).

[0158] 4. Decitabine (or its derivatives) (4-amino-1-(2-deoxy-bD-erythropentofuranosyl)-1,3,5-triazine-2(1H)-one) (in derivatization, the linker group L or -(L-CLM) is attached, for example, via a hydroxyl group or at an amino group).

[0159] VII. Angiogenesis inhibitors: Examples of angiogenesis inhibitors include, but are not limited to, the following.

[0160] 1. GA-1 (and its derivatives) and their derivatives and analogs having a 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 binding to a linker.

[0161] 2. Estradiol (and its derivatives) that can bind to a linker group L or -(L-CLM) group, generally as 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 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 binding to a linker group L or -(L-CLM) group, including but not limited to DHT and its derivatives and analogs.

[0163] 4. Obalicin, fumagilin (derivatives), and derivatives and analogs thereof, having the structure generally 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. Patent No. 7,208,157, and bound to a linker group L or -(L-CLM) group.

[0164] VIII. Immunosuppressive compounds: Examples of immunosuppressive compounds include, but are not limited to, the following.

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

[0166] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (in derivatization, the linker group L or -(L-CLM) is bonded to either a hydroxyl group, for example) and beclomethasone dipropionate (in derivatization, the linker group L or -(L-CLM) is bonded to a propionic acid group, for example).

[0167] 3. Methotrexate (in derivatization, the linker group L or -(L-CLM) is attached to one of the terminal hydroxyls, for example).

[0168] 4. Cyclosporine (In derivatization, the linker group L or -(L-CLM) can be bonded with, for example, a butyl group).

[0169] 5. Tacrolimus (FK-506) and rapamycin (in derivatization, the linker group L or -(L-CLM) can be bonded with, for example, one of the methoxy groups).

[0170] 6. Actinomycin (In derivatization, the linker group L or -(L-CLM) can be bonded with one of the isopropyl groups, for example).

[0171] IX. Compounds that target aryl hydrocarbon acceptors (AHRs): Compounds that target aryl hydrocarbon acceptors (AHRs) include, but are not limited to, the following:

[0172] 1. Apigenin is derivatized by bonding to a linker group L or -(L-CLM) in the manner generally 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 (derivativeized to have a linker group L or -(L-CLM) attached) 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] Compounds that target the X.RAF receptor (kinase): TIFF2026094376000062.tif49128 (In derivatization, for example, "R" specifies the linker group L or -(L-CLM) group binding site).

[0175] Compounds that target XI.FKBP: TIFF2026094376000063.tif64128 (In derivatization, for example, "R" specifies the linker group L or -(L-CLM) group binding site).

[0176] XII. Compounds that target the androgen receptor (AR) 1. Androgen receptor RU59063 ligand (or derivative thereof) TIFF2026094376000064.tif29128 (In derivatization, for example, "R" specifies the linker group L or -(L-CLM) group binding site).

[0177] 2. SARM ligands (or derivatives) of androgen receptors TIFF2026094376000065.tif29128 (In derivatization, for example, "R" specifies the linker group L or -(L-CLM) group binding site).

[0178] 3. Androgen receptor ligand DHT (or its derivatives) TIFF2026094376000066.tif35128 (In derivatization, for example, "R" specifies the linker group L or -(L-CLM) group binding site).

[0179] 4. MDV3100 ligand (or derivative thereof) TIFF2026094376000067.tif22128

[0180] 5. ARN-509 ligand (or derivative thereof) TIFF2026094376000068.tif22128

[0181] 6. Hexahydrobenzoisoxazole TIFF2026094376000069.tif22128

[0182] 7. Tetramethylcyclobutane TIFF2026094376000070.tif28128

[0183] XIII. Compounds targeting the estrogen receptor (ER) ICI-182780 1. Estrogen receptor ligand TIFF2026094376000071.tif28128 (In derivatization, "R" specifies the linker group L or -(L-CLM) group binding site).

[0184] XIV. Compounds that target thyroid hormone receptors (TRs) 1. Thyroid hormone receptor ligands (or derivatives thereof) TIFF2026094376000072.tif62128 (In derivatization, "R" specifies the linker group L or -(L-CLM) group binding site, and MOMO indicates a methoxymethoxy group).

[0185] Compounds that target XV HIV protease 1. HIV protease inhibitors (or derivatives thereof) TIFF2026094376000073.tif24128 (In derivatization, "R" specifies the linker group L or -(L-CLM) binding site). See J. Med. Chem. 2010, 53, 521-538.

[0186] 2. HIV protease inhibitors TIFF2026094376000074.tif34128 (In derivatization, "R" specifies a site where a linker group L or -(L-CLM) group may be attached). See J. Med. Chem. 2010, 53, 521-538.

[0187] XVI. Compounds targeting HIV integrase 1. HIV integrase inhibitors (or derivatives thereof) TIFF2026094376000075.tif49128 (In derivatization, "R" specifies the linker group L or -(L-CLM) binding site). See J.Med.Chem.2010, 53, 6466.

[0188] 2. HIV integrase inhibitors (derivatives) TIFF2026094376000076.tif47128

[0189] 3. HIV integrase inhibitor Isentress (or its derivatives) TIFF2026094376000077.tif31128 (In derivatization, "R" specifies the linker group L or -(L-CLM) binding site). See J. Med. Chem. 2010, 53, 6466.

[0190] XVII. Compounds targeting HCV protease 1. Inhibitors (or derivatives) of HCV protease TIFF2026094376000078.tif70128 (In derivatization, "R" specifies the linker group L or -(L-CLM) group binding site).

[0191] XVIII. Compounds targeting acyl protein thioesterase-1 and -2 (APT1 and APT2) 1. Inhibitors (or derivatives) of APT1 and APT2 TIFF2026094376000079.tif52128 (In derivatization, "R" specifies the binding site of the linker group L or -(L-CLM) group). See Angew. Chem. Int. 2011, 50, 9838-9842, where L is a linker group as described herein, and the CLM group is as described herein, where -(L-CLM) is used to bond the CLM group to the PTM group as described herein.

[0192] therapeutic composition A further embodiment of the present disclosure is a pharmaceutical composition comprising, in an effective amount, at least one of the bifunctional compounds described herein, and all of the one or more compounds described herein in effective amounts, and further comprising a pharmaceutically effective amount of a carrier, excipient, or other excipient.

[0193] This disclosure includes, where applicable, compositions comprising pharmaceutically acceptable salts of the compounds described herein, more particularly, acid or base addition salts. Acids used to prepare pharmaceutically acceptable acid addition salts of the above basic compounds useful in this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acidic phosphates, acetates, lactates, citrates, acidic citrates, tartrates, bisulfates, succinates, maleates, fumarates, glucons, sugarates, benzoates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates [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 produce pharmaceutically acceptable salts of the compounds or derivatives of the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the acidic compounds of the present invention are those that form a non-toxic base salt with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmaceutically 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 other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines.

[0195] The compounds described herein may be administered orally, parenterally, or topically in single or divided doses, according to this disclosure. Administration of the active compounds can range from continuous administration (intravenous infusion) to multiple daily oral administrations (e.g., QID), and among the routes of administration, oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include osmotic enhancers), buccal, sublingual, and suppository administration are particularly possible. Enteric-coated oral tablets can also be used to improve the bioavailability of the compounds from the oral administration route. The most effective dosage form will depend on the pharmacokinetics of the selected specific activator and the severity of the patient's disease. Administration of the compounds according to this disclosure as sprays, mists, or aerosols for nasal, intratracheal, or pulmonary administration is also possible. Accordingly, this disclosure also relates to pharmaceutical compositions containing the compounds described herein in effective amounts, in combination with optionally pharmaceutically acceptable carriers, excipients, or additives. The compounds according to this disclosure may be administered in immediate-release, intermediate-release, or sustained-release or controlled-release formulations. Sustained-release or controlled-release formulations are preferably administered orally, but may also be administered in suppositories and transdermal or other topical formulations. Intramuscular injection in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0196] The compositions described herein can be formulated conventionally using one or more pharmaceutically acceptable carriers and can also be administered as controlled-release formulations. Examples of pharmaceutically 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, buffering 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, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid compounds, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0197] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an indwelling reservoir. The term “parenterally,” as used herein, refers to subcutaneous, intravenous, intramuscular, intra-articular, intrabursal, intrasternal, subarachnoid, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0198] The sterile injectable dosage forms of the compositions described herein may be aqueous or oily suspensions. Such suspensions can be formulated using appropriate dispersants or wetting agents and suspending agents by techniques known in the art. The sterile injectable formulation may also be a sterile injectable solution or suspension using a non-toxic, parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are, in particular, water, Ringer's solution, and isotonic sodium chloride solution. Sterile non-volatile oils have also been conventionally used as solvents or suspension media. For this purpose, any brand of non-volatile oil, including synthetic mono or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the manufacture of injectable solutions as naturally pharmaceutically acceptable oils, such as olive oil or castor oil, and especially as polyoxyethylated variants thereof. Such oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0199] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or liquids. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically used. For oral administration in capsule form, lactose and dried corn starch are useful diluents. If an oral aqueous suspension is required, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavorings, or colorants may also be added, if desired.

[0200] Alternatively, the pharmaceutical compositions described herein may be administered in the form of rectal suppositories. Suppositories can be prepared by mixing the activating agent with a suitable non-irritating excipient, which is a solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Examples of such materials include cocoa butter, beeswax, and polyethylene glycol.

[0201] Pharmaceutical compositions as described herein may be administered topically. Suitable topical formulations can be readily prepared for each of these areas or organs. Topical administration for the lower intestinal tract can be achieved with rectal suppository formulations (see above) or with suitable enema formulations. Topical-permitted transdermal patches may also be used.

[0202] In the case of topical formulations, the pharmaceutical composition can be formulated as a suitable ointment containing an active ingredient suspended or dispersed in one or more carriers. Examples of topical carriers for the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. In certain preferred embodiments of the present invention, the compounds may be used to coat a stent intended for surgical implantation in a patient, for the purpose of preventing or reducing the possibility of occlusion occurring in the stent in the patient.

[0203] Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing an active ingredient suspended or dispersed in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0204] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension of isotonic, pH-adjusted sterile physiological saline, or preferably as a solution of isotonic, pH-adjusted sterile physiological saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated into an ointment such as petrolatum.

[0205] Pharmaceutical compositions as described herein may also be administered by nasal aerosol, i.e., by inhalation. Such compositions may be prepared in accordance with techniques well known in the field of pharmaceutical formulation and may be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, carbon fluoride, and / or other conventional solubilizers or dispersants.

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

[0207] Naturally, regardless of who the patient is, a specific medication and treatment regimen for that particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, concomitant medications, the judgment of the treating physician, and the severity of the specific disease or condition being treated.

[0208] Patients or subjects requiring treatment using the compounds in accordance with the methods described herein may be treated by administering to the patient (subject) an effective amount of the compounds according to the present invention, including its pharmaceutically acceptable salts, solvates, or polymorphs, in addition to an optionally pharmaceutically acceptable carrier or diluent, either alone or in combination with other known erythropoiesis-stimulating agents as identified herein.

[0209] These compounds can be administered via any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically (topical applications include liquid, cream, gel, or solid transdermal routes), or in aerosol dosage form.

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

[0211] The compound is administered in any suitable unit dosage form, which may contain less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of the active ingredient per unit dosage form, but is not limited to these. An oral dose of approximately 25 to 250 mg is often convenient.

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

[0213] The concentration of the active compound in the drug composition will depend on the drug's absorption rate, distribution rate, inactivation rate, and elimination rate, as well as other factors known to those skilled in the art. The dosage will also vary with the severity of the symptoms to be alleviated. Furthermore, naturally, for any particular subject, the specific drug regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the composition. The concentration ranges described herein are illustrative and not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered in a single dose or in multiple smaller doses at various intervals.

[0214] Oral compositions will generally contain an inert diluent or an edible carrier. These may be encapsulated in gelatin capsules or compressed into tablets. When intended for oral administration for therapeutic purposes, the active compound or its prodrug derivative can be combined with excipients and used in the form of tablets, lozenges, or capsules. A pharmaceutically acceptable binder and / or adjuvant material may be included as part of the composition.

[0215] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds having similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch or lactose; dispersants, e.g., alginic acid, Primogel, or corn starch; lubricants, e.g., magnesium stearate or sterote; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose or saccharin; or flavorings, e.g., peppermint, methyl salicylate, or orange flavorings. If the dosage unit is a capsule, the capsule may contain a liquid carrier, e.g., fatty oil, in addition to the above types of materials. The dosage unit may also contain various other materials that modify the physical shape of the dosage form, e.g., sugar coatings, shellac, or enteric coatings.

[0216] The active compound or a pharmaceutically acceptable salt thereof can be administered as an ingredient in elixirs, suspensions, syrups, wafers, chewing gums, and the like. In addition to the active compound, the syrup may contain sucrose as a sweetener, and may also contain preservatives, colorants and pigments, and flavorings.

[0217] The active compound or a pharmaceutically acceptable salt thereof may also be mixed with other active materials that do not impair the desired effect, or with materials that complement the desired effect, such as erythropoietin stimulants, including, in particular, EPO and darbepoetin alfa. In certain preferred embodiments of the present invention, one or more compounds according to the present invention are administered co-administered with another bioactive agent, such as an erythropoietin stimulant or a wound-healing agent including an antibiotic, as described in any of the foregoing.

[0218] Liquids or suspensions used for parenteral, intradermal, subcutaneous, or topical administration may contain the following components: sterile diluents, e.g., water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetates, citrates, or phosphates; and reagents for adjusting isotonicity, e.g., sodium chloride or glucose. Parenteral formulations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0219] When administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS).

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

[0221] Liposome suspensions can also serve as pharmaceutically acceptable carriers. Liposome suspensions can be prepared according to methods known to those skilled in the art, such methods are described, for example, in USPat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, a liposome formulation can be prepared by dissolving a suitable lipid (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonoylphosphatidylcholine, and cholesterol) in an inorganic solvent, and then evaporating the inorganic solvent, leaving the lipid as a thin film of dry lipid on the surface of a container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to free the lipid material from the sides of the container, dispersing lipid aggregates and thereby forming a liposome suspension.

[0222] Treatment method In a further embodiment, this description provides a therapeutic composition comprising an effective amount of a compound or salt thereof as described herein and a pharmaceutically acceptable carrier. The therapeutic composition modulates proteolysis in a patient or subject, such as an animal such as a human, and can therefore be used to treat or alleviate diseases or conditions regulated through proteolysis.

[0223] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any effect that may benefit a patient to whom the compound may be administered, and include the treatment of any disease condition or symptom regulated through the protein to which the compound binds. Disease conditions or symptoms that can be treated with the compounds according to the present invention, including cancer, are described above herein.

[0224] This description provides therapeutic compositions, as described herein, for bringing about the degradation of a target protein for the treatment or remission of a disease, such as cancer. In a particular further embodiment, the disease is multiple myeloma. Thus, in another embodiment, this description provides a method for ubiquitinating / degrading a target protein in cells. In a particular embodiment, the method comprises administering a bifunctional compound as described herein, the bifunctional compound comprising, for example, CLM and PTM, preferably linked through a linker moiety, as described in either of the herein, CLM coupled with PTM such that degradation of the target protein occurs when the target protein is positioned in close proximity to the ubiquitin ligase, resulting in degradation / inhibition of the effect of the target protein and control of protein levels, CLM recognizing a ubiquitin pathway protein (e.g., ubiquitin ligase, preferably E3 ubiquitin ligase, e.g., cereblon), and PTM recognizing the target protein. The control of protein levels provided by the present invention offers treatment of disease conditions or symptoms regulated through a target protein by reducing the level of that protein in cells, for example, in a patient's cells. In certain embodiments, the method involves administering a compound as described herein in an effective amount, including optionally pharmaceutically acceptable excipients, carriers, adjuvants, other bioactive agents, or combinations thereof.

[0225] In further embodiments, this description provides a method for treating or relieving a disease, disorder, or symptom thereof in a subject or patient, such as an animal, such as a human, the method comprising administering to a subject in need of such a method an effective amount, for example, a therapeutically effective amount, of a compound or salt thereof as described herein, and a composition comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, the composition being effective in treating or relieving a disease or disorder, or symptom thereof, in the subject.

[0226] In another embodiment, this description provides a method for identifying the effects of the degradation of a target protein in a biological system using compounds according to the present invention.

[0227] In another embodiment, the present invention relates to a method for treating human patients who require the modulation of a disease state or symptoms through a protein, where the degradation of that protein provides a therapeutic effect to the patient, the method comprising administering to the patient in need an effective amount of the compound according to the present invention, optionally combined with another bioactive agent. The disease state or symptoms may be caused by microbial pathogens or other exogenous pathogens, such as viruses, bacteria, fungi, protozoa, or other microorganisms, or they may be caused by the overexpression of a protein that leads to the disease state and / or symptoms.

[0228] The term “disease condition or symptom” is used to describe any disease condition or symptom in which protein dysregulation (i.e., increased levels of protein expression in the patient) is occurring, and the breakdown of one or more proteins in the patient may result in beneficial treatment or relief of symptoms in a patient who requires such treatment or relief. In certain cases, the disease condition or symptom may be curable.

[0229] Disease conditions or symptoms that can be treated using the compounds according to the present invention include, for example, autoimmune diseases such as asthma and multiple sclerosis, various cancers, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromocytic disorders, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome (PKD1) or PKD4 (PKD2), sickle cell anemia, Tay-Sachs disease, and Turner syndrome.

[0230] Further disease conditions or symptoms that can be treated with the compounds according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes mellitus, type 2 diabetes mellitus, 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, sarcomatoidism, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, and vasculitis.

[0231] Further disease conditions or symptoms treatable with the compounds according to the present invention include, in particular, aceruloplasminemia, type II achondroplasia, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocronosis, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitors, Emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary amelodysplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse trunk angiokeratoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, arachnidactyly (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #arthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyrus Sclerocutaneous syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuroma (neurofibromatosis type II), factor V Leiden thrombosis, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonneby-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Dube syndrome, fragile osteopathy (osteogenesis imperfecta), broad thumb / hallux syndrome (Rubinstein-Taybe syndrome), bronze-colored diabetes mellitus / bronze-colored cirrhosis (hemochromatosis), spinal and bulbar muscular atrophy (Kennedy disease) ), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat-meow syndrome, CAVD (congenital vas deferens deficiency), Caylor-cardiofacial syndrome (CBAVD), CEP (congenital erythropoiesis-porphyria), cystic fibrosis, congenital hypoparathyroidism, chondrodysplasia (achondroplasia), giant epiphyseal dysplasia of the ostratum, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome,Familial adenomatous polyposis, congenital erythropoiesis-porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagen disease, conotibial stolonitis syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden disease, craniofacial dysostosis (Crouzon disease), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden disease, Curschmann-Batten-Steinert syndrome (myotonic dystrophy) ), Beare-Stevenson gyriform cutaneous syndrome, primary hyperoxaluria, spondyloepiphysital dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker muscular dystrophy (DBMD), neurodegenerative diseases including Usher syndrome, deGrouchy syndrome and Dejurine-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, short stature, erythropoiesis Toporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythropoiesis-induced porphyria, erythropoiesis-induced protoporphyria, erythropoiesis-induced uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late-onset cutaneous porphyria, familial pressure-fragile neuropathy, primary pulmonary hypertension (PPH), fibrocystic disease of the pancreas, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemoglobinosis), Glenblatt-Strandberg syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythropoiesis-induced porphyria) Hemochromocytosis, Hargren's syndrome, sickle cell anemia, hemophilia, hepatomelae porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), androgen hyperplasia, achondroplasia, 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 diseases including hyperoxaluria, Klinefelter syndrome, Kniist's dysplasia,Lacunar dementia, Langer-Sardino achondroplasia, telangiectasia ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muwenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landu disease, Peutz-Jegers syndrome, polycystic kidney disease, Polyostotic fibrous dysplasia (McKeown-Albright syndrome), Peutz-Jegers syndrome, Prader-Raaphardt-Willi syndrome, hemochromocytic syndrome, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (psoadhesive elasticus) Xanthomas, Rb (retinoblastoma), neurofibromatosis type 1, relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy Levy syndrome, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, breast cancer, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis, SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Strudwick-type SED (spondyloepiphyseal metaphysis dysplasia, Strudwick Wick type), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, Strudwick type (spondyloepiphyseal metaphysical dysplasia, Strudwick type), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Oppitz syndrome, South African hereditary porphyria (atypical porphyria), infantile onset upward-moving hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disorders,Examples include sausage-like neuropathy (hereditary pressure-fragility neuropathy), Treacher Collins syndrome, Triple X syndrome, trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum.

[0232] The terms “neoplasm” or “cancer” are used throughout this specification to describe the pathological processes that result in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that proliferate by cell proliferation, at a rate faster than normal, and continue to proliferate even after stimuli that would otherwise cause cessation of growth. 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 be fatal to the patient if not treated appropriately. As used herein, the term neoplasm is used to describe all cancerous disease conditions and encompasses or includes pathological processes associated with malignant hematogenous, ascites, and solid tumors. Examples of cancers that can be treated either by this compound alone or in combination with at least one further anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestines, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, and capillary cancer. This includes disarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliomas, gangliogliomas, medulloblastoma, spinal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwann cell tumor; 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 teratoma. Further cancers treatable using the compounds according to the present 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, giant B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0233] The term "bioactive agent" is used to describe agents other than the compounds according to the present invention that are used in combination with the present compound as agents having biological activity that helps achieve the therapeutic, inhibitory and / or preventive / preventive effects for which the present compound is intended. Suitable bioactive agents for use herein include agents having pharmacological activity similar to the activity for which the present compound is used or administered, such as anticancer agents, antiviral agents, particularly anti-HIV and anti-HCV agents, antimicrobial agents, and antifungal agents.

[0234] The term "further anticancer agents" is used to describe anticancer agents that can be used in combination with the compounds according to the present invention for the treatment of cancer. Examples of such agonists include 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, and 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, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batablin, ofatumumab, zanorimumab, edtecarin, tetrandrin, rubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamate,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazine methyl)-indolyl-quinolone, ba Taranib, AG-013736, AVE-0005, Goserelin acetate, Leuprolide acetate, Triptorelyn pamoate, Medroxyprogesterone acetate, Hydroxyprogesterone caproate, Megestrol acetate, Raloxifene, Bicalutamide, Flutamide, Niltamide, Megestrol acetate, CP-724714;TAK-165, HKI-272, Erlotinib, Lapatinib, Canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ronafarnib, BMS-214662, Tipifarnib Amifostin, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, di Ethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Fluoxymesterone, Flutamide, Gleebec, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Lebamisol, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed,Rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimasut, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, i Centaleukin-12, IM862, angiostatin, vitaxin, droloxifen, idoxifen, spironolactone, finasteride, cymitidine, trastuzumab, denileukin difutitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremohol, docetaxel, epotilon B, BMS-247550, BMS-310705, droloxifen, 4-hydroxytamoxifen, pipendoxifen, ERA-923, alzoxifen, fulvestrant, acorbifen, rasofoxifen, idoxifen, 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, Waltmannin, 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, netsupitant, NK Examples include -1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0235] The terms “anti-HIV agents” or “further anti-HIV agents” include, in particular, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those not representative of the present invention), protease inhibitors, and fusion inhibitors, and examples of such compounds include, in particular, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), and D-D4FC. Fusion inhibitors such as (Reverset), D4T (Stabuzin), Lacivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirzine), EFV (Efavirenz), SQVM (Saquinavir Mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), and T20, as well as their fusions and mixtures, are included, and this term also includes anti-HIV compounds currently in clinical trials or development.

[0236] Other anti-HIV agents that can be used in co-administration with the compounds according to the present invention include, for example, other NNRTIs (i.e., those other than the NNRTIs according to the present invention), which include, in particular, nevirapine (BI-R6-587), delavirdin (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-francarbothioamide), etravirine (TMC125), trovirdin (Ly300046.HCl), MKC-442 (emivirin, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY097, DMP266, baicalin (TJN-151), and ADAM-II (methyl 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)hepta-1-enyl)-2-Methoxybenzoate (Alkenyldiarylmethane analog, Adam analog), (5-Chloro-3-(phenylsulfinyl)-2'-Indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Caplavillin (AG-1549, S-1153), Atevildine (U-87201E), Aurintricarboxylic acid (SD-095345), 1-[(6-Cyano-2-Indolyl)carbonyl]-4-[3-(Isopropylamino)-2-Pyridinyl]piperazi N, 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), Caranolid A (NSC675451), Caranolid B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidine-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), Inofilm P, L-737,126, Mikelamin A (NSC650898), Mikelamin B (NSC649324), Mikelamin F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-Dimethylbenzyl)-1-(ethyloxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Ortiplasm (4-methyl-5-(pyradinyl)-3H-1,2-dithiol-3-thion), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea{PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea{PETT pyridyl derivative), 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-difluorobenzoxazole-2-yl)ethyl]-5-ethyl-6-methyl(pyridinone-2H)-thion (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridinone-2H)-thion, R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, Suramin sodium, TBZ (thiazolobenzimidazole, NSC The group consisting of 625487), thiazoloisoindole-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindole-5(9bH)-one, tibirapine (R86183), UC-38, and UC-84 can be selected.

[0237] The term "pharmaceutically acceptable salt" is used throughout this specification to describe, where applicable, a salt of one or more of the compounds described herein, which is made into a salt to enhance the solubility of the compound in gastric juice of the patient's gastrointestinal tract for the purpose of promoting the solubility and bioavailability of the compound. Examples of pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include, among many acids and bases well known in the pharmaceutical field, those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, and ammonium salts. Sodium salts and potassium salts are particularly suitable as neutralizing salts of the phosphoric acid 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 an ester, amide, or other prodrug group) that, when administered to a patient, directly or indirectly provides the Compound or an active metabolite of the Compound.

[0239] General synthesis approach The synthesis and optimization of bifunctional molecules as described herein may be undertaken in a stepwise or modular manner. For example, identifying compounds that bind to the target molecule may involve high-throughput or moderate-throughput screening operations if a suitable ligand is not immediately available. Typically, it is not necessary to have iterative design and optimization cycles to improve upon the suboptimal form identified by appropriate in vitro and pharmacological and / or ADMET assay data for the initial ligand. The optimization / SAR operation portion would involve searching for a site on the ligand that is resistant to substitution and appears suitable for binding the linker chemical group mentioned above. If crystal or NMR structural data is available, that data can be used to focus such synthetic efforts.

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

[0241] Using readily available PTM and ULM (e.g., CLM), those skilled in the art can use known synthetic methods to combine them, with or without a linker moiety. The linker moiety can be synthesized in a wide range of compositions, lengths, and flexibility, and can be functionalized so that the PTM and ULM groups are sequentially bonded to the distal end of the linker. That is, a library of bifunctional molecules can be realized and characterized in vitro and in vivo by pharmacological and ADMET / PK experiments. Having PTM and ULM groups allows the final bifunctional molecules to be subjected to iterative design and optimization cycles to identify molecules with desired properties.

[0242] The following are some examples, not limiting, of the methods for generating CLM as described herein. TIFF2026094376000080.tif188154TIFF2026094376000081.tif214152TIFF20260943760 00082.tif120154TIFF2026094376000083.tif205155TIFF2026094376000084.tif149155

[0243] As shown in Reaction Example 1, a dimethyl phthalate derivative can be condensed with glutamine (racemic or enantiomer) or a glutamine analog, and then further reacted with an activating agent such as carbonyldiimidazole to form a 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0244] Alternatively, as shown in Reaction Example 2, the intermediate phthalimide produced in the first condensation described 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-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative. The same intermediate phthalimide can also be reacted with Lawson's reagent and then subjected to a dehydration step to obtain thio analogs such as those shown in Reaction Examples 8 and 9.

[0245] Representative example 3 shows N 1 - In this example, protected species of 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives, such as the BOC species, can be deprotected using reagents such as TFA or silica to obtain the desired 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0246] Phthalic anhydrides, such as those shown in Representative Example 4, undergo ring-opening upon reaction with amines such as 3-aminopiperidine-2,6-dione to form an intermediate carboxylate species. This intermediate can then be treated with carbonyldiimidazole and benzotriazole to form the desired 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative. Alternatively, as shown in Representative Reaction Example 13, the desired product may be obtained by combining the two components in the presence of acetic acid.

[0247] In a similar reaction, an anhydride derivative, such as that shown in 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-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0248] If phthaloyl chloride is available, direct condensation with glutamine (racemic or enantiomer) or a glutamine analog is possible, as shown in Reaction Example 6. Subsequently, it is further reacted with an activating agent such as carbonyldiimidazole to form a 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0249] As shown in Reaction Example 7, 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-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative. Alternatively, the desired product may be produced using CO gas itself in combination with a rhodium(II) catalyst and silver carbonate.

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

[0251] Alternatively, as shown in Reaction Example 12, the 5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-diazinan-2,4,6-trione derivative can be prepared by reacting the 5-amino-1,3-diadinan-2,4,6-trione derivative with monotert-butyl phthalate in the presence of a Hünig base, carbodiimide, and benzotriazole. Similar conditions can also be used to prepare the 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative from monotert-butyl phthalate, as shown in Reaction Example 14.

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

[0253] The 3-(2,6-dioxopiperidine-3-yl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione analog can be prepared by activating salicylic acid with a chloroformate compound and then condensing it with 3-aminopiperidine-2,6-dione, as shown in representative reaction example 17.

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

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

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

[0257] As shown in 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 obtain 3-(2-methyl-1,3-dioxo-1H-indene-2-yl)piperidine-2,6-dione.

[0258] 2-[1-(benzyloxy)-2,6-dioxopiperidine-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione, etc. 1 -The preparation of the substituted compound (representative reaction example 22) can be achieved by reacting 2-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)pentanedioic acid with N-benzylhydroxylamine and trifluoroacetic anhydride.

[0259] Next, molecules such as 2-[1-(benzyloxy)-2,6-dioxopiperidine-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (representative reaction example 23) are converted to N2-(1-hydroxy-2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione by removing benzyl under hydrogenation conditions. 1 -A hydroxyl analog may also be used.

[0260] In representative reaction example 24, methyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (and its analogues) is reacted with 3-aminopiperidine-2-one to form 2-(2-oxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

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

[0262] Isomer derivatives such as 2-(6-oxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione, as shown in representative reaction example 27, can be obtained through the reaction of phthalic acid with 5-aminopiperidine-2-one.

[0263] N such as 2-(1-benzyl-2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,4-dione 1- The preparation of substituted compounds (representative reaction examples 28 and 29) can be achieved through multiple routes. For example, anhydrous (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 example 28), or, as shown in representative reaction example 29, a derivative of 2-(2,6-dioxopiperidine-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione can be alkylated with an electrophile such as benzyl bromide in the presence of a base.

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

[0265] control at the gene level This description also provides a method for controlling protein levels in cells. This method is based on the use of compounds, as described herein, that are known to interact with specific target proteins so that the degradation of the target protein in vivo results in control of the amount of protein in the biological system, preferably giving a specific therapeutic effect.

[0266] The following examples are provided to aid in explaining the present invention and are not intended to limit the invention in any way.

[0267] Specific embodiments of this disclosure This disclosure encompasses the following specific embodiments. These embodiments may include all of the features listed in the embodiments described herein, as described. Where applicable, the embodiments may also include comprehensive features listed in any of the embodiments described herein, or features listed in alternative embodiments thereof (for example, Embodiment (8) may include the features listed in Embodiment (1), as listed, and / or features of any of Embodiments (2) through (7)). (1) Chemical structure including the following: L-CLM It has, in the formula, L is a linker group; and CLM is the celeron E3 ubiquitin ligase binding site, The linker group is chemically bonded to the CLM. A compound, or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, or polymorphs. (2) Chemical structure including the following: PTM-L-CLM It has, in the formula, PTM is a protein targeting moiety that binds to a target protein or target 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, thioimide, amide, or 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, their analogues, their homologues, or their derivatives. (6) The compound further comprises ULM, a second CLM, CLM', or a combination thereof, ULM is the E3 ubiquitin ligase binding site, The second CLM has the same chemical structure as the CLM, CLM' is a cereblon E3 ubiquitin ligase binding portion that has a different structure from CLM. The ULM, the second CLM, the CLM', or a combination thereof may be coupled with a further linker group. The compound described in (1). (7) The CLM has the following chemical structure: TIFF2026094376000085.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-hetalyl, 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 CH2-heterocyclyls which may be substituted with H, alkyl, OH, or R', and benzyls which may be substituted with R'; Q1, Q2, Q3, and Q4 represent carbon atoms C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the following groups: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetalil, -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' 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 bond, H, alkyl, cycloalkyl, aryl, hetalyl, and heterocyclyl; TIFF2026094376000086.tif2128 represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and, R n However, it contains a functional group or atom, In the formula, n is an integer between 1 and 4, and in the formula, If n is 1, R n However, it is modified to be covalently bonded to the linker group (L), and If n is 2, 3, or 4, then one R n The other R is modified so that it is covalently bonded to the linker group (L), and the other R n It may be modified to be covalently bonded with PTM, ULM, a second CLM having the same chemical structure as the CLM, CLM', a second linker, or any multiple or combination thereof. The compound described in (1). (8) The CLM is selected from the group consisting of the following compounds as described in (1): 4-{3-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azatridecane-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidined-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}-4,7,10-trioxa-1-azadodecane-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}-4,7,10-trioxa-1-azadodecane-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; 4-{3-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecane-18-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-(3-{4-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azatetradecane-14-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-{[5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azatridecane-13-yl}oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile; 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminopentyl)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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azadodecane-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10,13-tetraoxa-1-azapentadecane-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)acetamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy)phenyl]amino}pyrimidine-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecane-18-yl}oxy)phenyl]amino}pyrimidine-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10,13-tetraoxa-1-azapentadecane-15-yl}oxy)phenyl]amino}pyrimidine-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide; 4-(4-{[(5Z)-3-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethyl]-2,4-dioxo-1,3-thiazolidined-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)propyl]-2,4-dioxo-1,3-thiazolidined-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile; 4-(4-{[(5Z)-3-{2-[2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)ethoxy]ethyl}-2,4-dioxo-1,3-thiazolidined-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminopropyl)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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)phenyl]pyrimidine-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy)phenyl]acetamide. (9) The linker group (L) is defined by the following formula: -A q - It includes chemical structural units represented by the formula, q is an integer greater than 1; and A is independent, combined, CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 , SONR L3 CONR L3 , NR L3CONR L4 , NR L3 SO2NR L4 CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN)NR L4 , NR L3 C (=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C may be substituted with a base. 3-11 Cycloalkyl, 0-6 R L1 and / or R L2 C may be substituted with a base. 3-11 Heterocycline, 0-6 R L1 and / or R L2 Aryl groups that may be substituted with R groups, 0 to 6 R groups L1 and / or R L2 Selected from the group consisting of heteroaryls which may be substituted with a group; R L1 , R L2 , R L3 , R L4 , and R L5 However, each is independent of H, Haro, 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 Heterocycline, 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 Selected from the group consisting of alkyl)2 and NHSO2NH2; and If q is greater than 1, R L1 or R L2 However, each can independently connect to another A group, resulting in 0 to 4 R groups. L5 It is possible to form cycloalkyl and / or heterocyclyl moieties that can be further substituted with groups. The compound described in (1). (10) The compound according to (2), wherein the PTM is a protein target-directed 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 structure, regulation, hormone, enzyme, gene, immunity, contraction, storage, transport, and signal transduction. (11) The PTM group is the portion that binds to the target protein, and the target protein is B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners of the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDE IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitor, 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 receptor, 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-alpha R, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspase, 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 transport protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, Compounds as described in (2), selected from the group consisting of lysine receptors, noradrenaline reuptake receptors, estrogen receptors, estrogen-related receptors, adhesion plaque phosphorylation enzymes, Src, endothelin receptors, neuropeptide Y and receptors, adenosine receptors, adenosine kinases and AMP deaminases, purine receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferases, geranylgeranyltransferases, TrkA, i.e., NGF receptors, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptors, integrin receptors, Her-21 neu, telomerase inhibitors, cytoplasmic phospholipase A2, and EGF receptor tyrosine kinases. Further protein targets include, for example, ecdysone 20-monooxygenase, ion channels of GABAergic chloride channels, acetylcholinesterases, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. Further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvirshikimicate-phosphate synthase. (12) The compound according to (2), wherein the PTM group is an Hsp90 inhibitor; kinase inhibitor, phosphatase inhibitor, HDM2 / MDM2 inhibitor, a compound targeting human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting the RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressive 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 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 α (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc. A composition comprising the compound described in (14)(2). A pharmaceutical composition comprising the compounds described in (15)(2), and pharmaceutically acceptable carriers, additives, and / or excipients. (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, immunoactive agents, cardiovascular agents, and neuroactive agents. (22) The pharmaceutical composition according to (16), wherein the bioactive agent is an anticancer agent. (23) The anticancer drugs include 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, and 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, adhesion plaque kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, olegobomab, Lep-etu, noratexed, azd2171, batablin, ofatumumab, zanorimumab, edtecarin, tetrandrin, rubitecan, tesmirifen, oblimersen, tisilimmumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Silengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Tarampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazine methyl)-indolyl]-quinolone, batalanib, 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[In the formula, x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptrelin 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, ronafarnib, BMS-214662, tipifarnib; amifostine, NVP- LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guélain bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol Epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleebec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisol, lomustine, mechloretamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, larcitrexed, rituximab, streptomycin Zosyn, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-cis-retinoic acid, Phenylalanine mustard, Uracil mustard, Estramustine, Altretamine, Phloxuridine, 5-Deoxyuridine, Cytosine Arabinoside, 6-Mercaptopurine, Deoxycoformycin, Calcitriol, Barrubicin, Mitramycin, Vinblastine, Vinorelbine, Topotecan, Lazoxin, Marimast, COL-3, Neovastat, BMS-275291, Squalamine,Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Doroxifene, Idoxifene, Spironolactone, Finasteride, Cymitidine, Trastuzumab, Denileukin Difutitox, Gefitinib, Bortezomib, Paclitaxel, Paclitaxel without Cremohol, Docetaxel, Epotilon B, BMS-247550, BMS-310705, Doroxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Alzoxifene, Fulvestrant, Acorbifen, 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, Waltmannin, 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-Ax 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, netsupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,The composition according to (22), selected from the group consisting of lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. (24) A method for inducing the degradation of a target protein in a cell, (2) The method comprising the step of administering an effective amount of the compound described in (2) to the cells. (25) A method for inducing the degradation of a target protein in cells, The method comprising the step of administering an effective amount of the compound described in (10) to the cells. (26) A method for inducing the degradation of a target protein in a cell, The method comprising the step of administering an effective amount of the compound described in (11) to the cells. (27) A method for inducing the degradation of a target protein in a patient, (2) The method comprising the step of administering an effective amount of the compound described in (2) to the patient. (28) A method for treating a disease condition or symptom in a patient in which the disease condition or symptom is caused by dysregulated protein activity, the method comprising the step of administering an effective amount of the compound described in (2). (29) The method according to (28), wherein the disease state or symptom is asthma, multiple sclerosis, cancer, ciliary disease, cleft palate, diabetes mellitus, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemoglobinosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, Prader-Willi syndrome (PKD1) or PKD2, sickle cell anemia, Tay-Sachs disease, or 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, type 1 diabetes mellitus, type 2 diabetes mellitus, 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, sarcomatoidism, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, or vasculitis. (31) The disease state or symptoms described above include aceruloplasminemia, type II chondroagenesis, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocronosis, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, and Alström's disease. Syndrome, Alexander disease, hereditary amelodysplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse trunk angiokeratoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, arachnidactyly (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #polyarthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson gyruform cutaneous syndrome, Mediterranean fever, familial, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuroma (neurofibromatosis type II), factor V Leiden thrombosis, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonneby-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Dube syndrome, fragile osteodystrophy (osteogenesis imperfecta), broad thumb / hallux syndrome (Rubinstein-Taybe syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal and bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome Syndrome (Lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat-meow syndrome, CAVD (congenital vas deferens absence), Caylor-cardiafacial syndrome (CBAVD), CEP (congenital erythropoiesis-porphyria), cystic fibrosis, congenital hypoparathyroidism, chondrodysplasia (achondroplasia), megaepiphyseal dysplasia of the ostratum, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis),Congenital erythropoiesis-induced porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, collagen disease, conotibial stump dysfacial syndrome, Cooley's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden disease, craniofacial dysostosis (Crouzon disease), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden disease, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Beare-Stevenson gyrocutaneous syndrome, primary hyperoxaluria, spondyloepiphysital dysplasia (Strudwick type), muscular dystrophy, Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Neurodegenerative diseases 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, short stature, erythropoietic protoporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late-onset cutaneous porphyria, familial pressure-fragile neuropathy, primary pulmonary hypertension (PPH), fibrocystic pancreatic disease, fragile X syndrome, galactosemia, hereditary brain disorders, giant cell Hepatitis (neonatal hemoglobinosis), Glenblatt-Strandberg syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythropoiesis-porphyria), hemoglobinosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatomelae porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), androgen hyperplasia, achondroplasia, 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 diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, lacunar dementia,Langer-Sardino achondroplasia, telangiectasia ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muwenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Landu disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteal stenosis Physical dysplasia (McKeown-Albright syndrome), Peutz-Jegers syndrome, Prader-Raaphardt-Willi syndrome, hemochromocytosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary disease (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (pseudomyelitis elastica) Xanthomas, Rb (retinoblastoma), neurofibromatosis type 1, relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy-Levy syndrome, severe achondroplasia with growth retardation and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, breast cancer, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis, SDAT, congenital SED (congenital spondyloepiphyseal dysplasia), Strudwick-type SED (spondyloepiphyseal metaphysis dysplasia, Str Strudwick type), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, Strudwick type (spondyloepiphyseal metaphysical dysplasia, Strudwick type), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Oppitz syndrome, South African hereditary porphyria (atypical porphyria), infantile onset upward-moving hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia,The method according to (28), which includes thyroid disorders such as sausage-like neuropathy (hereditary pressure-fragility neuropathy), 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), Floric disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymuller syndrome, Wolf-Hirschhorn syndrome, Wolf periodic disease, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum. (32) The method according to (28), wherein the disease state or symptoms are cancer. (33) The cancers mentioned above include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, especially Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; multiple myeloma; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myasthenia, peripheral neuroepithelioma, and sarcoma. The method according to (32) includes: siphono-sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliomas, gangliogliomas, medulloblastoma, spinal cell tumor, meningioma, meningiosarcoma, neurofibroma, and Schwann cell tumor; 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) 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, giant B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML. (35) A compound library containing more than one of the compounds listed in (1). (36) A method for identifying a compound containing an E3 ubiquitin ligase binding site that recognizes cereblon (CRBN), The step of incubating the test compound with the CRBN protein; Step to determine the amount of the test compound bound to the CRBN protein. The method, including the method described above. (37) Chemical structure represented below: It has TIFF2026094376000087.tif127132, and in the 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-hetalyl, 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 CH2-heterocyclyls which may be substituted with H, alkyl, OH, or R', and benzyls which may be substituted with R'; Q1, Q2, Q3, and Q4 represent carbon atoms C substituted with a group independently selected from R', N, or N-oxide; A is independently selected from the following groups: alkyl, cycloalkyl, Cl, and F; R is -CONR'R'', -OR', -NR'R'', -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, -aryl, -hetalil, -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' 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 bond, H, alkyl, cycloalkyl, aryl, hetalyl, and heterocyclyl; TIFF2026094376000088.tif2128 represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and, R n However, it contains a functional group or atom, In the formula, n is an integer between 1 and 4. Cereblon E3 ubiquitin ligase binding site (CLM). (38) The R n The CLM according to (37), wherein the CLM comprises a linker group (L), a protein targeting moiety (PTM), an E3 ubiquitin ligase binding moiety (ULM), or any combination thereof, a functional group or atom covalently bonded 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, CLM', or any multiple or combination thereof. The second CLM has the same chemical structure as the CLM, and The CLM' is structurally different from the CLM according to (38). [Examples]

[0268] A. assay 1. CRBN assay - Cloning, expression, and purification of human CRBN and DDB1 This procedure is standard practice for those skilled in the art, and the description by 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) is a typical example.

[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. TIFF2026094376000089.tif44160

[0270] Using nucleic acid-linking-independent cloning method26, 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 cloning into the mammalian vector pMA-HT-LIC, the C-terminal FLAG tag is attached to the CRBN-Flag-Reverse oligo for immunodetection. DDB1-Rev is tagged with StrepTag27. ZZ-tag28 is necessary to achieve high expression of soluble CRBN; without it, His-CRBN is expressed at low levels, while GST-CRBN results in aggregated proteins. Recombinant baculoviruses of ZZ-His-CRBN and DDB1-StrepTag(ST) are generated and amplified in Sf9 insect cells using a Bac-to-Bac baculovirus expression system obtained from in vitrogens. ZZ-His-CRBN and DDB1-ST were co-expressed in High Five (Tni) insects in a 10 L wave bag at 27°C using unrefilled ESF921 medium obtained from Expression Systems. 48 hours after infection, cells were harvested by centrifugation, and the paste was resuspended in PBS + 5x protease inhibitor cocktail (Roche, Indianapolis, IN).

[0271] All subsequent protein purification steps are performed at 4°C. Frozen cells are thawed and resuspended in 5x volume cell lysate (50 mM Tris-HCl (pH 8.0), 0.5 M NaCl, 10% glycerol, 2 mM DTT) with 20 mM imidazole and protease inhibitor added. The cells are dissolved and centrifuged to obtain a clear supernatant. CRBN-DDB1 is purified using nickel-Sepharose and S200 Sephacryl chromatography on an AKTA-xpress system (GE Healthcare). The complex is then further purified by anion exchange chromatography on an 8 ml MonoQ column and secondly by S-200 gel filtration. CRBN-DDB1 is identified by SDS-PAGE, and the CRBN-DDB1-containing fraction is pooled and stored at -70°C.

[0272] 2. Measurement of the binding of the compound to recombinant CRBN by fluorescence heat dissolution assay. This assay is standard practice for those skilled in the art, and the description by 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) is a typical example.

[0273] The thermal stability of CRBN-DDB1 in the presence or absence of the test compound was investigated in a microplate format in the presence of Cypro Orange, with or without the test compound, 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). 2 mg of protein was added to 20 ml of assay buffer (25 mM Tris HCl (pH 8.0), 150 mM NaCl, 2 μM Cypro Orange) and subjected to a stepwise temperature increase from 20°C to 70°C, with fluorescence measured every 1°C using an ABIPrism 7900HT (Applied Biosystems, Carlsbad, CA, USA). The compound was dissolved in DMSO (final concentration during the assay was 1%) and tested in sets of four at concentrations ranging from 30 nM to 1000 uM; the control contained only 1% DMSO.

[0274] 3.LCMS method Analysis will be performed at 45°C using a Poroshell 120 EC C18 column (50 mm x 3.0 mm inner diameter, 2.7 μm packing diameter).

[0275] The solvents used were as follows: A formic acid aqueous solution with A = 0.1% v / v. A solution of formic acid in acetonitrile with B = 0.1% v / v.

[0276] The solvent gradient used is as follows: TIFF2026094376000090.tif52128

[0277] UV detection involves averaging signals from wavelengths between 210 nm and 350 nm, and the mass spectrum is recorded using a mass spectrometer with positive-mode electrospray ionization.

[0278] The following shows the mobile phase and solvent gradient used when purifying compounds by preparative HPLC.

[0279] 4.Preparative HPLC (formic acid modification) HPLC analysis was performed at ambient temperature using an X Bridge RP18 OBD column (150 mm x 19 mm inner diameter, 5 μm packing diameter).

[0280] The solvents used were as follows: A formic acid aqueous solution with A = 0.1% v / v. B = Acetonitrile

[0281] 5. Preparative HPLC (ammonium bicarbonate modification) HPLC analysis was performed at ambient temperature using an X Bridge RP18 OBD column (150 mm x 19 mm inner diameter, 5 μm packing diameter).

[0282] The solvents used were as follows: A 10 mM ammonium bicarbonate aqueous solution. B = Acetonitrile

[0283] For each preparative purification, regardless of the mobile phase used, the solvent gradient employed was based on the retention time recorded by analytical LC-MS of the specific compound being purified. The flow rate was 20 mL / min.

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

[0285] Although preferred embodiments of the present invention have been described herein, such embodiments are, of course, provided for illustrative purposes only. Those skilled in the art will be able to conceive of numerous modifications, alterations, and substitutions without departing from the spirit of the invention. Accordingly, the appended claims shall encompass all such modifications that fall within the spirit and scope of the invention.

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

[0287] 1. 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione TIFF2026094376000091.tif18128 Step 1: 4-Fluorisobenzofuran-1,3-dione A mixture of 3-fluorophthalic acid (50 g, 271.7 mmol) and acetic anhydride (400 mL) was refluxed for 2 hours. Volatile components were removed under reduced pressure, and the residue was added to acetic anhydride and crystallized to obtain 4-fluoroisobenzofuran-1,3-dione (40 g, unpurified) as a brown solid. TIFF2026094376000093.tif13147 Step 2: 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid TIFF2026094376000094.tif19128 The mixture of 4-fluoroisobenzofuran-1,3-dione (40 g, unpurified) and L-glutamine (35 g, 239 mmol) added to dry DMF (200 mL) was stirred at 90°C for 8 hours. The solvent was removed under reduced pressure. The residue was redissolved in 4N HCl (200 mL) and stirred for a further 8 hours. The resulting precipitate was collected by filtration, washed with water, and dried to obtain 5-amino-2-(4-fluoro-1,3-dioxoisoindorin-2-yl)-5-oxopentanoic acid (37 g, unpurified) as an off-white solid. TIFF2026094376000095.tif20153 Step 3: 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione The mixture of 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, unpurified), 1,1'-carbonyldiimidazole (CDI) (24.2 g, 149.4 mmol), and 4-dimethylaminopyridine (DMAP) (1.3 g, 11.5 mmol) added to 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 obtain the crude product, which was purified by silica gel chromatography using 1-10% MeOH-containing DCM as the eluent to obtain 2-(2,6-dioxopiperidine-3-yl)-4-fluoroisoindorin-1,3-dione (9.0 g, yield 12% over 3 steps) as a pale yellow solid. TIFF2026094376000097.tif20148

[0288] 2. N-(3-(5-bromo-2-chloropyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide TIFF2026094376000098.tif14128 Step 1: tert-butyl N-{3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}-N-methylcarbamate TIFF2026094376000099.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) was added to MeOH (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by Teledyne ISCO chromatography [0 → 35% siRNA / heptane] to obtain tert-butyl N-{3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}-N-methylcarbamate (615 mg, yield 92%). LC-MS (ES + ):m / z=381.05 / 383.05[MH + ], tR =2.55 minutes. Step 2: {3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}(methyl)amine TIFF2026094376000100.tif15128tert-butyl N-{3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}N-methylcarbamate (615 mg, 1.62 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (0.54 mL, 6.5 mmol) was added at room temperature. After stirring for 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by Teledyne ISCO chromatography [0 → 15% methanol-containing DCM] to obtain {3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}(methyl)amine (371 mg, yield 82%). LC-MS (ES + ):m / z=280.99 / 282.99[MH + ], t R =1.13 minutes. Step 3: N-{3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide TIFF2026094376000101.tif16128 {3-[(5-bromo-2-chloropyrimidine-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutane carbonyl chloride (188 mg, 1.60 mmol) were dissolved in DCM (10 mL), and triethylamine (0.41 mL, 2.92 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by Teledyne ISCO chromatography [0 → 100% siRNA / heptane] to obtain N-{3-[(5-bromo-2-chloropyrimidine-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]diazepine-6-yl)acetic acid The compound described in TIFF2026094376000102.tif36128 was prepared according to the procedure described in WO2011 / 143660.

[0290] 4. (Z)-4-(4-((2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile The compound described in TIFF2026094376000103.tif23128 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 The compound described in TIFF2026094376000104.tif28128 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 hydrogen chloride The compound described in TIFF2026094376000105.tif21128 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-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide] TIFF2026094376000106.tif25128 (Compound structure #17 shown in Table 1) Step 1: 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzene sulfonate TIFF2026094376000107.tif91282,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (3g, 5.96 mmol), 4-nitrophenol (813 mg, 5.84 mmol), and potassium carbonate (1.65 g, 11.94 mmol) were added to dry N,N-dimethylformamide (20 mL) and stirred overnight at 50°C. The mixture was cooled to room temperature, poured into water (60 mL), and then extracted with ethyl acetate (80 mL x 3). The organic phases were combined, 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 hexane containing 10-20% ethyl acetate) to obtain 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzene sulfonate (2.65 g, yield 95%) as a yellow oily substance. 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] TIFF2026094376000108.tif101282-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzene sulfonate (2.65 g, 5.64 mmol) and sodium azide (734 mg, 11.29 mmol) were added to ethanol (30 mL) and the mixture was refluxed for 16 hours. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with water (50 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 1-(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)ethaneamine] TIFF2026094376000109.tif10128 The above 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) was added to tetrahydrofuran (10 mL) and stirred at room temperature under a nitrogen atmosphere for 14 hours. The volatile components were removed under reduced pressure to obtain a crude residue, which was purified by silica gel flash column chromatography (eluted with 3-5% methanol-containing dichloromethane) to obtain 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine (661 mg, 83% yield) as a yellow oil. TIFF2026094376000110.tif20148 Step 4: tert-butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate A 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) was added to dichloromethane (25 mL) and 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 hexane containing 20-40% ethyl acetate) to obtain tert-butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl carbamate (818 mg, 94% yield) as a yellow oily substance. TIFF2026094376000112.tif20147 Step 5: tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate TIFF2026094376000113.tif101282-(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) were added to ethanol (20 mL) and water (5 mL), and the mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature, and the solid precipitate was removed by filtration and washed with ethyl acetate (20 mL x 2). The filtrate was partitioned with 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 (elution with hexane containing 30-40% ethyl acetate) to obtain tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethyl carbamate (512 mg, 67% yield) as a yellow oily substance. Step 6: tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamide)propylamino)pyrimidine-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate A mixture of tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethyl carbamate (130 mg, 0.34 mmol), N-(3-(5-bromo-2-chloropyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (24 mg, 0.06 mmol), and p-toluenesulfonic acid (11.6 mg, 0.07 mmol) was added to dioxane (1.5 mL) and refluxed for 16 hours. 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 organic phases were combined and 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 hexane containing 50% ethyl acetate) to obtain tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamide)propylamino)pyrimidine-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, yield 17%) as a yellow oily substance. Step 7: N-(3-(2-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide TIFF2026094376000115.tif13128tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamide)propylamino)pyrimidine-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, 0.06 mmol) was added to 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours. Volatile components were removed under reduced pressure. The residue was partitioned with 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 obtain N-(3-(2-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (18 mg, yield 52%) as a yellow oil. Step 8: N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide A mixture of N-(3-(2-(4-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (130 mg, 0.03 mmol), 2-(2,6-dioxopiperidine-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) added to dry N,N-dimethylformamide (1 mL) was stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature and partitioned with 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 obtain N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidine-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (10.2 mg, yield 40%) as a yellow solid. LC-MS (ES) + ):m / z=865.27 / 867.27(1:1)[MH] + .t R =2.06 minutes. TIFF2026094376000117.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]diazepine-6-yl)-N-(4-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide TIFF2026094376000118.tif34128 (Compound structure #14 shown in Table 1) Step 1: (2-(2,6-dioxopiperidine-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethanamine (128 mg, 0.41 mmol), 2-(2,6-dioxopiperidine-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) was added to dry N,N-dimethylformamide (2 mL) and 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 x 2). The organic phases were combined, 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 obtain 2-(2,6-dioxopiperidine-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindorin-1,3-dione (73 mg, yield 31%) 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-dioxopiperidine-3-yl)isoindorin-1,3-dione) TIFF2026094376000120.tif251282-(2,6-dioxopiperidine-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) were added to a suspension in ethanol (2 mL). At room temperature, a solution of ammonium chloride (68 mg, 1.26 mmol) in water (0.5 mL) was added, and the resulting mixture was stirred at 80°C for 1 hour. After the mixture cooled to room temperature, the solid precipitate was filtered and washed with ethyl acetate (10 mL x 2). The filtrate was partitioned with 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 obtain 4-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (66.5 mg, unrefined) as a yellow oily substance. 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]diazepine-6-yl)-N-(4-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide TIFF2026094376000121.tif341284-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidine-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) Diazepine-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). While stirring at 0°C, (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (82 mg, 0.21 mmol) was added. The resulting mixture was allowed to rise naturally 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 x 2). The organic phases were combined, 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 obtain 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)-N-(4-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide (52 mg, yield 52%) as a yellow solid. LC-MS (ES) + ):m / z923.29 / 925.29(3:1)[MH + ], t R =2.689 minutes. TIFF2026094376000122.tif34154

[0295] 9. (Z)-4-(4-((3-(2-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile TIFF2026094376000123.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-dioxothiazolidine-3-yl)ethoxy)ethoxy)ethyl=4-methylbenzenesulfonate) A mixture of (Z)-4-(4-((2,4-dioxothiazolidine-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) was added to N,N-dimethylformamide (10 mL) and stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with water (50 mL) and 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 hexane containing 10-30% ethyl acetate) to obtain (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidine-3-yl)ethoxy)ethoxy)ethyl=4-methylbenzenesulfonate (1.0 g, yield 61%) as a pale yellow solid. Step 2: (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile A mixture of (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidine-3-yl)ethoxy)ethoxy)ethyl=4-methylbenzenesulfonate (1.0 g, 1.4 mmol) and sodium azide (185 mg, 2.8 mmol) was added to ethanol (20 mL) and refluxed for 16 hours. 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 obtain (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (130 mg, unrefined) as a bright yellow oil. This was used in the next step without further purification. Step 3: (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile The mixture of (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (130 mg, unpurified) and triphenylphosphine (100 mg, 0.34 mmol) was added to water (0.2 mL) and tetrahydrofuran (20 mL), and stirred at room temperature for 14 hours. The mixture was then concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 3-5% methanol-containing dichloromethane) to obtain (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (60 mg, yield 8% through 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-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile A mixture of (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (60 mg, 0.10 mmol), 2-(2,6-dioxopiperidine-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) added to 1-methylpyrrolidine-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 x 3). The organic layers were combined and washed with water (10 mL x 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to obtain (Z)-4-(4-((3-(2-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-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. TIFF2026094376000128.tif26152

[0296] 10. 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile TIFF2026094376000129.tif18128 (Compound structure #1 shown in Table 1) Step 1: 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane TIFF2026094376000130.tif41282-(2-(2-(trityloxy)ethoxy)ethoxy)ethanol (7g, 17.7 mmol) was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (60% in mineral oil, 707 mg, 17.7 mmol) was slowly added at 0°C. The mixture was stirred at room temperature for 30 minutes, and then 3-(benzyloxy)propyl 4-methylbenzenesulfonate (5.8 g, 18.0 mmol) was added all at once at 0°C. The resulting mixture was stirred overnight at 70°C. After cooling to room temperature, the mixture was carefully quenched with water (40 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (elution with hexane containing 5-10% ethyl acetate) to obtain 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g, yield 50%) as a colorless oil. TIFF2026094376000131.tif20146 Step 2: 1-phenyl-2,6,9,12-tetraoxatetradecane-14-ol TIFF2026094376000132.tif41281,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g, 8.8 mmol) was dissolved in methylene chloride (10 mL) and methanol (10 mL), to which 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 organic phases were combined and washed with aqueous sodium bicarbonate (1 N, 50 mL), water (30 mL), and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluting with hexane containing 20-40% ethyl acetate) to obtain 1-phenyl-2,6,9,12-tetraoxatetradecane-14-ol (1.9 g, 73% yield) as a colorless oil. Step 3: 1-Phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate A mixture of 1-phenyl-2,7,10,13-tetraoxapentadecane-15-ol (1.9 g, 6.3 mmol), triethylamine (1.3 mL, 9.5 mmol), N,N-dimethylpyridine-4-amine (75 mg, 0.63 mmol), and 4-methylbenzene-1-sulfonyl chloride (1.45 g, 7.65 mmol) was added to dichloromethane (20 mL) and stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL) and the product was extracted with dichloromethane (40 mL x 3). The organic phases were combined, 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 (eluting with hexane containing 10-30% ethyl acetate) to obtain 1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate (2.2 g, yield 78%) as a colorless oil. TIFF2026094376000134.tif20148 Step 4: 14-Azido-1-phenyl-2,6,9,12-tetraoxatetradecane TIFF2026094376000135.tif41281-phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate (2.2 g, 4.9 mmol) and sodium azide (420 mg, 6.3 mmol) were added to ethanol (10 mL) and refluxed for 5 hours. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with dichloromethane (50 mL x 3). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane (1.4 g, unpurified) as a colorless oil. This was used in the next step without further purification. Step 5: tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl)carbamate TIFF2026094376000136.tif4128 The mixture of 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane (1.4 g, unpurified) and triphenylphosphine (1.7 g, 6.5 mmol) added to tetrahydrofuran (15 mL) and water (0.5 mL) was stirred overnight at room temperature under a 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 rise naturally to room temperature and stirred at room temperature for 2 hours. The volatile components were evaporated under reduced pressure, and the residue was partitioned with 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 silica gel flash chromatography (elution with hexane containing 30-50% ethyl acetate) to obtain tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecane-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 TIFF2026094376000137.tif4128 A mixture of tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl) carbamate (1.2 g, 3 mmol) and palladium carbon (10%, 200 mg) was added to ethanol (50 mL) and stirred at room temperature under a hydrogen atmosphere (hydrogen balloon). The palladium carbon was removed by filtration and washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure to obtain tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethyl carbamate (900 mg, unrefined) as a colorless oil. This was used in the next step without further purification. Step 7: 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecane-17-yl 4-methylbenzenesulfonate The mixture of tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethyl carbamate (900 mg, unpurified), triethylamine (0.6 mL, 4.35 mmol), N,N-dimethylpyridine-4-amine (16 mg, 0.14 mmol), and 4-methylbenzene-1-sulfonyl chloride (660 mg, 3.5 mmol) added to anhydrous dichloromethane (15 mL) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL), and the product was extracted with dichloromethane (50 mL x 3). The organic phases were combined, 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 (eluting with hexane containing 20-30% ethyl acetate) to obtain 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecane-17-yl 4-methylbenzenesulfonate (650 mg, yield 77%) as a bright yellow oil. TIFF2026094376000139.tif20147 Step 8: tert-butyl (2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethyl)carbamate A mixture of 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecane-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-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.25 mmol) was added to acetonitrile (5 mL) and stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, 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 hexane containing 10-30% ethyl acetate) to obtain tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethylcarbamate (150 mg, yield 82%) as a yellow oily substance. LC-MS (ES + ):m / z695.40[MH + ], t R =2.79 minutes. Step 9: 4-(3-(4-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile TIFF2026094376000141.tif15128tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidine-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethyl carbamate (150 mg, 0.21 mmol) was added to anhydrous dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 1 hour. The volatile components were evaporated under reduced pressure, and the residue was poured into an aqueous sodium bicarbonate solution (1 N, 20 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(3-(4-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, unrefined) as a brown oily substance. This was used in the next step without further purification. Step 10: 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile The above 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, unpurified), 2-(2,6-dioxopiperidine-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 x 3). The organic layers were combined and washed with water (30 mL x 2) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to obtain 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (34.5 mg, yield 27%) as a yellow solid. LC-MS (ES) + ):m / z851.25[MH + ], t R =2.652 minutes. TIFF2026094376000143.tif27135

[0297] 11. 4-{[5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide TIFF2026094376000144.tif30128 Step 1: 3-[(5-hydroxypentyl)oxy]propanenitrile TIFF2026094376000145.tif7128 Sodium hydride (60% dispersed in mineral oil, 820 mg, 34.2 mmol) was added to a suspension in THF (50 mL), to which pentane-1,5-diol (2.98 g, 28.6 mmol) was added. After stirring at room temperature for 20 minutes, 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 hours. Part of the solvent was removed under reduced pressure, and the residue was poured into water. The mixture was extracted with DCM (3×). The organic layer was filtered through a Biotage universal phase separator and concentrated under reduced pressure. The crude substance was purified by silica gel chromatography using MeOH / DCM (from 0:100 to 3:97) elution from a Teledyne Combiflash ISCO column to obtain 3-[(5-hydroxypentyl)oxy]propanenitrile (635 mg, yield 18%). TIFF2026094376000146.tif20151 Step 2: tert-butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate TIFF2026094376000147.tif121283-[(5-hydroxypentyl)oxy]propanenitrile (400 mg, 2.54 mmol) was dissolved in MeOH (12 mL) and H2O (2.0 mL). Nickel(II) chloride (393 mg, 3.04 mmol), followed by sodium borohydride (360 mg, 9.52 mmol), was added little by little to this solution. The mixture was stirred at room temperature for 3 hours and then quenched with MeOH (12 mL). The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (5 mL). To this solution, 6 M aqueous NaOH (0.5 mL) and di-tert-butyl dicarbonate (831 mg, 3.81 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude substance was purified by silica gel chromatography using MeOH / DCM (0:100 to 4:96) elution from a Teledyne Combiflash ISCO column to obtain tert-butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate (366 mg, yield 55%). TIFF2026094376000148.tif19146 Step 3: tert-butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate TIFF2026094376000149.tif13128 A solution of tert-butyl (3-((5-hydroxypentyl)oxy)propyl) carbamate (300 mg, 3.88 mmol) dissolved in DCM (10 mL) was to which DIPEA (599.3 μL, 3.44 mmol), tosyl chloride (262.3 mg, 1.38 mmol), and 4-dimethylaminopyridine (14.0 mg, 0.115 mmol) were added. The resulting mixture was stirred at room temperature for 20 hours. The reaction was quenched with semi-saturated sodium bicarbonate, extracted with DCM (2×), filtered through a Biotage universal phase separator, and concentrated under reduced pressure. The crude substance was purified by silica gel chromatography using elution with siRNA / heptane (0:100 to 30:70) from a Teledyne Combiflash ISCO column to obtain tert-butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate (914 mg, yield 26%). TIFF2026094376000150.tif27152 Step 4: Methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate TIFF2026094376000151.tif16128 A 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), and potassium carbonate (203 mg, 1.47 mmol) was added to MeCN (10 mL) and stirred at 80°C for 24 hours. The reaction mixture was diluted with SiO2, washed with semi-saturated sodium bicarbonate solution (1 ×), water (2 ×), and 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 using elution with  / heptane (0:100 to 50:50) on a Teledyne Combiflash ISCO column to obtain methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (300 mg, yield 93%). LC-MS (ES) + ):m / z418.21[MNa + ], t R =2.74 minutes. Step 5: 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid TIFF2026094376000152.tif161284-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (150 mg, 0.38 mmol) was dissolved in 1:1:1 THF / water / MeOH (6.0 mL, v / v / v), to which lithium hydroxide (81.6 mg, 3.41 mmol) was added. The resulting mixture was stirred overnight at room temperature, 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 ELISA, washed with water (2×) and brine (2×), 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 / z404.20[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 TIFF2026094376000153.tif191284-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid (124 mg, 0.322 mmol) and 2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (89.8 mg, 0.322 mmol) were dissolved in DMF (5 mL), to which DIPEA (112 μL, 0.65 mmol) and TBTU (155 mg, 0.48 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then diluted with ethyl acetate, washed with water (3 ×) and brine (1 ×), filtered through a Biotage universal phase separator, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a Teledyne Combiflash ISCO column with elution at MeOH / DCM (0:100 to 5:95) to obtain 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, yield 82%). 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 TIFF2026094376000154.tif17128tert-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) was dissolved in DCM (5 mL), and trifluoroacetic acid (372 μL, 4.86 mmol) was added to the solution and heated at 45°C for 1 hour until the reaction was complete. The reaction product was then concentrated under reduced pressure to obtain a solid, which was used in the next step without further purification (104 mg, yield 99%). LC-MS (ES + ):m / z543.27 / 545.26(3:1)[MH + ], t R =2.26 minutes.

[0299] 13. 4-{[5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide TIFF2026094376000155.tif30128 (Compound structure #11 shown in Table 1) 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) was dissolved in 1,4-dioxane (2 mL) and diisopropylethylamine (384 μL, 2.21 mmol) and 2-(2,6-dioxopiperidine-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (18.3 mg, 0.0664 mmol) were added. The resulting mixture was refluxed for 16 hours, then diluted with ethyl acetate, washed with semi-saturated brine solution (2 ×), filtered through a Biotage universal phase separator, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a Teledyne Combiflash ISCO column with elution at MeOH / DCM (0:100 to 7:93) to obtain 4-{[5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (12 mg, yield 28%). LC-MS (ES) + ):m / z799.31 / 801.31(3:1)[MH + ], t R =2.97 minutes. TIFF2026094376000156.tif54151

[0300] C. Protein degradation bioassay: The following bioassays were performed to evaluate the levels of proteolysis observed in various cell types using representative compounds disclosed herein.

[0301] In each bioassay, cells were treated with varying amounts of the compounds included in this disclosure, as shown in Table 1. This study evaluated the degradation of the following proteins: TANK-binding kinase 1 (TBK1), estrogen receptor α (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 of human recombinant insulin (Gibco). They were cultured in 12-well plates for 16 hours under DMSO control and compound treatment (0.1 μM, 0.3 μM, and 1 μM). For the last 3 hours, the TLR3 agonist PolyI:C (Invivogen; tlrl-pic) was added. The 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. The lysates were centrifuged at 16,000 g for 10 minutes to clarify, and the supernatant was separated by SDS-PAGE. Immunoblotting was performed using a standard protocol. The antibodies used were TBK1 (Cell Signaling #3504), pIRF3 (abcam #ab76493), and GAPDH (Cell Signaling #5174). Bands were quantified using the 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 incubation (0.1 μM, 0.3 μM, and 1 μM) were performed in 24-well plates for 16 hours. Cells were harvested and lysed with cell lysate containing a protease inhibitor (Thermo Scientific) (Cell Signaling Technologies). The lysate was centrifuged at 16,000 g for 10 minutes to clarify, and the supernatant was separated by SDS-PAGE. Immunoblotting was performed using a standard protocol. The antibodies used were ERRα (Cell Signaling #8644) and GAPDH (Cell Signaling #5174). Bands were quantified using the 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 medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). Cells were treated with DMSO control and compound treatments (0.003 μM, 0.01 μM, 0.03 μM, and 0.1 μM) for 16 hours in 12-well plates. 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. The lysates were centrifuged at 16,000 g for 10 minutes to clarify, and protein concentration was measured. Equivalent volumes of protein (20 μg) were analyzed using SDS-PAGE, followed by immunoblotting according to a standard protocol. 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). They were treated with DMSO control and compound treatment (0.0001 μM to 1 μM) in 96-well plates for 16 hours. Cells were harvested and lysed in cell lysate (Catalog #9803) with 20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5 mM sodium pyrophosphate, 1 mM β-glycerophosphate, 1 mM Na3VO4, and 1 ug / ml leupeptin. The lysate was centrifuged at 16,000 g for 10 minutes to clarify, and then subjected to PathScan AR ELISA (Cell Signaling It was added to Catalog #12850. The PathScan® Total Androgen Receptor Sandwich ELISA Kit is a solid-phase sandwich enzyme-coupled immunosorbent assay (ELISA) that detects the endogenous level of total androgen receptor protein. Rabbit androgen receptor mAbs are coated in microwells. When incubated with cell lysates, the coated antibodies capture the androgen receptor proteins. After thorough washing, mouse detection androgen receptor mAbs are added to detect the captured androgen receptor proteins. Then, anti-mouse IgG, HRP-conjugated antibodies are used to recognize the bound detection antibodies. TMB, an HRP substrate, is added to induce color development. The absorbance of the color development is proportional to the amount of total androgen receptor protein.

[0306] The antibodies included in the kit are a custom formulation specific to that kit.

[0307] 5. c-MycELISA 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 into 96-well plates at a volume of 75 μL / well of RPMI + 10% FBS medium, with a density of 30,000 cells / well. The cells were administered a compound diluted with 0.1% DMSO, incubated for 18 hours, washed, and then lysed in 50 μL 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. The lysate was centrifuged at 4000 rpm for 10 minutes at 4°C to clarify it, and a fixed amount was then added to a 96-well ELISA plate of the Novex Human c-myc ELISA kit from Life Technologies Catalog#KHO2041. 50 μL of c-Myc detection antibody was added to each well, and the plate was incubated at room temperature for 3 hours, then washed with ELISA wash buffer. 100 μL 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, 100 μL of TMB was added to each well, and the color change was observed every 5 minutes. 100 μL of stop solution was added, and the plate was read at 450 nm.

[0308] D. Results Table 1 presents experimental data obtained with several representative compounds included in this disclosure. Specifically, various cell types were treated with the compounds listed in Table 1. These compounds are identified by their chemical structure, mass spectrometry characterization, and compound name.

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

[0310] All references, patents, continuation patent applications, and published patents mentioned throughout this application are expressly incorporated herein by reference.

[0311] Those skilled in the art will recognize, or can verify, many equivalent forms of the particular embodiments of the invention described herein, or can verify such equivalent forms using conventional experiments. Such equivalent forms are included in the following claims. Naturally, the detailed examples and embodiments described herein are provided for illustrative purposes only and are not intended to be construed as limiting the invention in any way. Various modifications and alterations will be suggested to those skilled in the art in light of them, and such modifications and alterations are considered to fall within the spirit and scope of this application and within the scope of the appended claims. For example, the relative amounts of components may be changed to optimize the desired effect, additional components may be added, and / or one or more of the described components may be replaced with similar components. Further advantages, features, and functions relating to the systems, methods, and processes of the invention will become apparent from the appended claims. Furthermore, those skilled in the art will recognize, or can verify, many equivalent forms of the particular embodiments of the invention described herein, or can verify such equivalent forms using conventional experiments. Such equivalent forms are included in the following claims.

[0312] [Table 1] TIFF2026094376000158.tif209141 TIFF2026094376000159.tif208144 TIFF2026094376000160.tif208128 TIFF2026094376000161.tif208142 TIFF2026094376000162.tif208128 TIFF2026094376000163.tif208131 TIFF2026094376000164.tif208132 Category of degrading activity: A=1uM, 10-30% decomposition. With B=1uM, 31-50% decomposition is achieved. With C=1uM, >50% decomposition is achieved. D=IC 50 <50nM E=IC 50 >50nM Cells used in the bioassay: 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

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