Imide-based modulators of proteolysis and related methods of use

Abstract

The present invention relates to imide-based compounds, including bifunctional compounds comprising the same, which are useful as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins degraded and / or otherwise inhibited by the bifunctional compounds according to the invention. In particular, the description provides compounds containing on one end a ligand that binds to the cerebellar protein E3 ubiquitin ligase and on the other end a moiety that binds a target protein such that the target protein is positioned in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the protein. Compounds exhibiting a wide range of pharmacological activity consistent with degradation / inhibition of almost any type of targeting polypeptides can be synthesized.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application date of April 14, 2015, application number 201580028623.2, and invention name “Imide-based proteolysis regulators and related use methods”.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application is an International PCT application claiming the benefit of and priority to U.S. Provisional Application No. 61 / 979,351, filed on April 14, 2014, entitled “IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE,” which is incorporated herein by reference in its entirety.

[0005] Incorporated by Reference

[0006] Pursuant to 37 CFR §1.52(e), the sequence listing information in a computer-readable format is submitted herewith in .txt format, file name: Sequence_Listing_ST25.txt; size 2KB; generated on April 14, 2015 using PatentIn-3.5, which is incorporated herein by reference in its entirety. Field of the Invention

[0007] The present invention provides imide-based compounds, including bifunctional compounds containing the same; and related methods of use. The bifunctional compounds can be used as modulators of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds according to the present invention. background

[0009] Most small molecule drugs bind to enzymes or receptors in tight and well-defined pockets. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity for ubiquitination and are therefore more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, other compounds targeting E3 ligases have been reported, but the field remains underdeveloped.

[0010] One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor. VHL contains a substrate recognition subunit / E3 ligase complex, VCB, which includes elongation factors B and C, and a complex including Cullin-2 and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the pro-angiogenic growth factor VEGF and the red blood cell-inducing cytokine erythropoietin in response to low oxygen levels. We have targeted the substrate recognition subunit of the E3 ligase VCB (cancer, chronic anemia, and ischemia) to investigate its potential therapeutic potential. 2 The first small-molecule ligand of von Hippel-Lindau (VHL) was generated from a single-molecule, ligand (an important target in the mitochondria) and the crystal structure was obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0011] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which emphasizes its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A) and regulator of cullin 1 (ROC1). This complex ubiquitinates a variety of other proteins. Through a mechanism that has not been fully elucidated, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a variety of developmental processes, such as limb and ear capsule formation. The end result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which acts as a DNA damage binding protein.

[0012] Thalidomide, which has been approved for the treatment of a variety of immunological indications, has also been approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogs are currently being studied for the treatment of a variety of other types of cancer. Although the precise mechanism of thalidomide's antitumor activity is still emerging, it is known to inhibit angiogenesis. Recent literature discussing imide biology includes Lu et al. Science 343, 305 (2014) and et al. Science 343, 301 (2014).

[0013] Notably, thalidomide and its analogs (e.g., pomalidomide and lenalinomide) are known to bind to cerebellin. These agents bind to cerebellin, altering the specificity of the complex to induce ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for the growth of multiple myeloma. Indeed, higher expression of cerebellin correlates with increased efficacy of imide drugs in the treatment of multiple myeloma.

[0014] There is a continuing need in the art for effective treatments for diseases, particularly hyperplasia and cancers such as multiple myeloma. However, nonspecific effects and the inability to co-target and modulate certain classes of proteins such as transcription factors remain obstacles to the development of effective anti-cancer agents. Therefore, small molecule therapeutics that exploit or enhance the substrate specificity of cerebellin and that are simultaneously "tunable" so that a wide variety of protein classes can be specifically targeted and modulated would be very useful as therapeutic agents. SUMMARY OF THE INVENTION

[0015] The present disclosure describes bifunctional compounds that act to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of use thereof. Specifically, the present invention provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds, which are used as regulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by bifunctional compounds as described herein. The advantage of the compounds provided herein is that a wide range of pharmacological activities are possible, consistent with the degradation / inhibition of targeted polypeptides from almost any protein class or family. In addition, the present invention provides methods for treating or improving disease conditions (such as cancer, e.g., multiple myeloma) using an effective amount of compounds as described herein.

[0016] Thus, in one aspect, the present disclosure provides novel imide-based compounds as described herein.

[0017] In another aspect, the present disclosure provides bifunctional or PROTAC compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or "ULM" group) and a moiety that binds to a target protein so that the target protein / polypeptide is positioned close to the ubiquitin ligase to achieve degradation (and inhibition) of the protein (i.e., a protein / polypeptide targeting ligand or "PTM" group). In a preferred embodiment, the ULM is a cerebellum E3 ubiquitin ligase binding moiety (i.e., a "CLM"). For example, the structure of the bifunctional compound can be depicted as:

[0018]

[0019] The corresponding positions of the PTM and CLM moieties as described herein and their number are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by the skilled artisan, the bifunctional compounds as described herein can be synthesized so that the number and position of the corresponding functional moieties can be varied as desired.

[0020] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be depicted as:

[0021]

[0022] where PTM is the protein / peptide targeting moiety, L is the linker, and CLM is the cerebellin E3 ubiquitin ligase binding moiety.

[0023] In certain preferred embodiments, the E3 ubiquitin ligase is cerebellin. Thus, in certain other embodiments, the CLM of the bifunctional compound comprises a chemical substance such as an imide, an amide, a thioamide, a thioimide derived moiety. In other embodiments, the CLM comprises a phthalimido group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a phthalimido-glutarimido group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and an analog or derivative thereof.

[0024] In certain embodiments, the compounds as described herein comprise multiple CLMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0025] On the other hand, the present invention provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition regulates protein degradation in a patient or subject (e.g., an animal, such as a human being), and can be used to treat or improve a disease state or condition regulated by the degraded protein. In certain embodiments, the therapeutic composition as described herein can be used to practice the degradation of the protein of interest for treating or improving a disease (e.g., cancer). On the other hand, the present invention provides a method of ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, the bifunctional compound as further described herein comprises a CLM and a PTM preferably connected by a linker group moiety, wherein the CLM is coupled to the PTM, and wherein the CLM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase, such as cerebellin), and the PTM recognizes the target protein so that the degradation of the target protein will occur when the target protein is positioned close to the ubiquitin ligase, thereby resulting in the degradation / inhibition of the effect of the target protein and the control of protein levels. The control of protein levels achieved by the present invention provides for the treatment of a disease state or condition by targeting a protein to modulate it by reducing the levels of that protein in the patient's cells.

[0026] On the other hand, the present invention provides a method for evaluating (i.e., determining and / or measuring) the binding affinity of CLM. In certain embodiments, the method includes providing a test agent or compound of interest, such as an agent or compound having an imide moiety (e.g., phthalimido, phthalimido-glutarimido, derivative thalidomide, derivative lenalidomide, or derivative pomalidomide); and comparing the cerebellum protein binding affinity and / or inhibitory activity of the test agent or compound with an agent or compound known to bind to cerebellum protein and / or inhibit cerebellum protein activity.

[0027] In another aspect, the present invention provides a method for treating or improving a disease, disorder or symptom thereof in a subject or patient (e.g., an animal, such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound as described herein or a salt form thereof; and a pharmaceutically acceptable carrier, wherein the composition is effective in treating or improving the disease, disorder or symptom thereof in the subject.

[0028] In another aspect, the invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the invention.

[0029] The above general application areas are given only by way of example and are not intended to limit the scope of the present disclosure and the appended claims. Those of ordinary skill in the art will understand other goals and advantages associated with the compositions, methods and processes of the present invention based on the claims. For example, various aspects and embodiments of the present invention can be used in numerous combinations, all of which are clearly covered by the present invention. These other advantages, goals and embodiments are clearly included within the scope of the present invention. Publications and other materials used herein to illustrate the background of the invention and to provide other details about practice in specific cases are incorporated by reference.

[0030] Brief description of the diagram

[0031] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and are used together with the present invention to explain the principles of the present invention. The drawings are only used for the purpose of illustrating the embodiments of the present invention and should not be construed as limiting the present invention. Other objects, features and advantages of the present invention will become apparent from the following embodiments in conjunction with the accompanying drawings showing illustrative embodiments of the present invention, in which:

[0032] Figure 1 .Illustration of the general principle of PROTAC functionality. (A) An exemplary PROTAC comprises a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and an optional linker moiety (L; black line) that couples or tethers the PTM to the ULM. (B) Illustrated are functional uses of PROTACs as described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein into close proximity with 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 the attachment of ubiquitin (dark circle) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome machinery.

[0033] Details

[0034] The following are provided to help those skilled in the art to practice the present invention. Those of ordinary skill in the art may make modifications and changes in the embodiments described herein without departing from the spirit or scope of the present disclosure. All disclosures, patent applications, patents, figures and other references mentioned herein are expressly incorporated by reference in their entirety.

[0035] The present invention describes compositions and methods involving the surprising and unexpected discovery that E3 ubiquitin ligase proteins (e.g., cerebellin) ubiquitinate target proteins when they are positioned in proximity to the target protein through a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein. Thus, the present invention provides such compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein targeting binding moiety ("PTM") that results in ubiquitination of a selected target protein, which results in degradation of the target protein by the proteasome (see Figure 1 ). The present invention also provides a composition library and its use.

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. The terminology used in the present invention is only for describing particular embodiments and is not intended to limit the invention.

[0037] Where a range of values ​​is provided, it is understood that each intervening value (to one-tenth of a unit of the lower limit) between the upper and lower limits of the range, as well as any other stated or intervening value in the stated range, is encompassed within the invention unless the context clearly indicates otherwise (such as in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the stated range is provided). The upper and lower limits of these smaller ranges may be independently included in smaller ranges that are also encompassed within the invention, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the stated limits, ranges excluding one or both of those included limits are also encompassed within the invention.

[0038] The following terms are used to describe the present invention. In the event that a term is not specifically defined herein, the term is given the meaning generally recognized in the art by one of ordinary skill in the art as the term is applied in the context to describe the present invention.

[0039] Unless the context clearly indicates otherwise, as used herein and in the appended claims, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical objects of the article. For example, "an element" means one element or more than one element.

[0040] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "one or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open language (such as "comprising"), reference to "A and / or B" may refer to only A (optionally including elements other than B) in one embodiment; only B (optionally including elements other than A) in another embodiment; both A and B (optionally including other elements) in yet another embodiment; etc.

[0041] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of a plurality of elements or lists of elements and including more than one and optionally other unlisted items. Only terms that clearly indicate the opposite (such as "only one of..." or "exactly one of..." or "consisting of..." when used in the claims) will refer to including exactly one element in a plurality of elements or lists of elements. In general, as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by an exclusive term (such as "one of...", "only one of..." or "exactly one of...").

[0042] In the claims and the above specification, all transitional phrases (such as "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," etc.) shall be understood as open-ended, i.e., meaning including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0043] As used herein, in the specification and claims, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting 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") may refer to at least one, optionally including more than one A, without B (and optionally including elements other than B) in one embodiment; at least one, optionally including more than one B, without A (and optionally including elements other than A) in another embodiment; at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including other elements) in yet another embodiment; etc.

[0044] It should also be understood that in certain methods described herein that include more than one step or action, 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 listed unless the context dictates otherwise.

[0045] The term "co-administration / co-administering" or "combination therapy" refers to both simultaneous administration (administering two or more therapeutic agents at the same time) and time-varying administration (administering one or more therapeutic agents at a time different from the time of administration of the additional therapeutic agent), as long as the therapeutic agents are present in the patient at the same time to some extent (preferably in effective amounts). In certain preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional biologically active agent, particularly including anticancer agents. In particularly preferred aspects, co-administering the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0046] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein when the context is applicable and includes its tautomers, positional isomers, geometric isomers, and stereoisomers (including optical isomers (enantiomers) and other stereoisomers (diastereomers)) when applicable, as well as pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When it is used in the context, the term compound refers generally to a single compound, and may include other compounds, such as stereoisomers, positional isomers and / or optical isomers (including racemic mixtures) of the disclosed compounds, as well as specific enantiomers or enantiomerically enriched mixtures. The term in the context also refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds of the present invention, a number of substituents and variables associated therewith are particularly described. It should be understood by those of ordinary skill that the molecules described herein are stable compounds generally described below. When bonds are displayed, both double bonds and single bonds are represented in the context of the displayed compounds.

[0047] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins and target substrate proteins for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that causes ubiquitin to be attached to lysines on target proteins alone or in combination with an E2 ubiquitin conjugating enzyme and then targets specific protein substrates for degradation by the proteasome. Therefore, E3 ubiquitin ligases alone or in combination with E2 ubiquitin conjugating enzymes are responsible for the transfer of ubiquitin to target proteins. In general, ubiquitin ligases participate in polyubiquitination so that a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but may instead change in their cellular location or function, for example, via binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0048] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, that is treated (including prophylactic treatment) with a composition according to the present invention. For the treatment of those infections, conditions or disease states that are specific to a particular animal (such as a human patient), the term patient refers to the particular animal, including domestic animals such as dogs or cats; or farm animals such as horses, cows, sheep, etc. In general, in the present invention, the term patient refers to a human patient unless otherwise stated implied from the context in which the term is used.

[0049] The term "effective" is used to describe an amount of a compound, composition, or component thereof that achieves the intended result when used in the context of its intended use. The term effective includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0050] Compounds and compositions

[0051] In one aspect, the invention provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM"), which is a cerebellin E3 ubiquitin ligase binding moiety ("CLM"). In one embodiment, the CLM is coupled to a chemical linker (L) according to the following structure:

[0052] (I)L-CLM

[0053] Wherein L is a chemical linker group and CLM is a cerebellin E3 ubiquitin ligase binding moiety. The number and / or relative positions of the moieties in the compounds described herein are provided by way of example only. As will be appreciated by the skilled artisan, the compounds described herein can be synthesized to have any desired number and / or relative positions of the corresponding functional moieties.

[0054] Unless the context indicates otherwise, the terms ULM and CLM are used in their inclusive sense. For example, the term ULM includes all ULMs, including those that bind cerebellin (i.e., CLMs). Furthermore, the term CLM includes all possible cerebellin E3 ubiquitin ligase binding moieties.

[0055] On the other hand, the present invention provides bifunctional or multifunctional PROTAC compounds suitable for regulating protein activity by inducing degradation of target proteins. In certain embodiments, the compound comprises a CLM directly or indirectly coupled (e.g., covalently linked) to a portion that binds to a target protein (i.e., a protein targeting portion or "PTM"). In certain embodiments, CLM is connected or coupled to PTM via a chemical linker (L). CLM recognizes cerebellin E3 ubiquitin ligase and PTM recognizes target proteins, and the interaction of the corresponding portion with its target promotes the degradation of target proteins by positioning the target protein close to the ubiquitin ligase protein. Exemplary bifunctional compounds can be depicted as:

[0056] (II) PTM-CLM

[0057] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be depicted as:

[0058] (III) PTM-L-CLM

[0059] Wherein PTM is the protein / peptide targeting moiety, L is the linker, and CLM is the cerebellin E3 ligase binding moiety.

[0060] In certain embodiments, compounds as described herein comprise multiple PTMs (targeting the same or different protein targets), multiple CLMs, one or more ULMs (i.e., a portion that specifically binds to another E3 ubiquitin ligase, such as VHL), or a combination thereof. In any aspect of the embodiments described herein, the PTMs, CLMs, and ULMs may be coupled directly or via one or more chemical linkers, or a combination thereof. In other embodiments, when a compound has multiple ULMs, the ULMs may be used for the same E3 ubiquitin ligase or each corresponding ULM may specifically bind to a different E3 ubiquitin ligase. In yet other embodiments, when a compound has multiple PTMs, the PTMs may bind to the same target protein or each corresponding PTM may specifically bind to a different target protein.

[0061] In another embodiment, the invention provides a compound comprising a plurality of CLMs coupled directly or via a chemical linker moiety (L). For example, a compound having two CLMs can be depicted as:

[0062] (IV)CLM-CLM or

[0063] (V)CLM-L-CLM

[0064] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are the same. In other embodiments, a compound comprising multiple CLMs further comprises at least one PTM coupled to the CLMs directly or via a chemical linker (L) or both. In certain other embodiments, a compound comprising multiple CLMs further comprises multiple PTMs. In yet other embodiments, the PTMs are the same or optionally different. In yet other embodiments, where the PTMs are different, the corresponding PTMs may bind to the same protein target or specifically bind to different protein targets.

[0065] In other embodiments, the invention provides a compound comprising at least two different CLMs coupled directly or via a chemical linker (L) or both. For example, such a compound with two different CLMs can be depicted as:

[0066] (VI) CLM-CLM' or

[0067] (VII)CLM-L-CLM'

[0068] Wherein CLM' represents a cerebellin E3 ubiquitin ligase binding portion that is structurally different from CLM. In certain embodiments, the compound may comprise multiple CLMs and / or multiple CLM's. In other embodiments, the compound comprising at least two different CLMs, multiple CLMs and / or multiple CLM's further comprises at least one PTM coupled to CLM or CLM' directly or via a chemical linker or both. In any embodiment described herein, the compound comprising at least two different CLMs may further comprise multiple PTMs. In yet other embodiments, the PTMs are the same or optionally different. In yet other embodiments, where the PTMs are different, the corresponding PTMs may bind to the same protein target or specifically bind to different protein targets. In yet other embodiments, the PTM itself is a ULM or CLM (or a ULM' or CLM').

[0069] In a preferred embodiment, the CLM comprises a moiety that is a ligand for cerebellar protein E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM comprises a chemotype from the "imide" class of molecules. In certain other embodiments, the CLM comprises a phthalimido group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a phthalimido-glutarimidyl group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0070] In other embodiments, the present invention provides compounds as described herein, including enantiomers, diastereomers, solvates and polymorphs thereof, including pharmaceutically acceptable salt forms, such as acid and base salt forms, thereof.

[0071] New imide compounds

[0072] In one aspect, the invention provides compounds suitable for binding and / or inhibiting cerebellin. In certain embodiments, the compound is selected from the group consisting of the following chemical structures:

[0073]

[0074] in

[0075] W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0076] X is independently selected from the group consisting of O, S and H2;

[0077] Y is independently selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0078] Z is independently selected from the group consisting of O and S or H2, but wherein both X and Z cannot be H2;

[0079] G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';

[0080] Q1-Q4 represents a carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0081] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0082] R includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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)N R'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3

[0083] R' and R" are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl

[0084] n is an integer from 1 to 4;

[0085] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0086] R n Includes 1-4 independent functional groups or atoms.

[0087] Exemplary CLM

[0088] In any of the compounds described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0089]

[0090] in

[0091] W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0092] X is independently selected from the group consisting of O, S and H2;

[0093] Y is independently selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0094] Z is independently selected from the group consisting of O and S or H2, but wherein both X and Z cannot be H2;

[0095] G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';

[0096] Q1-Q4 represents a carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0097] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0098] R includes, but is not limited to, -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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)N R'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5 and -OCF3

[0099] R' and R" are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl

[0100] n is an integer from 1 to 4;

[0101] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0102] Rn includes 1-4 independent functional groups or atoms, and optionally one of them is modified to be covalently linked to a PTM, a chemical linker group (L), a ULM, a CLM (and CLM'), or a combination thereof.

[0103] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0104] The term "alkyl" in this context shall mean a straight-chain, branched or cyclic fully saturated hydrocarbon or alkyl group, preferably C1-C 10 , more preferably C1-C6, or C1-C3 alkyl, which may be optionally substituted. Examples of alkyl are especially 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 is terminated with a halogen group (At, Br, Cl, F or I). In certain preferred embodiments, the compounds according to the present invention can be used to covalently bind to dehalogenases. These compounds typically contain side chains (often connected by a polyethylene glycol group) terminated with an alkyl having a halogen substituent (often chlorine or bromine) at its end, which results in the covalent binding of the compound containing such a moiety to the protein.

[0105] The term "alkenyl" refers to a straight chain, branched chain or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0106] The term "alkynyl" refers to a straight chain, branched chain or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0107] The term "alkylene" when used herein refers to -(CH2) n-group (n is an integer generally from 0 to 6), which may be optionally substituted. When substituted, the alkylene group is preferably substituted on one or more methylene groups with a C1-C6 alkyl group (including cyclopropyl or tert-butyl), but may also be substituted with one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C1-C6 alkyl) or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a carbamate or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (having 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with a single halogen group, preferably a chloro group (preferably, but not exclusively at the end of the polyethylene glycol chain). In yet other embodiments, the alkylene group (often a methylene group) can be substituted with an amino acid side chain radical, such as a side chain radical of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0108] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A carbon atom range including CO means that the carbon is not present and is replaced with H. Thus, a carbon atom range of CO-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for CO, H is present in place of carbon.

[0109] The term "substituted" or "optionally substituted" shall independently mean (i.e., each substituent is independent of the other when more than one substituent is present) one or more substituents at a carbon (or nitrogen) position anywhere on the molecule within the context (independently up to five substituents, preferably up to three substituents, often 1 or 2 substituents on the moiety in the compounds according to the invention, and may include substituents which themselves may be further substituted), and include the following as substituents: hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2 or 3 halogens, especially on alkyl, especially methyl, such as trifluoromethyl), alkyl (preferably C1-C 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl), including alkylene esters (so that the attachment is on the alkylene rather than at the ester function, which is preferably substituted with C1-C6 alkyl or aryl), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five-membered or six-membered cycloalkylene amine, Further include C1-C6 alkylamine or C1-C6 dialkylamine, the alkyl group may be substituted with one or two hydroxy groups) or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) (which may be optionally substituted with a polyethylene glycol chain further bonded to an alkyl group containing a single halogen, preferably chlorine substituent), hydrazine, acylamino groups preferably substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups), alkanols (preferably C1-C6 alkyl or aryl groups) or alkanoic acids (preferably C1-C6 alkyl or aryl groups). Substituents according to the present invention may include, for example, -SiR1R2R3 groups, wherein each of R1 and R2 is as otherwise described herein, and R3 is H or C1-C6 alkyl, preferably R1, R2, R3 in this regard are C1-C3 alkyl groups (including isopropyl or tert-butyl groups). Each of the above groups may be directly attached to the substituted moiety, or alternatively the substituent may be attached via an optionally substituted -(CH2) m - or alternatively optionally substituted -(OCH2) m -、-(OCH2CH2) m -or-(CH2CH2O) m -group is attached to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety), which may be substituted by any one or more of the above substituents. As defined above, alkylene -(CH2) m -or-(CH2) n-groups or other chains, such as ethylene glycol chains, can be substituted anywhere on the chain. Preferred substituents on the alkylene include halogen or C1-C6 (preferably C1-C3) alkyl, which can be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F) or amino acid side chains as otherwise described herein and optionally substituted amides (preferably substituted carboxamides as described above) or carbamate groups (often with one or two C0-C6 alkyl substituents, which groups can be further substituted). In certain embodiments, the alkylene (often a single methylene) is substituted with one or two optionally substituted C1-C6 alkyl, preferably C1-C4 alkyl, most often methyl or O-methyl or amino acid side chains as otherwise described herein. In the present invention, a moiety in the molecule can be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present invention, a substituted moiety is substituted with one or two substituents.

[0110] The term "substituted" (each substituent being independent of any other substituent) within the context of its use shall also mean C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxyl, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, carbamate -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano and amine (especially including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl substituted amine, which may be optionally substituted with one or two hydroxyl groups). Unless otherwise indicated, within the context, each of these groups contains between 1 and 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m -(wherein 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) nOH, -(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)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 groups), NO2, CN or halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. R1 and R2 are each H or C1-C6 alkyl (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine) within the context. The term "substituted" within the chemical context of compound definitions and substituent use shall also mean optionally substituted aryl or heteroaryl or optionally substituted heterocyclyl as otherwise described herein. Alkylene may also be substituted as otherwise disclosed herein, preferably with optionally substituted C1-C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), an amino acid side chain as otherwise described herein, an amido as described above, or a carbamate OC(O)-NR1R2 group (wherein R1 and R2 are as otherwise described herein), but numerous other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably 1 or 2 substituents. It should be noted that where molecular substitution at a particular position is desired in a compound (primarily for valency reasons), but no substitution is indicated, then the substituent is interpreted or understood to be H unless the context of the substitution implies otherwise.

[0111] The term "aryl" or "aromatic" in the context refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or a condensed ring (e.g., naphthyl, anthracenyl, phenanthryl, etc.), and can be bound to the compounds according to the invention at any available stable position on the ring or as otherwise indicated in the presented chemical structure. Other examples of aryl groups in the context may include, among others, heterocyclic aromatic ring systems, "heteroaryl" having one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic), such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole; or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which may be optionally substituted as described above. Among the heteroaryl radicals that may be mentioned are especially nitrogen-containing heteroaryl radicals such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolo ... pyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazolooxazole, imidazothiazole, thienofuran, furopyrrole, pyridooxazine, furopyridine, furanopyrimidine, thienopyrimidine and oxazole, all of which may be optionally substituted.

[0112] The term "substituted aryl" refers to an aromatic carbocyclic group containing at least one aromatic ring or multiple condensed rings (at least one of which is aromatic), wherein the ring is substituted with one or more substituents. For example, the aryl group may contain a substituent 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-C6alkyl)amine (wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups), OH, COOH, C1-C6alkyl (preferably CH3), CF3, OMe, OCF3, NO2 or CN groups (each of which may be substituted at the ortho, meta and / or para position, preferably the para position, of the phenyl ring), optionally substituted phenyl (the phenyl group itself is preferably substituted with a linker group connected to a PTM group, including a ULM group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (at the ortho, meta and / or para position, preferably the para position, of the phenyl ring), naphthyl (which may be optionally substituted), optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl substituted isoxazole; optionally substituted oxazole, including methyl substituted oxazole; optionally substituted thiazole, including methyl substituted thiazole; optionally substituted isothiazole, including methyl substituted isothiazole; optionally substituted pyrrole, including methyl substituted pyrrole; optionally substituted imidazole, including methylimidazole; optionally substituted benzimidazole or methoxybenzylimidazole; optionally substituted oximeimidazole or methyloximeimidazole; optionally substituted oxadiazole, including methyloxadiazole; optionally optionally substituted triazolyl, including methyl substituted triazolyl; optionally substituted pyridinyl, including halo (preferably F) or methyl substituted pyridinyl or oxapyridinyl (wherein the pyridinyl is attached to the phenyl group through an oxygen); optionally substituted furan; optionally substituted benzofuran; optionally substituted dihydrobenzofuran; optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine); optionally substituted quinoline) and combinations thereof.

[0113] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and these general substituents have the same meanings as defined herein.

[0114] The term "heteroaryl" or "hetaryl" may refer to, but is in no way limited to, optionally substituted quinoline (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxfuran, 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, triisopropylsilyl, optionally substituted -(CH2) m -O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), optionally substituted pyridine (2, 3 or 4-pyridine) or a group according to the following chemical structure:

[0115]

[0116] in

[0117] S c It is CHR SS NR URE or O;

[0118] R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups, such as CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted alkynyl -C≡CR a (where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0119] 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);

[0120] R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluoro groups), or an optionally substituted heterocycle (e.g., piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted), and

[0121] Y C Is N or CR YC , where R YC is 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 alkynyl -C≡CR a (where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl).

[0122] The terms "aralkyl" and "heteroarylalkyl" refer to a group containing both an aryl or respectively heteroaryl group as defined above and an alkyl and / or heteroalkyl and / or a carbocyclic and / or heterocycloalkyl ring system.

[0123] As used herein, the term "arylalkyl" refers to an aryl group as defined above connected to an alkyl group as defined above. The arylalkyl group is connected to the parent moiety through the alkyl group, wherein the alkyl group has one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0124] The term "heterocycle" refers to a ring radical containing at least one heteroatom (e.g., N, O, or S), and can be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included under the definition of heterocycle, depending on the context in which they are used. Exemplary heteroaryl groups are described above.

[0125] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiophenyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolyl, indolyl, isoquinolinyl, isothiazolidinyl, Isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxirane, oxetanyl, oxathiolanyl, cyclopentane sulfide.

[0126] The heterocyclic group may be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioaryloxy, thioheterocyclicoxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclicoxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SOaryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, oxo (=O), and —SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholinyl, piperidinyl, tetrahydrofuranyl, etc., and N-alkoxy-nitrogen heterocycles. The term "heterocycle" also includes bicyclic groups in which any one of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0127] The term "cycloalkyl" may mean, but is by no means limited to, a monovalent group derived from a monocyclic or polycyclic alkyl or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may mean, but is by no means limited to, a monocyclic or polycyclic alkyl group and is substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, divalent carbonyl, divalent carbonyl, aryl, nitro, thiol or sulfonyl, and these general substituents have the same meanings as the definitions of the corresponding groups as defined in this example.

[0128] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the ring structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, divalent carbonyl, divalent carbonyl mercapto, aryl, nitro, mercapto or sulfo, and these general substituents have the same meanings as the definitions of the corresponding groups as defined in this example.

[0129] The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic, and includes aryl, alkyl, alkenyl and alkynyl groups.

[0130] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R", Q1-Q4, A and Rn can be independently covalently coupled to a linker and / or a linker to which one or more PTM, ULM, CLM or CLM' groups are attached.

[0131] More specifically, non-limiting examples of CLMs include those shown below as well as those 'hybrid' molecules resulting from the combination of 1 or more of the different features shown in the following molecules.

[0132]

[0133]

[0134]

[0135]

[0136]

[0137] Exemplary Linkers

[0138] 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 structural unit A (e.g., -A1 ... A q -), wherein A1 is a group coupled to at least one of a ULM, a PTM, or a combination thereof. In certain embodiments, A1 directly connects a ULM, a PTM, or a combination thereof to another ULM, a PTM, or a combination thereof. In other embodiments, A1 connects a ULM, a PTM, or a combination thereof to another ULM, a PTM, or a combination thereof through A q Indirectly connected to another ULM, PTM, or a combination thereof.

[0139] In certain embodiments, A1 to A q Each is independently a key, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,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 , optionally through 0-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally with 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally 0-6 R L1 and / or R L2 The aryl group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 , each independently can be connected to other A groups to form can be further connected to 0-4 R L5 The cycloalkyl and / or heterocyclyl moieties are substituted with a group; wherein

[0140] R L1 , R L2 , R L3 , R L4 and R L5 are independently H, halogen, 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 Heterocyclic group, 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)(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 1-8Alkyl), N(C 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 Alkyl)2, NH SO2NH2.

[0141] In certain embodiments, q is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0142] In certain embodiments, for example when q is greater than 2, A q is a group attached to the ULM or ULM' moiety, and A1 and A q The connection is via structural units A (the number of such structural units A: q-2).

[0143] In certain embodiments, for example when q is 2, A q is a group connected to A1 and the ULM or ULM' moiety.

[0144] In certain embodiments, for example when q is 1, the structure of the linker group L is -A1-, and A1 is a group that connects to the ULM or ULM' moiety and the PTM moiety.

[0145] In other embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

[0146] In certain embodiments, the linker (L) is selected from the group consisting of:

[0147]

[0148]

[0149] In other embodiments, the linker group is an optionally substituted (poly)ethylene glycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, and between 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl. In certain embodiments, the linker can be asymmetric or symmetric.

[0150] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.

[0151] Although the CLM (or ULM) group and the PTM group can be covalently linked to the linker group by any group that is suitable and stable for the chemical nature of the linker, in preferred aspects of the present invention, the linker is preferably independently covalently bonded to the CLM group and the PTM group by amide, ester, thioester, keto, carbamate / urethane, carbon and ether, each of which can be inserted anywhere on the CLM group and the PTM group to provide maximum binding of the CLM group on the ubiquitin ligase to the PTM group on the target protein to be degraded. (It should be noted that in certain aspects where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself). In certain preferred aspects, the linker can be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl or heterocyclic group on the CLM and / or PTM group.

[0152] Exemplary PTMs

[0153] In a preferred aspect of the invention, the PTM group is a group that binds to a target protein. The target species of the PTM group are numerous and are selected from proteins expressed in cells so that at least a portion of the sequence is found in the cell and can be bound to the PTM group. The term "protein" includes oligopeptides and polypeptide sequences of sufficient length that can be bound to the PTM group according to the invention. Any protein in a eukaryotic system or microbial system (including viruses, bacteria or fungi) as described elsewhere herein is a target for ubiquitination mediated by a compound according to the invention. The target protein is preferably a eukaryotic protein. In certain aspects, the protein binding moiety is a haloalkane, preferably a C1-C2 substituted with at least one halo, preferably at the end of the alkyl group (i.e., away from the linker or CLM group) substituted with a halo. 10 An alkyl group that can be covalently bound to a dehalogenase in a patient or subject or in a diagnostic assay.

[0154] PTM groups according to the present invention include, for example, any portion that specifically binds to a protein (binds to a target protein) and include the following non-limiting examples of small molecule target protein portions: 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 (AHR), as well as numerous others. The compositions described below illustrate some members of these nine types of small molecule target protein binding portions. Such small molecule target protein binding portions also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding portions are preferably connected to the ubiquitin ligase binding portion via a linker so that the target protein (to which the protein target portion is bound) is present in close proximity to the ubiquitin ligase for ubiquitination and degradation.

[0155] Any protein that can be conjugated to a protein targeting moiety or PTM group and act upon or be degraded by a ubiquitin ligase is a target protein according to the present invention. In general, target proteins can include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of the cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Proteins of interest can include proteins from eukaryotic and prokaryotic organisms, including humans, other animals (including domestic animals) as targets for drug therapy, microorganisms used as targets for testing antibiotics and other antimicrobials and plants and even viruses, among many others.

[0156] In yet other embodiments, the PTM group is a haloalkyl group, wherein the size of the alkyl group is typically in the range of about 1 or 2 carbons to about 12 carbons, often about 2 to 10 carbons, often about 3 carbons to about 8 carbons, and more often about 4 carbons to about 6 carbons. The haloalkyl group is typically a straight chain alkyl group (although branched alkyl groups may be used) and terminates with at least one halogen group, preferably a single halogen group, often a single chloride group. The haloalkyl PT group used in the present invention is preferably composed of the chemical structure -(CH2) v -halo means where v is any integer from 2 to about 12, often from about 3 to about 8, more often from about 4 to about 6. Halo can be any halogen, but is preferably Cl or bromine, more often Cl.

[0157] In another embodiment, the invention provides a library of compounds. The library comprises more than one compound, wherein each composition has the formula AB, wherein A is an ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin ligase moiety as otherwise disclosed herein) and B is a protein binding member of a molecular library, wherein A is coupled (preferably through a linker moiety) to B, and wherein the ubiquitin pathway protein binding moiety recognizes ubiquitin pathway proteins, particularly E3 ubiquitin ligases, such as cerebellin. In a specific embodiment, the library contains a specific cerebellin E3 ubiquitin ligase binding moiety (e.g., a chemical compound library) bound to a random target protein binding element. Thus, the target protein is not determined in advance, and the method can be used to determine the activity of a putative protein binding element and its pharmacological value as a target after degradation by a ubiquitin ligase.

[0158] The present invention can be used to treat a variety of disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and the patient would benefit from protein degradation.

[0159] On the other hand, the present invention provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive or excipient, and optionally another bioactive agent. The therapeutic composition regulates protein degradation in a patient or subject (e.g., an animal, such as a human being), and can be used to treat or improve a disease state or condition regulated by the degraded protein. In certain embodiments, the therapeutic composition as described herein can be used to practice degradation of a protein of interest for treating or improving a disease (e.g., cancer). In certain other embodiments, the disease is multiple myeloma.

[0160] In alternative aspects, the present invention relates to a method for treating a disease state of a subject in need thereof or improving the symptoms of a disease or condition by degrading a protein or polypeptide regulated by the disease state or condition, the method comprising administering to the patient or subject an effective amount (e.g., a therapeutically effective amount) of at least one compound as described above, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient and optionally another bioactive agent, wherein the composition is effective to treat or improve the subject's disease or disorder or its symptoms. The method according to the present invention can be used to treat many disease states or conditions, including cancer, by administering an effective amount of at least one compound as described herein. The disease state or condition can be a disease caused by a microbial agent or other exogenous agent (such as a virus, bacteria, fungus, protozoa or other microorganism), or can be a disease state caused by protein overexpression (which leads to a disease state and / or condition).

[0161] In another aspect, the invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the invention.

[0162] The term "target protein" is used to describe below a protein or polypeptide that is bound to a compound according to the invention and is targeted for degradation by a ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions and other small molecules that can target the protein of interest. These binding moieties are linked to the CLM or ULM group via a linker group L.

[0163] Target proteins that can be bound to a protein targeting portion and degraded by a ligase bound by a ubiquitin ligase binding portion include any protein or peptide, including fragments thereof, analogs thereof, and / or homologs thereof. Target proteins include proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction. In certain embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins associated with the integral functions of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretion activity, electron transport activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Proteins of interest can include proteins from eukaryotic and prokaryotic organisms, including microbes, viruses, fungi, and parasites, among many others, including humans, microbes, viruses, fungi, and parasites as targets for drug therapy, other animals (including domestic animals), microbes used as targets for testing antibiotics and other antimicrobials and plants, and even viruses, among many others.

[0164] More specifically, various drug targets of human therapeutics represent protein targets to which protein target moieties may bind and be incorporated into compounds according to the invention. It includes proteins that can be used to restore function in a wide range of polygenic diseases, including, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other chaperones in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and analogs, 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-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptors, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA of NGF a receptor, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel. Other target proteins include acetyl CoA carboxylase, adenylo succinate synthetase, protoporphyrinogen oxidase and enolpyruvylshikimate-phosphate synthase.

[0165] Haloalkane dehalogenase is another target of specific compounds according to the invention. Compounds according to the invention containing a chloroalkane peptide binding moiety (C1-C12, often about C2-C10 alkyl halide) can be used to inhibit and / or degrade haloalkane dehalogenase, which is used in fusion proteins or related diagnostic proteins, as described in PCT / US2012 / 063401 filed on December 6, 2011 and published on June 14, 2012 as WO 2012 / 078559, the contents of which are incorporated herein by reference.

[0166] These various protein targets can be used in screens to identify compound moieties that bind to the protein, and by incorporating such moieties into compounds according to the invention, the activity level of the protein can be altered for a therapeutic end result.

[0167] The term "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; and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among many others. The compositions described below exemplify some members of these nine types of small molecule target proteins.

[0168] Exemplary protein targeting moieties according to the present disclosure include haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0169] The compositions described below exemplify some members of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions and other small molecules that can target proteins of interest. The references cited below are incorporated herein by reference in their entirety.

[0170] I. Heat shock protein 90 (HSP90) inhibitors:

[0171] HSP90 inhibitors as used herein include but are not limited to:

[0172] 1. HSP90 inhibitors identified in Vallee et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo [4,5-C] Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone" (2011) J. Med. Chem. 54: 7206, including YKB (N- [4- (3H-imidazo [4,5-C] pyridine-2-yl) -9H-fluoren-9-yl] - succinamide):

[0173]

[0174] derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a terminal amide group;

[0175] 2. HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfonyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

[0176]

[0177] wherein the linker group L or -(L-CLM) group is attached, for example, via a terminal ethynyl group;

[0178] 3. HSP90 inhibitors (modified) identified in Brough et al., “4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer”, J. MED. CHEM. Vol. 51, p. 196 (2008), including compound 2GJ (5-[2,4-dihydroxy-5-(1-methylethyl]phenyl)-n-ethyl-4-[4-(morpholin-4-ylmethyl]phenyl)isoxazole-3-carboxamide) having the following structure:

[0179]

[0180] Derivatized, where a linker group L or a -(L-CLM) group is attached, for example, via an amide group (at an amine or an alkyl group on an amine);

[0181] 4. HSP90 inhibitors (modified) identified in Wright et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun; 11(6):775-85, including HSP90 inhibitor PU3 having the following structure:

[0182]

[0183] wherein the linker group L or -(L-CLM) is attached, for example, via a butyl group; and

[0184] 5. HSP90 inhibitor geldanamycin (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] (derivatized) or any of its derivatives (e.g., 17-alkylamino-17-demethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin ("17-DMAG")) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via an amide group).

[0185] II. Kinase and phosphatase inhibitors:

[0186] Kinase inhibitors as used herein include but are not limited to:

[0187] 1. Erlotinib derivative tyrosine kinase inhibitors:

[0188]

[0189] wherein R is a linker group L or a -(L-CLM) group, for example, linked via an ether group;

[0190] 2. Kinase inhibitor sunitinib (derivative):

[0191]

[0192] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, a pyrrole moiety);

[0193] 3. Kinase inhibitor sorafenib (derivative):

[0194]

[0195] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, an amide moiety);

[0196] 4. Kinase inhibitor desatinib (derivative):

[0197]

[0198] (derivatized, where R is a linker group L or -(L-CLM) attached to, for example, pyrimidine);

[0199] 5. Kinase inhibitor lapatinib (derivative):

[0200]

[0201] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via the terminal methyl group of a sulfonylmethyl group);

[0202] 6. Kinase inhibitor U09-CX-5279 (derivative):

[0203]

[0204] derivatized, wherein the linker group L or -(L-CLM) group is attached to the cyclopropyl group, or the cyclopropyl group, for example via an amine (aniline), a carboxylic acid or an amine alpha;

[0205] 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, p. 7797 (2011), including kinase inhibitors Y1W and Y1X (derivative) having the following structures:

[0206]

[0207] YIX(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfonyl}benzyl)urea)

[0208] Derivatized, wherein the linker group L or -(L-CLM) group is for example i Propyl connection;

[0209]

[0210] YW

[0211] 1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfonyl}benzyl)urea

[0212] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, preferably via an isopropyl or tert-butyl group;

[0213] 8. Kinase inhibitors identified in Schenkel et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J. Med. Chem., 2011, 54(24), pp. 8440-8450, including compounds 6TP and OTP (derivative) having the following structures:

[0214]

[0215] 6TP

[0216] 4-amino-2-[4-(tert-butylsulfamoyl]phenyl)-N-methylthieno[3,2-c]pyridine-7-carboxamidethienopyridine 19

[0217] derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a terminal methyl group bound to an amide moiety;

[0218]

[0219] 0TP

[0220] 4-amino-N-methyl-2-[4-(morpholin-4-yl]phenyl)thieno[3,2-c]pyridine-7-carboxamidethienopyridine 8

[0221] derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a terminal methyl group bound to an amide moiety;

[0222] 9. Kinase inhibitors identified in Van Eis et al., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes", Biorg. Med. Chem. Lett. 2011 Dec 15; 21(24): 7367-72, including kinase inhibitor 07U having the following structure:

[0223]

[0224] 07U

[0225] 2-Methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine

[0226] derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a secondary amine or a terminal amino group;

[0227] 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, p. 292 (2011), including the kinase inhibitor YCF having the following structure:

[0228]

[0229] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via either of the terminal hydroxyl groups;

[0230] 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, p. 292 (2011), including kinase inhibitors XK9 and NXP (derivative) having the following structures:

[0231]

[0232] XK9

[0233] N-{4-[(1E)-N-(N-hydroxycarbamoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide;

[0234]

[0235] NXP

[0236] N-{4-[(1E)-N-aminocarboximidoylethanehydrazineyl]PHENYL}-1H-indole-3-carboxamide

[0237] derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a terminal hydroxyl group (XK9) or a hydrazone group (NXP);

[0238] 12. The kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via an aliphatic amine group);

[0239] 13. The kinase inhibitor fostamatinib (derivatized) (phospho[6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl disodium salt hexahydrate) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a methoxy group);

[0240] 14. Kinase inhibitor gefitinib (derivative) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

[0241]

[0242] (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a methoxy or ether group);

[0243] 15. The kinase inhibitor lenvatinib (derivative) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivative, wherein the linker group L or -(L-CLM) group is attached, for example, via a cyclopropyl group);

[0244] 16. The kinase inhibitor vandetanib (derivatized)(N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a methoxy or hydroxyl group);

[0245] 17. The kinase inhibitor vemurafenib (derivatized) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a sulfonylpropyl group);

[0246] 18. Kinase inhibitor Gleevec (derivative):

[0247]

[0248] (derivatized, wherein R is a linker group L or a -(L-CLM) group, for example, attached via an amide group or via an aniline amine group);

[0249] 19. Kinase inhibitor pazopanib (derivative) (VEGFR3 inhibitor):

[0250]

[0251] (derivatized, where R is a linker group L or a -(L-CLM) group, for example, attached to a phenyl moiety or via an aniline amine group);

[0252] 20. Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor

[0253]

[0254] (wherein R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0255] 21. Kinase inhibitor TAE684 (derivative) ALK inhibitor

[0256]

[0257] (wherein R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0258] 22. Kinase inhibitors Nilotanib (derivative) Abl inhibitors:

[0259]

[0260] (derivatized, where R is a linker group L or a -(L-CLM) group, for example, attached to a phenyl moiety or an amine group of anilino);

[0261] 23. Kinase inhibitor NVP-BSK805 (derived) JAK2 inhibitor

[0262]

[0263] (derivatized, where R is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety or an oxadiazole group);

[0264] 24. Alk inhibitors derived from kinase inhibitor crizotinib

[0265]

[0266] (derivatized, where R is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety or an oxadiazole group);

[0267] 25. Kinase inhibitors JNJ FMS (derived) inhibitors

[0268]

[0269] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0270] 26. Kinase inhibitors Foretinib (derivative) Met inhibitors

[0271]

[0272] (derivatized, wherein R is a linker group L or a -(L-CLM) group, for example, a hydroxyl or ether group attached to a phenyl moiety or a quinoline moiety);

[0273] 27. Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivative):

[0274]

[0275] derivatized, wherein a linker group L or a -(L-CLM) group is attached as indicated, e.g., at R;

[0276] 28. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatives):

[0277]

[0278] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, at R; 29. ​​BRAF (BRAF V600E ) / MEK inhibitors (derivatives):

[0279]

[0280] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, at R; 30. Inhibitors of tyrosine kinase ABL (derivative)

[0281]

[0282] Derivatized, wherein the linker group L or -(L-CLM) group is attached at R, for example; 31. Kinase inhibitor OSI-027 (derivative) mTORC1 / 2 inhibitor

[0283]

[0284] Derivatized, wherein the linker group L or -(L-CLM) group is attached at R, for example; 32. Kinase inhibitor OSI-930 (derivative) c-Kit / KDR inhibitor

[0285]

[0286] Derivatized, wherein the linker group L or -(L-CLM) group is attached at R, for example; and 33. Kinase inhibitor OSI-906 (derivative) IGF1R / IR inhibitor

[0287]

[0288] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R;

[0289] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group on the piperazine moiety).

[0290] III. HDM2 / MDM2 inhibitors:

[0291] As used herein, HDM2 / MDM2 inhibitors include but are not limited to:

[0292] 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, pp. 844-848 (2004) and Schneekloth et al., Targeted intracellular protein degradation induced by a small molecule: Enroute to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or in addition to) the compounds nutlin-3, nutlin-2 and nutlin-1 (derivative) as described below and all derivatives and analogs thereof:

[0293]

[0294] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at a methoxy or hydroxyl group);

[0295]

[0296] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at a methoxy or hydroxyl group);

[0297]

[0298] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a methoxy or hydroxyl group); and

[0299] 2. trans-4-iodo-4'-boryl-chalcone

[0300]

[0301] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a hydroxyl group).

[0302] IV. Compounds Targeting Human BET Bromodomain-Containing Proteins:

[0303] Compounds targeting human BET bromodomain-containing proteins include, but are not limited to, compounds associated with the targets described below, wherein "R" indicates a site for attachment of a linker group L or -(L-CLM) group, for example:

[0304] 1.JQ1, Filippakopoulos et al. Selective inhibition of BETbromodomains. Nature (2010):

[0305]

[0306] 2. I-BET, Nicodeme et al. Supression of Inflammation by aSynthetic HistoneMimic. Nature (2010). Chung et al. Discovery and Characterization of Small MoleculeInhibitors of the BET Family Bromodomains. J. Med Chem. (2011):

[0307]

[0308] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.

[0309]

[0310] 4.I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia. Nature (2011):

[0311]

[0312] (wherein R in each case indicates the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0313] V.HDAC inhibitors:

[0314] HDAC inhibitors (derivatives) include but are not limited to:

[0315] 1. Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999).

[0316]

[0317] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group); and

[0318] 2. Compounds as defined in formula (I) of PCT WO0222577 ("DEACETYLASE INHIBITORS") (derivatized wherein the linker group L or the -(L-CLM) group is attached, for example, via a hydroxyl group);

[0319] VI. Human lysine methyltransferase inhibitors:

[0320] Human lysine methyltransferase inhibitors include, but are not limited to:

[0321] 1. Chang et al. Structural Basis for G9a-Like protein LysineMethyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16 (3) 312.

[0322]

[0323] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group);

[0324] 2. Liu, F. et al. Discovery of a 2,4-Diamino-7-aminoalkoxyquina zoline as aPotent and Selective Inhibitor of Histone Methyltransfer ase G9a.J.Med.Chem. (2009) 52(24)7950.

[0325]

[0326] (derivatized, wherein "R" indicates a potential site for attachment of, for example, a linker group L or a -(L-CLM) group);

[0327] 3. azacitidine (derivatized)(4-amino-1-β-D-ribofuranosyl-1,3,5-triazine-2(1H)-one)(derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a hydroxyl or amino group); and

[0328] 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazine-2(1H)-one) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via either the hydroxyl group or at the amino group).

[0329] VII. Angiogenesis Inhibitors:

[0330] Angiogenesis inhibitors include but are not limited to:

[0331] 1. GA-1 (derivative) and its derivatives and analogs having structures and conjugated to linker groups as described in Sakamoto et al., Development of Protacs to target cancer-promoting proteins forubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12): 1350-8;

[0332] 2. Estradiol (derivatized), which may be conjugated to a linker group L or a -(L-CLM) group as generally described in Rodriguez-Gonzalez et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211;

[0333] 3. Estradiol, testosterone (derived) and related derivatives, including but not limited to DHT and its derivatives and analogs, having a structure and conjugated to a linker group L or -(L-CLM) group as generally 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

[0334] 4. Ovalicin, fumagillin (derivatives) and derivatives and analogs thereof having structures and conjugated to a linker group L or -(L-CLM) group as generally described in Sakamoto et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex forubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and U.S. Pat. No. 7,208,157.

[0335] VIII. Immunosuppressive Compounds:

[0336] Immunosuppressive compounds include, but are not limited to:

[0337] 1. AP21998 (derivatized) having a structure and conjugated to a linker group L or -(L-CLM) group as generally described in Schneekloth et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754;

[0338] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone and methylprednisolone) (derivatized, wherein the linker group L or -(L-CLM) group is, for example, bound to any of the hydroxyl groups) and beclometasone dipropionate (derivatized, wherein the linker group or -(L-CLM) is, for example, bound to a propionate ester);

[0339] 3. methotrexate (derivatized, wherein a linker group or a -(L-CLM) group may be attached, for example, to either of the terminal hydroxyl groups);

[0340] 4. ciclosporin (derivatized, wherein the linker group or -(L-CLM) group can be attached, for example, at either of the butyl groups);

[0341] 5. tacrolimus (FK-506) and rapamycin (derivatized, wherein the linker group L or -(L-CLM) group may be attached, for example, at one of the methoxy groups); and

[0342] 6. Actinomycin (derivatized, wherein a linker group L or a -(L-CLM) group may be attached, for example, at one of the isopropyl groups).

[0343] IX. Compounds targeting the aryl hydrocarbon receptor (AHR):

[0344] Compounds targeting the aryl hydrocarbon receptor (AHR) include, but are not limited to:

[0345] 1. apigenin (derivatized by binding to a linker group L or -(L-CLM) group, as generally described in Lee et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Vol. 8, No. 17, pp. 2058-2062, Nov. 23, 2007); and

[0346] 2. SR1 and LGC006 (derivatized so as to bind a linker group L or -(L-CLM)) as described in Boitano et al., ArylHydrocarbon Receptor Antagonists Promote the Expansion of Human HematopoieticStem Cells, Science 2010 Sep 10: Vol. 329 No. 5997 pp. 1345-1348.

[0347] X. Compounds targeting RAF receptor (kinase):

[0348]

[0349] PLX4032

[0350] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0351] XI. Compounds targeting FKBP:

[0352]

[0353] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0354] XII. Compounds Targeting Androgen Receptor (AR)

[0355] 1. RU59063 ligand for androgen receptor (derivative)

[0356]

[0357] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0358] 2. SARM ligands for androgen receptor (derivatives)

[0359]

[0360] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0361] 3. Androgen receptor ligand DHT (derived)

[0362]

[0363] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0364] 4.MDV3100 ligand (derivative)

[0365]

[0366] 5.ARN-509 ligand (derivatized)

[0367]

[0368] 6. Hexahydrobenzisoxazole

[0369]

[0370] 7. Tetramethylcyclobutane

[0371]

[0372] XIII. Compounds targeting estrogen receptor (ER) ICI-182780 1. Estrogen receptor ligands

[0373]

[0374] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group).

[0375] XIV. Compounds Targeting Thyroid Hormone Receptor (TR)

[0376] 1. Thyroid hormone receptor ligand (derivative)

[0377]

[0378] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group and MOMO indicates methoxymethoxy).

[0379] XV. Compounds Targeting HIV Protease

[0380] 1. HIV protease inhibitors (derivatives)

[0381]

[0382] (derivatized, where "R" indicates the site for attachment of a linker group L or a -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0383] 2. HIV protease inhibitors

[0384]

[0385] (derivatized, where "R" indicates a potential site for attachment of a linker group L or a -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0386] XVI. Compounds Targeting HIV Integrase

[0387] 1. HIV integrase inhibitors (derivatives)

[0388]

[0389] (derivatized, where "R" indicates the site for attachment of a linker group L or a -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0390] 2. HIV integrase inhibitors (derivatives)

[0391]

[0392] 3. HIV integrase inhibitor Isetntress (derivative)

[0393]

[0394] (derivatized, where "R" indicates the site for attachment of a linker group L or a -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0395] XVII. Compounds Targeting HCV Protease

[0396] 1. Inhibitors of HCV protease (derivatives)

[0397]

[0398] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group).

[0399] XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 and APT2)

[0400] 1. Inhibitors of APT1 and APT2 (derivatives)

[0401]

[0402] (derivatized, wherein "R" indicates a site for attachment of a linker group L or a -(L-CLM) group). See Angew. Chem. Int. Ed. 2011, 50, 9838-9842, wherein L is a linker group as otherwise described herein and the CLM group is as otherwise described herein, such that -(L-CLM) binds the CLM group to a PTM group as otherwise described herein.

[0403] Therapeutic Compositions

[0404] The following pharmaceutical compositions represent another aspect of the present disclosure, comprising an effective amount of at least one bifunctional compound as described herein and a combination of one or more of the compounds otherwise described herein (all in effective amounts), and a pharmaceutically effective amount of a carrier, additive or excipient.

[0405] The present disclosure includes compositions, where applicable, comprising pharmaceutically acceptable salts, particularly acid or base addition salts, of compounds as described herein. The acids used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned base compounds useful in this aspect are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, acetates, lactates, citrates, acid citrates, tartrates, bitartrates, succinates, maleates, fumarates, gluconates, sugarates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylenebis-(2-hydroxy-3-naphthoate) and many others.

[0406] Pharmaceutically acceptable base addition salts can also be used to prepare pharmaceutically acceptable salt forms of compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of compounds of the present invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those particularly derived from such pharmacologically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium); ammonium or water-soluble amine addition salts, such as N-methyl reduced glucosamine-(glucamine); and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines.

[0407] According to the present disclosure, compounds as described herein can be administered in single or divided doses by oral, parenteral or topical routes. The administration of active compounds can vary from continuous (intravenous infusion) to oral administration several times a day (e.g., QID), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include penetration enhancers), buccal, sublingual and suppository administration and other administration routes. Enteric coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form will depend on the pharmacokinetics of the selected specific agent and the severity of the patient's disease. It is also possible to use the administration of compounds according to the present disclosure, such as spraying, spraying or aerosol for intranasal, intratracheal or pulmonary administration. The present disclosure therefore also relates to pharmaceutical compositions, which include an effective amount of compounds as described herein, optionally in combination with pharmaceutically acceptable carriers, additives or excipients. Compounds according to the present disclosure can be administered in an immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but also in suppositories and transdermal or other topical forms. Intramuscular injection of liposome forms can also be used to control or sustain the release of the compound at the injection site.

[0408] Compositions as described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in the form of controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as prolamin sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0409] The compositions as described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally or intravenously.

[0410] Aseptic injectable forms of compositions as described herein can be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic mono- or diglycerides. Fatty acids (such as oleic acid) and their glyceride derivatives can be used to prepare injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0411] The pharmaceutical compositions as described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are typically also added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added.

[0412] Alternatively, the pharmaceutical compositions as described herein can be administered in the form of suppositories for rectal administration. They can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0413] The pharmaceutical compositions as described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these regions or organs. Topical administration to the lower intestinal tract may be achieved with a rectal suppository formulation (see above) or with a suitable enema formulation. Topically acceptable transdermal patches may also be used.

[0414] For topical application, the pharmaceutical composition can be formulated in the form of an appropriate ointment containing an active component suspended or dissolved in one or more carriers. The carrier for topical application of the compound of the present invention includes, but is not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. In some preferred aspects of the present invention, the compound can be applied to a stent implanted in a patient in order to suppress or reduce the possibility of occlusion of the stent in the patient.

[0415] Alternatively, the pharmaceutical composition may be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0416] For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH adjusted sterile saline, or preferably as a solution in isotonic pH adjusted sterile saline, either with or without a preservative, such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated in an ointment such as paraffin.

[0417] Pharmaceutical compositions as described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters (to enhance bioavailability), fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0418] The amount of compound that can be combined with a carrier material to prepare a single dosage form in a pharmaceutical composition as described herein will vary depending on the host and disease being treated, the particular mode of administration, etc. The composition should preferably be formulated to contain between about 0.05 mg to about 750 mg or more, more preferably about 1 mg to about 600 mg, and even more preferably about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one other compound according to the invention.

[0419] It is also understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the specific disease or condition being treated.

[0420] Patients or subjects in need of therapy using compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the invention (including a pharmaceutically acceptable salt, solvate or polymorph thereof), optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known erythropoiesis stimulators as otherwise identified herein.

[0421] These compounds may be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, including transdermally, in liquid, cream, gel or solid form or by aerosol form.

[0422] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient for the intended indication without causing serious toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein are in the range of about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more usually 0.5 to about 25 mg / kg of recipient / patient body weight per day. Typical topical doses will be in the range of 0.01-5% wt / wt in a suitable carrier.

[0423] The compound is conveniently administered in any suitable unit dosage form, including but not limited to a unit dosage form containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of about 25-250 mg is often appropriate.

[0424] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or administered as a bolus of the active ingredient. Oral administration is also suitable for producing an effective plasma concentration of the active agent.

[0425] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation and excretion rate of the drug and other factors known to those skilled in the art. It should be noted that the dosage value will also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, a specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or directing the administration of the composition, and the concentration ranges set forth herein are only exemplary and are not intended to limit the scope or practice of the desired composition. The active ingredient can be administered at once; or it can be divided into multiple smaller doses administered at different time intervals.

[0426] Oral compositions will typically include an inert diluent or edible carrier. It may be enclosed in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be incorporated with an excipient and used in the form of a tablet, lozenge or capsule. Pharmaceutically compatible binding agents and / or adjuvant substances may be included as part of the composition.

[0427] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate or orange flavoring. When the unit dosage form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned types of materials. In addition, the unit dosage form may contain various other materials that modify the physical form of the dosage unit, such as sugar coatings, shellac or enteric solvents.

[0428] The active compound or its pharmaceutically acceptable salt may be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0429] The active compound or its pharmaceutically acceptable salt may also be mixed with other active substances that do not impair the desired effect or with substances that supplement the desired effect (such as erythropoietin stimulators, including especially EPO and darbapoietin alfa). In certain preferred aspects of the invention, one or more compounds according to the invention are co-administered with another biologically active agent as otherwise described herein, such as an erythropoietin stimulator or a wound healing agent, including an antibiotic.

[0430] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may include the following components: a sterile diluent, such as water for injection, physiological saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable ear tubes or multiple dose vials made of glass or plastic.

[0431] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0432] In one embodiment, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0433] Liposomal suspensions can also be pharmaceutically acceptable carriers. It can be prepared according to methods known to those skilled in the art, such as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared in the following manner: appropriate lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidyl phosphatidylcholine and cholesterol) are dissolved in an inorganic solvent, and then the solvent is evaporated, leaving a dry lipid film on the surface of the container. The aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand so that the lipid material is released from the side of the container and the lipid aggregates are dispersed, thereby forming a liposome suspension.

[0434] Treatment

[0435] In another aspect, the present invention provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition regulates protein degradation in a patient or subject (e.g., an animal, such as a human being), and can be used to treat or improve a disease state or condition regulated by the degraded protein.

[0436] As used herein, the term "treat / treating / treatment, etc." refers to any effect that provides a benefit to a patient to whom the compounds of the invention can be administered, including any disease state or condition to which the compounds of the invention bind. Disease states or conditions that can be treated using the compounds of the invention, including cancer, are described above.

[0437] The present invention provides a therapeutic composition as described herein for practicing the degradation of proteins of interest for treating or improving diseases (e.g., cancer). In certain other embodiments, the disease is multiple myeloma. Therefore, on the other hand, the present invention provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, the bifunctional compound comprising a CLM and a PTM preferably connected by a linker moiety as described herein, wherein the CLM is coupled to the PTM, and wherein the CLM recognizes ubiquitin pathway proteins (e.g., ubiquitin ligases, preferably E3 ubiquitin ligases, such as cerebellin), and the PTM recognizes the target protein so that the degradation of the target protein will occur when the target protein is positioned close to the ubiquitin ligase, thus resulting in the degradation / inhibition of the effect of the target protein and the control of the protein level. The control of the protein level achieved by the present invention provides treatment for a disease state or condition, which is regulated by the target protein by reducing the level of the protein in a cell (e.g., a patient's cell). In certain embodiments, the methods include administering an effective amount of a compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent, or a combination thereof.

[0438] In other embodiments, the present invention provides a method for treating or improving a disease, disorder or symptom thereof in a subject or patient (e.g., an animal, such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound as described herein or a salt form thereof; and a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent or a combination thereof, wherein the composition is effective in treating or improving the disease or disorder or symptom thereof in the subject.

[0439] In another aspect, the invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the invention.

[0440] In another embodiment, the present invention relates to a method for treating a disease state or condition regulated by a protein in a human patient in need thereof, wherein degradation of the protein will produce a therapeutic effect in the patient, the method comprising administering to the patient in need thereof an effective amount of a compound according to the invention, optionally in combination with another biologically active agent. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent (such as a virus, bacteria, fungus, protozoa or other microorganism), or may be a disease state caused by overexpression of a protein that results in a disease state and / or condition.

[0441] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation (i.e., elevated amounts of protein expressed in a patient) occurs and in which degradation of one or more proteins in a patient can provide beneficial therapy or relief of symptoms to a patient in need thereof. In some cases, the disease state or condition can be cured.

[0442] Disease states or conditions that can be treated using the compounds according to the invention include, for example, asthma, autoimmune diseases (such as multiple sclerosis), various cancers, ciliary diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0443] Other disease states or conditions that can be treated by 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, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

[0444] Still other disease states or conditions that can be treated by the compounds according to the invention include, inter alia, aceruloplasminosis, chondrodysplasia type II, achondroplasia, pointed head, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenyloylsuccinate lyase deficiency, adrenal reproductive syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, Alkaptonuricochronosis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome ( syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse body angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider feet (Marfan syndrome), Stickler syndrome, arthrogryposis multiplex congenita (Ehlers-Danlos syndrome), ataxia-telangiectasia, Rett syndrome, essential pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutis gyrata syndrome), familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), pan-hallucinogenemia (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), disease), Burger-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptomelia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), Cri du chat syndromechat), CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodystrophy syndrome (achondroplasia), aurispondyloepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, tibial disease, cone abnormal facial syndrome, Cooley's Anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disorders (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint deformities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Bill-Stevensson skin gyration syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker types of muscular dystrophy (DBMD), Usher syndrome, degenerative neurological diseases (including de Grouchy syndrome and Dejerine-Sottas syndrome), syndrome), developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse glomerulosclerosis (Krabbe disease), DiGeorge's syndromesyndrome), dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocytic 5-aminolevulinic acid synthetase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, inherited brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudocanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome (congenital erythropoietic porphyria). syndrome), sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilfordprogeria syndrome (progeria), hyperandrogenism, chondrodysplasia, hypochromic index 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 disease (including hyperoxaluria), Klinefelter syndrome, Kniest dysplasia, intermittent dementia, Langer-Saldino achondroplasia achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knister dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insley syndrome,syndrome, Nance-Sweeneychondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome syndrome), hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome (Li-Fraumeni syndrome), syndrome), Breast Sarcoma, Leukemia, and Adrenal (SBLA) syndrome, Tuberous Sclerosis (tuberous sclerosis), SDAT, Congenital SED (congenital spondyloepiphyseal dysplasia), Stradwick SED (Stradwick type spondyloepiphyseal dysplasia), SEDc (congenital spondyloepiphyseal dysplasia), SEMD, Stradwick type (Stradwick type spondyloepiphyseal dysplasia), Shprintzen syndrome, Skin pigmentation disorders, Smith-Lemli-Opitz syndrome (Smith-Lemli-Opitz syndrome),syndrome), South African hereditary porphyria (variant porphyria), infantile-onset ascending hereditary spastic palsy, speech and communication disorders, neurolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, dachshund neuropathy (hereditary neuropathy with a tendency to pressure palsy), Treacher Collins syndrome, trisomy X syndrome (triple X syndrome), triploidy 21 (Down syndrome), triploidy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Vrolik disease, Waardenburg syndrome, Warburg Sjo Fledelius syndrome, Weissenbacher-Zweymüller syndrome syndrome, Wolf-Hirschhorn syndrome, Wolff Periodic disease, Weissenbacher-Zawwimuller syndrome, and xeroderma pigmentosum.

[0445] The term "neoplasia" or "cancer" is used throughout this specification to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors (i.e., abnormal tissue that grows faster than normal due to cell proliferation and continues to grow after the stimulus that initiated the new growth has ceased). Malignant tumors exhibit a partial or complete lack of the structural organization and functional coordination found in normal tissues, and most invade surrounding tissues, metastasize to several sites, and are likely to reappear after attempted removal and will lead to the death of the patient unless properly treated. As used herein, the term neoplasia is used to describe all cancerous disease states, and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that may be treated by the compounds of the invention, alone or in combination with at least one other anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloid proliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and leukemia. sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated using the compounds according to the invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0446] The term "biologically active agent" is used to describe an agent other than the compounds according to the invention, which is used in combination with the compounds of the invention as an agent having biological activity that helps achieve the intended therapy, inhibition and / or prevention / prophylaxis for which the compounds of the invention are used. Preferred biologically active agents used herein include those having pharmacological activity similar to that for which the compounds of the invention are used or applied, and include, for example, anticancer agents, antiviral agents (especially including anti-HIV agents and anti-HCV agents), antimicrobial agents, antifungal agents, etc.

[0447] The term "another anticancer agent" is used to describe an anticancer agent that can be combined with the compounds according to the present invention to treat cancer. These agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY317615, Newdi, Vitspan, Rta 744,Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide omide), ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan irinotecan), tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, diethylstilbestrol (DES), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl)-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate 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,Ionafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone , fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin,Plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat astat), COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox), gefitinib, bortezimib, paclitaxel, paclitaxel without cremophor, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, azole Zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin white, nitrogen mustard, methylprednisolone, ibritigumomabtiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, N K-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine,Granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof.

[0448] The term "anti-HIV agent" or "another anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those not representing the present invention), protease inhibitors, fusion inhibitors, wherein exemplary compounds may include, for example, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Raci vir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors (such as T20), their fusions and mixtures, including anti-HIV compounds in clinical trials or development.

[0449] Other anti-HIV agents that can be used in combination with the compounds according to the invention include, for example, other NNRTIs (i.e., in addition to the NNRTIs according to the invention) and can be selected from the group consisting of nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy]phenyl)-2-methyl-3-furanthiocarboxamide), etravirine (TMC125), Trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151), ADAM-II (3',3'-dichloro-4',4"-dimethoxy-5',5"-bis(methoxycarbonyl)-6,6-diphenylhexenoic acid methyl ester), 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoic acid methyl ester (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), Capravirine (AG-1549, S-1153), atevirdine (U-87201E), aurintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridyl]piperazine, 1-[5-[[N-(methyl 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (Foscavir), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine ), Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC649324), Michellamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiolene-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivatives), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-69 7,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pyridine-2(1H)-thione (2-pyridone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, Suramin Sodium, TBZ (thiazolyl benzimidazole, NSC 625487), thiazolidoisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38 and UC-84.

[0450] The term "pharmaceutically acceptable salt" is used throughout this specification to describe, where applicable, a salt form of one or more of the compounds described herein, which is presented to increase the solubility of the compound in the gastrointestinal fluid of the patient's gastrointestinal tract so as to promote the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include salts derived from alkali metals (such as potassium and sodium), alkaline earth metals (such as calcium, magnesium and ammonium salts) and numerous other acids and bases well known in the pharmaceutical field. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present invention.

[0451] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (eg, esters, amides, other prodrug groups) which, upon administration to a patient, directly or indirectly provides a compound of the invention or an active metabolite of a compound of the invention.

[0452] General synthetic method

[0453] Synthetic realization and optimization of bifunctional molecules as described herein can be carried out in a step-by-step or modular manner. For example, if no suitable ligand is immediately available, identifying the compound that is attached to the target molecule can involve high or medium yield screening activities. It is common that the initial ligand needs iterative design and optimization cycles to improve the suboptimal aspects such as identified by data from suitable in vitro and pharmacological and / or ADMET analysis. A part of the optimization / SAR activity will be to detect the tolerant substitution of the ligand and can be the position of the suitable position of the joint chemical substance previously mentioned in this article. When crystallization or NMR structural data are available, it can be used to focus on this synthetic attempt.

[0454] Ligands for E3 ligases, ie, ULM / CLM, can be identified and optimized in a very similar manner.

[0455] Using PTMs and ULMs (e.g., CLMs), one skilled in the art can use known synthetic methods for their combination with or without a linker moiety. The linker moiety can be synthesized to have a range of compositions, lengths, and flexibility and functionalized so that the PTM and ULM groups can be sequentially attached to the ends of the linker. Thus, libraries of bifunctional molecules can be obtained and profiled in in vitro and in vivo pharmacology and ADMET / PK studies. As with the PTM and ULM groups, the final bifunctional molecules can undergo iterative design and optimization cycles in order to identify molecules with desirable properties.

[0456] Some non-limiting exemplary methods for producing CLMs as described herein are summarized below.

[0457]

[0458]

[0459]

[0460]

[0461]

[0462] As shown in Representative Reaction 1, dimethyl phthalate derivatives can be condensed with glutamine (racemate or enantiomer) or glutamine analogs and then further reacted with reagents such as carbonyldiimidazole to form 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives.

[0463] Alternatively, the intermediate phthalimide produced in the above initial condensation can be prepared and / or isolated separately, and then reacted with a dehydrating agent such as trifluoroacetamide, POCl3 or acetic anhydride to form the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative, as shown in Representative Reaction 2. The same type of intermediate phthalimide can also be reacted with Lawesson's reagent, followed by a dehydration step, to provide the thio analog, as shown in Representative Reactions 8 and 9.

[0464] Examples of protected 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives (such as N- 1 -BOC material) can be deprotected by using a reagent such as TFA or silica in this case to give the target 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0465] Phthalic anhydride, as shown in Representative Example 4, can be ring-opened by reaction with an amine such as 3-aminopiperidine-2,6-dione to form an intermediate carboxylate species, which upon treatment with carbonyldiimidazole and benzotriazole will form the target 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative. Alternatively, the two components can be combined in the presence of acetic acid to provide the desired product, as shown in Representative Reaction 13.

[0466] In a similar reaction, anhydride derivatives (as shown in Representative Reaction 5) can be reacted with an amine (ammonia in the example shown) and then with carbonyldiimidazole to form the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives.

[0467] When phthaloyl chloride is available, direct condensation with glutamine (racemate or enantiomer) or glutamine analogs is possible, followed by further reaction with reagents such as carbonyldiimidazole to form 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives as shown in Representative Reaction 6.

[0468] o-Bromobenzamide can be reacted with a CO source (such as an acid chloride as shown in representative reaction 7) in the presence of a palladium catalyst and a relevant phosphine ligand to produce the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative. Alternatively, CO gas itself can be used in conjunction with a rhodium (II) catalyst and silver carbonate to provide the desired product.

[0469] 2-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,3-dihydro-1H-isoindole-1,3-dione and 5-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-yl)-1,3-diazinane-2,4,6-trione derivatives can be prepared by methods similar to some of the methods described above for 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives. In representative reactions 20 and 21, phthalic anhydride can be reacted with 5-amino-1,2,3,4-tetrahydropyrimidine-2,4-dione or 5-amino-1,3-diazinane-2,4,6-trione derivatives, respectively, in the presence of acetic acid to form the desired product.

[0470] Alternatively, 5-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1,3-diazinane-2,4,6-trione derivatives can be prepared by reacting 5-amino-1,3-diazinane-2,4,6-trione derivatives with mono-tert-butyl phthalate in the presence of Hünig's base, carbodiimide and benzotriazole, as shown in Representative Reaction 12. Similar conditions can be used to prepare 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives from mono-tert-butyl phthalate, as shown in Representative Reaction 14.

[0471] Compounds such as 3-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinazoline-2,4-dione can be prepared from anthranilic acid derivatives by reacting 3-aminopiperidine-2,6-dione with a carbodiimide as shown in Representative Reaction 16. The intermediate benzamide product can be isolated (or generated separately) and further reacted with a carbodiimide to produce a 3-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinazoline-2,4-dione derivative as shown in Representative Reaction 15.

[0472] 3-(2,6-Dioxopiperidin-3-yl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione analogs can be prepared by activating salicylic acid with chloroformic acid followed by condensation with 3-aminopiperidine-2,6-dione as shown in representative reaction 17.

[0473] As shown in Representative Reaction 18, 3,3-dichloro-2,1λ 6 -Benzothiolene-1,1-dione can be prepared by reacting 2-sulfobenzoic acid with POCl3 and PCl5. These compounds can be reacted with amino derivatives to produce, for example, the desired 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ6 ,2-Benzothiazole-1,1,3-trione derivatives.

[0474] As shown in representative reaction 19, the anion of the saccharin derivative can be alkylated with an electrophile such as 3-bromo-3-methylpiperidin-2-one to generate the target 2-(3-methyl-2-oxopiperidin-3-yl)-2,3-dihydro-1λ 6 ,2-Benzothiazole-1,1,3-trione derivatives.

[0475] 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1λ 6 ,2-Benzothiazole-1,1,3-trione analogs can also be prepared by reacting methyl 2-[(2,6-dioxopiperidin-3-yl)sulfamoyl]benzoate with a strong base such as sodium hydride (see Representative Reaction 20).

[0476] The 2-methyl-2,3-dihydro-1H-indene-1,3,dione derivative is deprotected with sodium ethoxide and then reacted with an electrophilic reagent (such as 3-bromopiperidine-2,6-dione) to give 3-(2-methyl-1,3-dioxo-1H-indene-2-yl)piperidine-2,6-dione, as shown in Representative Reaction 21.

[0477] N 1 -substituted compounds such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindol-1,4-dione (Representative Reaction 22) can be prepared by reacting 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)glutaric acid with N-benzylhydroxylamine and trifluoroacetic anhydride.

[0478] In turn, molecules such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (representative reaction 23) can undergo benzyl removal under hydrogenation conditions to produce N 1 -Hydroxy analogs, such as 2-(1-hydroxy-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0479] In representative reaction 24, methyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (and analogs) reacts with 3-aminopiperidin-2-one to provide 2-(2-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione.

[0480] 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 produce the same type of product as shown in Representative Reaction 25. The isolated or otherwise prepared intermediate from this reaction (Representative Reaction 26) can be brought to full cyclization by using a dehydrating agent.

[0481] Isomeric derivatives such as 2-(6-oxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione as shown in representative reaction 27 can be obtained by reacting phthalic acid with 5-aminopiperidin-2-one.

[0482] N 1 The preparation of -substituted compounds such as 2-(1-benzyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,4-dione (Representative Reactions 28 and 29) can be achieved by a variety of routes. For example, an acid anhydride (2-(2,6-dioxooxan-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione) can be condensed with 3-aminopiperidine-2,6-dione in the presence of DMAP and carbonyldiimidazole (Representative Reaction 28), or a 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative can be alkylated with an electrophile such as benzyl bromide in the presence of a base, as shown in Representative Reaction 29.

[0483] In some cases, protecting group strategies and / or functional group interconversion (FGI) may be required to facilitate the preparation of the desired material. Such chemical processes are well known to synthetic organic chemists, and many of them can be found in texts such as "Greene's Protective Groups in Organic Synthesis" Peter GM Wuts and Theodora W. Greene (Wiley) and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley).

[0484] Protein level control

[0485] The present invention also provides methods for controlling protein levels in cells. This is based on the use of compounds as described herein, which are known to interact with specific target proteins, such that degradation of the target protein in vivo will result in the amount of protein in the biological system being controlled, preferably to achieve a specific therapeutic benefit.

[0486] The following examples are provided to help describe the present invention but should not be construed as limiting the present invention in any way.

[0487] Specific embodiments of the present disclosure

[0488] The present disclosure encompasses the following specific embodiments. These following embodiments may include all features listed in the previous embodiments as specified. Where applicable, the following embodiments may also include any of the features listed inclusively or alternatively in the previous embodiments (e.g., embodiment (8) may include the features listed in the listed embodiment (1) and / or the features of any one of embodiments (2) to (7)).

[0489] (1) A compound having a chemical structure comprising:

[0490] L-CLM

[0491] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein

[0492] L is a linker group; and

[0493] CLM is the E3 ubiquitin ligase binding part of cerebellum protein.

[0494] wherein the linker group is chemically linked to the CLM.

[0495] (2) The compound according to (1), wherein the compound has a chemical structure comprising:

[0496] PTM-L-CLM

[0497] in

[0498] PTMs are protein target moieties that bind to target proteins or target peptides.

[0499] wherein the PTM is chemically linked to the CLM via the linker group.

[0500] (3) The compound according to (1), wherein the CLM comprises a chemical group derived from imide, thioimide, amide or thioamide.

[0501] (4) The compound according to (1), wherein the chemical group is a phthalimido group or an analogue or derivative thereof.

[0502] (5) The compound according to (1), wherein the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

[0503] (6) The compound as described in (1), wherein the compound further comprises a ULM, a second CLM, a CLM' or more or a combination thereof, wherein

[0504] ULM is the E3 ubiquitin ligase binding part.

[0505] The second CLM has the same chemical structure as the CLM,

[0506] CLM' is a cerebellar protein E3 ubiquitin ligase binding portion that is structurally distinct from the CLM.

[0507] wherein the ULM, the second CLM, the CLM', or the plurality thereof, or the combination thereof, are optionally coupled to another linker group.

[0508] (7) The compound according to (1), wherein the CLM has a chemical structure represented by:

[0509]

[0510] in

[0511] W is selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0512] Each X is independently selected from the group consisting of: O, S and H2;

[0513] Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0514] Z is selected from the group consisting of: O, S and H2;

[0515] G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';

[0516] Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0517] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0518] R includes -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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;

[0519] R' and R" are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0520] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0521] R n including functional groups or atoms,

[0522] Where n is an integer from 1 to 4, and

[0523] When n is 1, R n is modified to be covalently attached to the linker group (L), and

[0524] When n is 2, 3, or 4, then an R n is modified to be covalently attached to the linker group (L), and any other R n Optionally modified to be covalently linked to a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0525] (8) The compound according to (1), wherein the CLM is selected from the group consisting of:

[0526] 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy]phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile;

[0527] 4-[3-(4-{3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile;

[0528] 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodec-12-yl}oxy]phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile;

[0529] 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodec-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

[0530] 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodec-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

[0531] 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadec-18-yl}oxy]phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile;

[0532] 4-(3-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

[0533] 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile;

[0534] 4-[3-(4-{3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile;

[0535] 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatetradec-14-yl}oxy]phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile;

[0536] 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide;

[0537] 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl}oxy]phenyl)-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile;

[0538] 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile;

[0539] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy]phenyl)acetamide;

[0540] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy]phenyl)acetamide;

[0541] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)acetamide;

[0542] N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodec-12-yl}oxy]phenyl)amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide;

[0543] N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadec-18-yl}oxy]phenyl)amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide;

[0544] N-{3-[(5-bromo-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13-tetraoxa-1-azapentadecan-15-yl}oxy]phenyl)amino}pyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide;

[0545] 4-(4-{[(5Z)-3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile;

[0546] 4-(4-{[(5Z)-3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile;

[0547] 4-(4-{[(5Z)-3-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethyl}-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl}-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile;

[0548] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy]phenyl)ethyl]acetamide;

[0549] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)propyl]acetamide;

[0550] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propyl)acetamide;

[0551] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1S)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide;

[0552] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]acetamide;

[0553] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butoxy]phenyl)ethyl]acetamide;

[0554] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-{4-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}ethyl]acetamide;

[0555] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[(1R)-1-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy]phenyl)ethyl]acetamide;

[0556] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ] tridecan-2(6),4,7,10,12-pentaen-9-yl]-N-{2-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy]phenyl)pyrimidin-5-yl}acetamide;

[0557] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)propoxy]-3-fluorophenyl}acetamide;

[0558] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-2-fluorophenyl}acetamide;

[0559] 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-{4-[4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)butoxy]-3-fluorophenyl}acetamide; and

[0560] 2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy]phenyl)acetamide.

[0561] (9) The compound according to (1), wherein the linker group (L) comprises a chemical structural unit represented by the following formula:

[0562] -A q -

[0563] in

[0564] q is an integer greater than 1; and

[0565] A is independently selected from the group consisting of: a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NRL3 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 , optionally through 0-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally with 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally 0-6 R L1 and / or R L2 The aryl group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group; wherein

[0566] R L1 , R L2 , R L3 , R L4 and R L5 are each independently selected from the group consisting of: H, halogen, 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 Heterocyclic group, 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)(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 1-8alkyl)=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, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2 and NHSO2NH2; and wherein

[0567] When q is greater than 1, R L1 or R L2 Each independently can be connected to another A group to form a further R L5 The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0568] (10) The compound according to (2), wherein the PTM is a protein target portion that binds to a target protein, a target polypeptide or a fragment thereof, wherein the target protein, the target polypeptide or the fragment thereof has a biological function selected from the group consisting of: structure, regulation, hormone, enzymatic, genetic, immune, contraction, storage, transport and signal transduction.

[0569] (11) A compound according to (2), wherein the PTM group is a portion that binds to a target protein, wherein the target protein is selected from the group consisting of: B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein Gq, histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosoma GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, 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-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGFβ-activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, estrogen receptor, estrogen-related receptor, focal adhesion kinase, Src, endothelin receptor, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA of NGF a receptor, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel. Other target proteins include acetyl CoA carboxylase, adenylo succinate synthetase, protoporphyrinogen oxidase and enolpyruvylshikimate-phosphate synthase.

[0570] (12) A compound according to (2), wherein the PTM group is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, a HDM2 / MDM2 inhibitor, a compound targeting human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting RAF receptor, a compound targeting FKBP, an angiogenesis inhibitor, an immunosuppressive compound, a compound targeting aryl hydrocarbon receptor, a compound targeting androgen receptor, a compound targeting estrogen receptor, a compound targeting estrogen-related receptor, a compound targeting thyroid hormone receptor, a compound targeting HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease, or a compound targeting acyl protein thioesterase 1 and / or 2.

[0571] (13) The compound as described in (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.

[0572] (14) A composition comprising the compound described in (2).

[0573] (15) A pharmaceutical composition comprising the compound as described in (2), and a pharmaceutically acceptable carrier, additive and / or excipient.

[0574] (16) The pharmaceutical composition as described in (15), further comprising a bioactive agent.

[0575] (17) The pharmaceutical composition according to (16), wherein the bioactive agent is an antiviral agent.

[0576] (18) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HIV agent.

[0577] (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.

[0578] (20) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HCV agent.

[0579] (21) The pharmaceutical composition according to (16), wherein the bioactive agent is selected from the group consisting of anti-inflammatory agents, immune agents, cardiovascular agents and neural agents.

[0580] (22) The pharmaceutical composition according to (16), wherein the bioactive agent is an anticancer agent.

[0581] (23) The composition according to (22), wherein the anticancer agent is selected from the group consisting of: everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC 1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalimumab, etakalimumab, tetrandrine, rubitecan, tesimifen, oblimersen, tesimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanthone, LY 317615, Newdi, Vitspan, Rta744, Sdx 102, Talanpanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, diethylstilbestrol (DES), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl)-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly 10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C, 59 H 84 N 18 Oi4-(C2H4O2) x, wherein x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714, TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, yonafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, so Rafenib, KRN951, amineglutethimide, aminebenacridine, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, dichloromethane, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide mitramide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimbrin, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neivastat, BMS-275291, squalamine, endostatin, SU5416, SU666 8. EMD121974, interleukin-12, IM862, angiostatin, vitacin, droloxifene, iodoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, episeron B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779,450, P EG-filgrastim, darbepoietin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone pine, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, nitrogen mustard, methylprednisolone, tentan isobetumomab, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, adipronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, card Sopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, dapoxetine, dronabitril, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0582] (24) A method for inducing degradation of a target protein in a cell, comprising:

[0583] An effective amount of the compound described in (2) is administered to the cell.

[0584] (25) A method for inducing degradation of a target protein in a cell, comprising:

[0585] An effective amount of the compound described in (10) is administered to the cell.

[0586] (26) A method for inducing degradation of a target protein in a cell, comprising:

[0587] An effective amount of the compound described in (11) is administered to the cell.

[0588] (27) A method for inducing degradation of a target protein in a patient, comprising:

[0589] An effective amount of the compound described in (2) is administered to the patient.

[0590] (28) A method of treating a disease state or condition in a patient, wherein dysregulated protein activity is the cause of the disease state or condition, the method comprising

[0591] An effective amount of the compound according to (2) is administered.

[0592] (29) The method of (28), wherein the disease state or condition is asthma, multiple sclerosis, cancer, ciliary disease, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Doucet disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome.

[0593] (30) The method of (28), wherein the disease state or condition 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, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

[0594] (31) The method of (28), wherein the disease state or condition is ceruloplasminosis, chondrodysplasia type II, achondroplasia, pointed head, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenyloylsuccinate lyase deficiency, adrenal reproductive syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocher, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity. syndrome, anemia, diffuse body angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider feet (Marfan syndrome), Stickler syndrome, congenital multiple arthrogryposis (Ehlers-Danlos syndrome # arthrogryposis type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Bill-Stevensson skin gyration syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberg syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonavi - Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Bert-Hoeg-Dub syndrome, brittle bone disease (osteogenesis imperfecta), pan-thump-big toe syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptolimb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, soft Osteodystrophy syndrome (achondroplasia), otovertebral epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, cone abnormal face syndrome, Wenkuli's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint deformity (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome,Cowden syndrome, Kirschman-Batten-Steinert syndrome (myotonic dystrophy), Bill-Stevensson skin gyration syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Stradwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, degenerative neurological diseases (including deGrown syndrome and DeGeliner-Sotas syndrome), developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globulosclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocytic 5-aminolevulinic acid synthetase deficiency, erythropoietic porphyria, erythroblastic Protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, inherited brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grunblad-Standberg syndrome (pseudoxanthoma elasticum), Genda disease (congenital erythropoietic porphyria), hemochromatosis, Holgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, soft tissue disease Bone dysplasia, 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 disease (including hyperoxaluria), Klinefelter syndrome, Knister dysplasia, intermittent dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knister dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Mink syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney soft tissue disease Bone dysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Lundy disease, Piots-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Piots-Jeghers syndrome, Prader-Labatt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma elasticum),Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS Type 3, Lake syndrome, Riley-Day syndrome, Lucey-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma of the breast, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tubercular sclerosis), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Stradwick SED (spondyloepiphyseal dysplasia type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Stradwick type (spondyloepiphyseal dysplasia type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemley-Opitz syndrome, South African hereditary porphyria (variant porphyria), hereditary spastic paralysis of infantile-onset ascending type paralysis, speech and communication disorders, neurolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, dactylyx neuropathy (hereditary neuropathy with a tendency to pressure paralysis), Treacher Collins syndrome, trisomy X syndrome (triple X syndrome), triploidy 21 (Down syndrome), triploidy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frohlich's disease, Waardenburg syndrome, Warburg-St. Joseph-Frederick syndrome, Weissenbacher-Zawie-Muller syndrome, Wolff-Hirshhorn syndrome, Wolff periodic disease, Weissenbacher-Zawie-Muller syndrome and xeroderma pigmentosum.

[0595] (32) The method of (28), wherein the disease state or condition is cancer.

[0596] (33) The method as described in (32), wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphoma, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloid proliferative disease; multiple myeloma, sarcoma, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myeloma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratoma.

[0597] (34) The method according to (32), wherein the cancer is T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

[0598] (35) A compound library comprising more than one compound as described in (1).

[0599] (36) A method for identifying a compound containing an E3 ubiquitin ligase binding moiety that recognizes cerebellin (CRBN), comprising:

[0600] The test compound is incubated with the CRBN protein;

[0601] The amount of the test compound bound to the CRBN protein is determined.

[0602] (37) A cerebellin E3 ubiquitin ligase binding moiety (CLM) having a chemical structure represented by:

[0603]

[0604]

[0605] in

[0606] W is selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0607] Each X is independently selected from the group consisting of: O, S and H2;

[0608] Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S;

[0609] Z is selected from the group consisting of: O, S and H2;

[0610] G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R';

[0611] Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0612] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0613] R includes -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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;

[0614] R' and R" are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0615] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0616] R n including functional groups or atoms,

[0617] Where n is an integer from 1 to 4.

[0618] (38) The CLM as described in (37), wherein the Rn Included are functional groups or atoms covalently linked to a linker group (L), a protein targeting moiety (PTM), an E3 ubiquitin ligase binding moiety (ULM), or any multiple or combination thereof.

[0619] (39) The CLM of (38), wherein the ULM is a second CLM, a CLM′, or any combination or more thereof, wherein

[0620] The second CLM has the same chemical structure as the CLM, and

[0621] The CLM' is structurally different from the CLM. Example

[0622] A. Determination

[0623] 1. CRBN Assay - Cloning, Expression, and Purification of Human CRBN and DDB1

[0624] The procedure is standard to those skilled in the art and is represented by the description in Lopez-Girona et al. (Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide, A Lopez-Girona, D Mendy, T Ito, K Miller, A K 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, T O Daniel, J F Evans, and R Chopra, Leukemia 26:2326-2335, 2012).

[0625] The cDNAs of the CRBN and DDB1 genes can be amplified by PCR using Pfusion (NEB) as the polymerase and the following primer sequences:

[0626]

[0627] CRBN can be cloned into pBV-ZZ-HT-LIC, pBV-GST-LIC, pMA-HT-LIC using ligation-independent cloning26, and DDB1 into pBV-notag-LIC. For cloning into the mammalian vector pMA-HT-LIC, CRBN-Flag-reverse oligomer adds a C-terminal FLAG tag for immunodetection. DDB1-Rev adds StrepTag27. The ZZ-tag28 is required to achieve high expression of soluble CRBN; in its absence, His-CRBN is expressed at low levels, while GST-CRBN causes protein aggregation. Recombinant baculoviruses of ZZ-His-CRBN and DDB1-StrepTag (ST) were generated and amplified in Sf9 insect cells using the Bac-to-Bac baculovirus expression system from Invitrogen. ZZ-His-CRBN and DDB1-ST were co-expressed in High Five (Tni) insects in 10 L wave bags at 27° C. using unsupplemented ESF921 medium from Expression Systems. Cells were harvested by centrifugation 48 hours post-infection and the paste was resuspended in PBS plus 5X protease inhibitor cocktail (Roche, Indianapolis, IN).

[0628] All subsequent protein purification steps are carried out at 4 ° C. Frozen cells are thawed, resuspended in 5 volumes of lysis buffer (50mM Tris HCl pH 8.0, 0.5M NaCl, 10% glycerol, 2mM DTT) plus 20mM imidazole and protease inhibitors, lysed and centrifuged to produce a transparent supernatant. Nickel-agarose and S200 Sephacryl chromatography are used to purify CRBN-DDB1 on AKTA-xpress system (GE Healthcare). The complex is then further purified by the second pass on anion exchange chromatography and S-200 gel filtration on 8ml MonoQ column. CRBN-DDB1 is identified by SDS-PAGE, and the fractions containing CRBN-DDB1 are pooled and stored at -70 ° C.

[0629] 2. Fluorescent Thermal Melting Assay to Measure Binding of Compounds to Recombinant CRBN

[0630] Assays are standard to those skilled in the art, as represented by the description in Lopez-Girona et al. (Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide, A Lopez-Girona, D Mendy, T Ito, K Miller, A K 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, T O Daniel, J F Evans, and R Chopra, Leukemia 26:2326-2335, 2012).

[0631] According to Pantoliano et al. (Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E et al. High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 2001; 6: 429-440), the thermal stability of CRBN-DDB1 in the presence or absence of test compounds was performed in a microplate format in the presence of SyproOrange. 2 mg of protein in 20 ml of assay buffer (25 mM Tris HCl, pH 8.0, 150 mM NaCl, 2 uM Sypro Orange) was subjected to a stepwise temperature increase from 20 to 70 ° C, and fluorescence was read at every 1 ° C on an ABI Prism 7900HT (Applied Biosystems, Carlsbad, CA, USA). Compounds were dissolved in DMSO (1% final in the assay) and tested in quadruplicate at concentrations ranging from 30 nM to 1000 uM; controls contained 1% DMSO only.

[0632] 3. LCMS method

[0633] The analysis was performed on a Poroshell 120EC C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) at 45°C.

[0634] The solvents used were:

[0635] A = 0.1% v / v solution of formic acid in water.

[0636] B = 0.1% v / v solution of formic acid in acetonitrile.

[0637] The gradient used is as follows:

[0638]

[0639] UV detection was the average signal from wavelengths from 210 nm to 350 nm, and mass spectra were recorded on a mass spectrometer using positive ion mode electrospray ionization.

[0640] The mobile phases and gradients used when the compounds were subjected to preparative HPLC purification are described below.

[0641] 4. Preparative HPLC (Formic Acid Modifier)

[0642] HPLC analysis was performed on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0643] The solvents used were:

[0644] A = 0.1% v / v solution of formic acid in water.

[0645] B = acetonitrile.

[0646] 5. Preparative HPLC (ammonium bicarbonate modifier)

[0647] HPLC analysis was performed on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0648] The solvents used were:

[0649] A = 10 mM ammonium bicarbonate aqueous solution.

[0650] B = acetonitrile.

[0651] For each preparative purification, regardless of the modifier used, the gradient used depended on the retention time of the specific compound undergoing purification as recorded in analytical LCMS. The flow rate was 20 mL / min.

[0652] UV detection is a signal from a wavelength of 254 nm or 220 nm.

[0653] Although preferred embodiments of the present invention have been shown and described herein, it should be understood that such embodiments are provided by way of example only. Those skilled in the art will appreciate numerous variations, changes and substitutions without departing from the spirit of the present invention. Therefore, it is contemplated that the appended claims cover all such variations within the spirit and scope of the present invention.

[0654] B. Synthesis:

[0655] The synthetic details of the examples included below represent general procedures for the syntheses set forth in the broader examples.

[0656] 1.2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione

[0657]

[0658] Step 1: 4-Fluoroisobenzofuran-1,3-dione

[0659]

[0660] A mixture of 3-fluorophthalic acid (50 g, 271.7 mmol) in acetic anhydride (400 mL) was refluxed for 2 hours. The volatiles were removed by vacuum, and the residue was crystallized in acetic anhydride to give 4-fluoroisobenzofuran-1,3-dione (40 g, crude) as a brown solid. LC-MS: 167.1 [MH] + . 1 H NMR (400MHz, CDCl3): δ7.58 (t, J=8.0Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.92-7.97 (m, 1H).

[0661] Step 2: 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid

[0662]

[0663] A mixture of the above 4-fluoroisobenzofuran-1,3-dione (40 g, crude) and L-glutamine (35 g, 239 mmol) in anhydrous 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 another 8 hours. The resulting precipitate was collected by filtration, washed with water and dried to give 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, crude) as an off-white solid. LC-MS: 295.2 [MH] + .1 H NMR (400MHz, CDCl3): δ2.16-2.20(m,2H),2.31-2.43(m,2H),4.79-4.83(m,1H),6 .79(br,1H),7.26(br,1H),7.77-7.85(m,2H),7.98-8.03(m,1H),13.32(br,1H).

[0664] Step 3: 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione

[0665]

[0666] A mixture of the above 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (37 g, crude), 1,1'-carbonyldiimidazole (CDI) (24.2 g, 149.4 mmol) and 4-dimethylaminopyridine (DMAP) (1.3 g, 11.5 mmol) in acetonitrile (80 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration and washed with acetonitrile (100 mL) to give a crude product, which was purified by silica gel chromatography using 1-10% MeOH / DCM as eluent to give 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindolin-1,3-dione (9.0 g, 12% yield over three steps) as a light yellow solid. LC-MS: 277.2 [MH] + . 1 H NMR (400MHz, CDCl3): δ2.14-2.19(m,1H),2.75-2.95(m,3H),4.97-5.01(m,1H),7.43(t,J=8.4Hz,1H),7.10-7.81(m,2H),8.08(br,1H).

[0667] 2. N-(3-(5-bromo-2-chloropyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide

[0668]

[0669] Step 1: tert-Butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate

[0670]

[0671] A mixture of tert-butyl N-(3-aminopropyl)-N-methylcarbamate (826 mg, 4.40 mmol) and 5-bromo-2,4-dichloropyrimidine (400 mg, 1.76 mmol) in MeOH (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo, and the residue was purified using Teledyne ISCO chromatography [0→35% EtOAc / heptane] to give tert-butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate (615 mg, 92% yield). LC-MS (ES + ):m / z=381.05 / 383.05[MH + ], t R =2.55min.

[0672] Step 2: {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine

[0673]

[0674] To a solution of tert-butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate (615 mg, 1.62 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.54 mL, 6.5 mmol) at room temperature. After stirring the mixture for 1 hour, it was concentrated in vacuo. The residue was purified using Teledyne ISCO chromatography [0→15% methanol / DCM] to give {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 82% yield). LC-MS (ES) + ):m / z=280.99 / 282.99[MH + ], t R =1.13min.

[0675] Step 3: N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide

[0676]

[0677] To a solution of {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine (371 mg, 1.33 mmol) and cyclobutanecarbonyl chloride (188 mg, 1.60 mmol) in DCM (10 mL) was added triethylamine (0.41 mL, 2.92 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified using Teledyne ISCO chromatography [0→100% EtOAc / heptane] to give N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcyclobutanecarboxamide (268 mg, 56%). LC-MS (ES + ):m / z=363.04 / 365.04[MH + ], t R =2.18min.

[0678] 3. (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid

[0679]

[0680] The title compound was prepared according to the procedure described in WO2011 / 143660.

[0681] 4. (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0682] The title compound was prepared according to the procedure described in Patch, RJ et al. J. Med. Chem. 2011, 54, 788-808.

[0683] 5.4-[3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

[0684]

[0685] The title compound was prepared according to the procedure described in Jung, ME et al. J. Med. Chem. 2010, 53, 2779-2796.

[0686] 6. 2-Chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutyloxy)benzonitrile hydrochloride salt

[0687]

[0688] The title compound was prepared according to the procedure described in Guo, C. et al. J. Med. Chem. 2011, 54, 7693-7704.

[0689] 7. [N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide]

[0690]

[0691] (Compound structure No. 17 shown in Table 1)

[0692] Step 1: 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0693]

[0694] A mixture of bis(4-methylbenzenesulfonic acid) 2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl)ester (3 g, 5.96 mmol), 4-nitrophenol (813 mg, 5.84 mmol) and potassium carbonate (1.65 g, 11.94 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred overnight at 50 ° C. The mixture was cooled to room temperature and poured into water (60 mL), then extracted with ethyl acetate (80 mL×3). The combined organic phase was 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 (eluting with 10-20% ethyl acetate / hexanes) to give 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.65 g, 95% yield) as a yellow oil. LC-MS (ES + ):m / z 470.2[MH + ](t R =2.83min)

[0695] Step 2: [1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene]

[0696]

[0697] A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.65 g, 5.64 mmol) and sodium azide (734 mg, 11.29 mmol) in ethanol (30 mL) was refluxed for 16 hours. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with water (50 mL) and brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene (865 mg) as a yellow oil.

[0698] Step 3: [2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethylamine]

[0699]

[0700] A mixture of the above 1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene (865 mg, 2.54 mmol), triphenylphosphine (999 mg, 3.81 mmol) and water (69 mg, 3.83 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature under nitrogen atmosphere for 14 hours. The volatiles were removed under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography eluting with 3-5% methanol in dichloromethane to give 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethanamine (661 mg, 83% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ2.86(t,J=5.2Hz,2H),3.51(t,J=5.6Hz,2H),3.63-3.75(m,8H ), 3.90 (t, J = 4.4Hz, 2H), 4.23 (t, J = 4.8Hz, 2H), 6.97-6.99 (m, 2H), 8.18-8.22 (m, 2H).

[0701] Step 4: tert-Butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0702]

[0703] A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamine (661 mg, 2.1 mmol), triethylamine (449 mg, 4.43 mmol) and di-tert-butyl dicarbonate (505 mg, 2.31 mmol) in dichloromethane (25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 ml), washed with water (30 mL×2) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20-40% ethyl acetate / hexane) to give tert-butyl 2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (818 mg, 94% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δ1.44 (s, 9H), 3.37 (d, J = 5.2Hz, 2H), 3.54 (t, J = 5.2Hz, 2H), 3.62-3.70 (m, 6H), 3.73-3. 76(m,2H),3.90(t,J=4.4Hz,2H),4.23(t,J=4.8Hz,2H),5.01(br,1H),6.96-7.00(m,2H),8.18-8.22(m,2H).

[0704] Step 5: tert-Butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0705]

[0706] A mixture of tert-butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (818 mg, 1.97 mmol), iron powder (1.1 g, 0.65 mmol) and ammonium chloride (528 mg, 9.87 mmol) in ethanol (20 mL) and water (5 mL) was stirred at 80 ° C for 1 hour. The mixture was cooled to room temperature, the solid precipitate was removed by filtration and washed with ethyl acetate (20 mL×2). The filtrate was partitioned between ethyl acetate (120 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30-40% ethyl acetate / hexanes to give tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (512 mg, 67% yield) as a yellow oil.

[0707] Step 6: tert-Butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0708]

[0709] A mixture of tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (130 mg, 0.34 mmol), N-(3-(5-bromo-2-chloropyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (24 mg, 0.06 mmol) and p-toluenesulfonic acid (11.6 mg, 0.07 mmol) in dioxane (1.5 mL) was refluxed for 16 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×3). The combined organic phase was washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexanes to afford tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, 17% yield) as a yellow oil.

[0710] Step 7: N-(3-(2-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide

[0711]

[0712] A mixture of tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (40 mg, 0.06 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and dichloromethane (1 mL) was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure. The residue was partitioned between dichloromethane (60 mL) and aqueous sodium bicarbonate solution (2.0 N, 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N-(3-(2-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (18 mg, 52% yield) as a yellow oil.

[0713] Step 8: N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide

[0714]

[0715] A mixture of N-(3-(2-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (130 mg, 0.03 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (8.2 mg, 0.03 mmol) and N-ethyl-N-isopropylpropan-2-amine (7.6 mg, 0.06 mmol) in anhydrous N,N-dimethylformamide (1 mL) was stirred at 90° C. for 12 hours. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (100 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to give N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (10.2 mg, 40% yield) as a yellow solid. LC-MS (ES) + ):m / z=865.27 / 867.27(1:1)[MH]+ .t R =2.06min. 1 HNMR (400MHz, CD3OD): δ1.68-1.77(m,3H),1.89-1.92(m,3H),2.08-2.15(m,3H),2.60-2.79(m,7H),3.28-3.35(m,6H),3.55-3.61(m,10H) ,3.69-3.72(m,2H),3.96-3.99(m,2H),4.91-4.95(m,1H),6.75-6.78 (m,2H),6.91-6.94(m,2H),7.34-7.42(m,3H),7.76(d,J=12.8Hz,1H).

[0716] 8. 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

[0717]

[0718] (Compound structure No. 14 shown in Table 1)

[0719] Step 1: (2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione

[0720]

[0721] A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethylamine (128 mg, 0.41 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (112.5 mg, 0.41 mmol) and N-ethyl-N-isopropylpropan-2-amine (105 mg, 0.81 mmol) in anhydrous N,N-dimethylformamide (2 mL) was stirred at 90° C. for 12 hours. The mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (35 mL×2). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione (73 mg, 31% yield) as a yellow solid. LC-MS (ES) + ):m / z 571.3[MH + ],t R =2.46min.

[0722] Step 2: (4-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione)

[0723]

[0724] To a suspension of 2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione (73 mg, 0.128 mmol) and iron powder (71.6 mg, 1.28 mmol) in ethanol (2 mL) was added a solution of ammonium chloride (68 mg, 1.26 mmol) in water (0.5 mL) at room temperature, and the resulting mixture was stirred at 80° C. for 1 hour. After the mixture was cooled to room temperature, the solid precipitate was filtered off and washed with ethyl acetate (10 mL×2). The filtrate was partitioned between ethyl acetate (60 mL) and water (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (66.5 mg, crude) as a yellow oil. LC-MS (ES +):m / z 541.5[MH + ], t R =1.593min.

[0725] Step 3: 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide

[0726]

[0727] 4-(2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58.4 mg, 0.11 mmol), (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] To a stirred solution of [1,4]diazepin-6-yl)acetic acid (43.3 mg, 0.11 mmol) and N-ethyl-N-isopropylpropan-2-amine (41.8 mg, 0.32 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate) (82 mg, 0.21 mmol). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 minutes. The mixture was poured into water (25 mL) and extracted with ethyl acetate (35 mL×2). The combined organic phase was washed with water (20 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)phenyl)acetamide (52 mg, 52% yield) as a yellow solid. LC-MS (ES) + ):m / z923.29 / 925.29(3:1)[MH + ], t R =2.689min. 1H NMR (400MHz, CDCl3): δ1.67(s,3H),2.05-2.12(m,1H),2.40(s,3H),2.65-2.85(m,6H),3.41-3 .54(m,4H),3.65-3.74(m,10H),3.81-3.85(m,2H),4.06-4.11(m,2H),4.63-4.69(m,1H),4.85 -4.93(m,1H),6.38-6.55(m,1H),6.83(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,1H),7.09(d,J=7.2H z, 1H), 7.33 (d, J = 8.4Hz, 2H), 7.39-7.51 (m, 5H), 8.59 (d, J = 5.2Hz, 1H), 8.77 (d, J = 3.2Hz, 1H).

[0728] 9. (Z)-4-(4-((3-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0729]

[0730] (Compound structure No. 22 shown in Table 1)

[0731] Step 1: (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0732]

[0733] 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 bis(4-methylbenzenesulfonic acid) 2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)ester (1.3 g, 2.7 mmol) in N,N-dimethylformamide (10 mL) was 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×3). The combined organic phase was 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 eluting with 10-30% ethyl acetate in hexanes to give (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.0 g, 61% yield) as a light yellow solid.

[0734] Step 2: (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0735]

[0736] A mixture of (Z)-2-(2-(2-(5-(4-(4-cyano-2-(trifluoromethyl)phenoxy)-3-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.0 g, 1.4 mmol) and sodium azide (185 mg, 2.8 mmol) in ethanol (20 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (20 mL). The organic layer was washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (130 mg, crude) as a pale yellow oil, which was used in the next step without further purification.

[0737] Step 3: (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0738]

[0739] A mixture of the above (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (130 mg, crude), triphenylphosphine (100 mg, 0.34 mmol) in water (0.2 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 3-5% methanol / dichloromethane) to give (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidine-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (60 mg, 8% yield over two steps) as a yellow oil. LC-MS(ES + ):m / z 552.1[MH + ], t R =2.15min.

[0740] Step 4: (Z)-4-(4-((3-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0741]

[0742] A mixture of (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile) (60 mg, 0.10 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (30 mg, 0.13 mmol) and N-ethyl-N-isopropylpropan-2-amine (50 mg, 0.39 mmol) in 1-methylpyrrolidin-2-one (1 mL) was stirred at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (10 mL × 2) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give (Z)-4-(4-((3-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (9.5 mg, 11.8% yield) as a yellow solid. LC-MS (ES + ):m / z808.19[MH + ], t R =3.022min. 1 H NMR (400MHz, CDCl3): δ2.12-2.16(m,1H),2.73-2.91(m,3H),3.42(s,2H),3.67-3.80(m,11H),3.99(s,2H),4.91-4.95(m ,1H),6.51(s,1H),6.76-6.86(m,2H),7.02-7.19(m,4H),7.43(t,J=7.6Hz,1H),7.68(d,J=8.0Hz,1H),7.85-8.12(m,3H).

[0743] 10. 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

[0744]

[0745] (Compound structure No. 1 shown in Table 1)

[0746] Step 1: 1,1,1,16-Tetraphenyl-2,5,8,11,15-pentaoxahexadecane

[0747]

[0748] To a solution of 2-(2-(2-(trityloxy)ethoxy)ethoxy)ethanol (7 g, 17.7 mmol) in N,N-dimethylformamide (50 mL) was slowly added sodium hydride (60% in mineral oil, 707 mg, 17.7 mmol) at 0°C. After the mixture was stirred at room temperature for 30 minutes, 3-(benzyloxy)propyl 4-methylbenzenesulfonate (5.8 g, 18.0 mmol) was added in one portion at 0°C, and the resulting mixture was stirred at 70°C overnight. After the mixture was cooled to room temperature, it was carefully quenched with water (40 mL), extracted with ethyl acetate (60 mL×3). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluting with 5-10% ethyl acetate / hexanes) to afford 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g, 50% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ1.85-1.92(m,2H),3.23(t,J=5.2Hz,2H),3.53-3.59(m ,6H),3.64-3.68(m,8H),4.47(s,2H),7.19-7.33(m,15H),7.45-7.47(m,5H).

[0749] Step 2: 1-phenyl-2,6,9,12-tetraoxatetradecan-14-ol

[0750]

[0751] To a solution of 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8 g 8.8 mmol) in dichloromethane (10 mL) and methanol (10 mL) was added aqueous hydrochloric acid solution (37%, 2.5 mL) 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 × 3). The combined organic phase was washed with aqueous sodium bicarbonate solution (1N, 50 mL), water (30 mL), brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 20-40% ethyl acetate / hexane) to obtain 1-phenyl-2,6,9,12-tetraoxa tetradecane-14-ol (1.9 g, 73% yield) as a colorless oil.

[0752] Step 3: 1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate

[0753]

[0754] A mixture of 1-phenyl-2,7,10,13-tetraoxapentadecan-15-ol (1.9 g, 6.3 mmol), triethylamine (1.3 mL, 9.5 mmol), N,N-dimethylpyridine-4-amine (75 mg, 0.63 mmol) and 4-methylbenzene-1-sulfonyl chloride (1.45 g, 7.65 mmol) in dichloromethane (20 mL) was stirred at room temperature for 3 hours. Water (20 mL) was added to quench the reactant, and the product was extracted with dichloromethane (40 mL × 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluted with 10-30% ethyl acetate / hexane) to obtain 4-methylbenzenesulfonic acid 1-phenyl-2,6,9,12-tetraoxa tetradecane-14-ester (2.2 g, 78% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ1.87-1.92(m,2H),2.43(s,3H),3.54-3.60(m,12H),3.67(t,J=5 .2Hz, 2H), 4.15 (t, J = 5.0Hz, 2H), 4.48 (s, 2H), 7.27-7.33 (m, 7H), 7.79 (d, J = 8.4Hz, 2H).

[0755] Step 4: 14-Azido-1-phenyl-2,6,9,12-tetraoxatetradecane

[0756]

[0757] A mixture of 4-methylbenzenesulfonic acid 1-phenyl-2,6,9,12-tetraoxa tetradecane-14-ester (2.2 g, 4.9 mmol) and sodium azide (420 mg, 6.3 mmol) in ethanol (10 mL) was refluxed for 5 hours. The reaction mixture was cooled to room temperature, poured into water (10 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 14-azido-1-phenyl-2,6,9,12-tetraoxa tetradecane (1.4 g, thick) as a colorless oil, which can be used in the next step without further purification.

[0758] Step 5: tert-Butyl (1-phenyl-2,6,9,12-tetraoxatetradec-14-yl)carbamate

[0759]

[0760] The mixture of the above 14-azido-1-phenyl-2,6,9,12-tetraoxa-tetradecane (1.4 g, thick) and triphenylphosphine (1.7 g, 6.5 mmol) in 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 warmed to room temperature and stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure, and the residue was distributed between dichloromethane (100 mL) and water (50 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography eluting with 30-50% ethyl acetate / hexanes to afford tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradec-14-yl)carbamate (1.2 g, 50% yield over two steps) as a colorless oil.

[0761] Step 6: tert-Butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate

[0762] A mixture of (1-phenyl-2,6,9,12-tetraoxa tetradecane-14-yl) tert-butyl carbamate (1.2 g, 3 mmol) and palladium / carbon (10%, 200 mg) in ethanol (50 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon). Palladium / carbon was removed by filtration and washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate (900 mg, thick) as a colorless oil, which was used in the next step without further purification.

[0763] Step 7: 2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate

[0764]

[0765] A mixture of the above tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate (900 mg, crude), triethylamine (0.6 mL, 4.35 mmol), N,N-dimethylpyridin-4-amine (16 mg, 0.14 mmol) and 4-methylbenzene-1-sulfonyl chloride (660 mg, 3.5 mmol) in anhydrous dichloromethane (15 mL) was stirred at room temperature for 3 hours. Water (20 mL) was added to quench the reactants, and the product was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate / hexanes) to afford 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate (650 mg, 77% yield) as a light yellow oil. 1 H NMR (400MHz, CDCl3): δ1.44(s,9H),1.88-1.95(m,2H),2.45(s,3H),3.29-3.33(m,2H),3.48- 3.61(m,12H),4.09-4.15(m,2H),5.04(brs,1H),7.34(d,J=8.0Hz,2H),7.79(d,J=8.0Hz,2H).

[0766] Step 8: tert-Butyl (2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethyl)carbamate

[0767]

[0768] A mixture of 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17- ester of 4-methylbenzenesulfonate (115 mg, 0.25 mmol), potassium carbonate (69 mg, 0.50 mmol) and 4-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.25 mmol) in acetonitrile (5 mL) was 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×3). The combined organic phase was 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 (eluting with 10-30% ethyl acetate / hexanes) to give tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethylcarbamate (150 mg, 82% yield) as a yellow oil. LC-MS (ES) + ):m / z 695.40[MH + ], t R =2.79min.

[0769] Step 9: 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

[0770]

[0771] A mixture of tert-butyl 2-(2-(2-(3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenoxy)propoxy)ethoxy)ethoxy)ethylcarbamate (150 mg, 0.21 mmol) in anhydrous dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure, and the residue was poured into aqueous sodium bicarbonate solution (1N, 20 mL) and extracted with dichloromethane (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, crude) as a brown oil which was used in the next step without further purification.

[0772] Step 10: 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

[0773]

[0774] The above 4-(3-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (115 mg, crude), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (41 mg, 0.15 mmol) and N-ethyl-N-isopropylpropan-2-amine (58 mg, 0.44 mmol) in N,N-dimethylformamide (2 mL) were stirred at 90 ° C for 16 hours. The reaction mixture was cooled to room temperature, quenched with water (3 mL), and extracted with ethyl acetate (30 mL×3). The combined organic layer was washed with water (30 mL×2) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 4-(3-(4-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (34.5 mg, 27% yield) as a yellow solid. LC-MS (ES) + ):m / z851.25[MH + ], t R =2.652min. 1 H NMR (400MHz, CD3OD): δ1.57(s,6H),2.07-2.11(m,3H),2.70-2.90(m,3H),3.46-3.72(m,14H),4.10(t,J=6.2Hz,2H), 4.88-4.92(m,1H),6.48-6.49(m,1H),6.91-7.26(m,6H),7.49(t,J=7.8Hz,1H),7.83-7.85(m,1H),7.97-8.02(m,3H).

[0775] 11. 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0776]

[0777] Step 1: 3-[(5-Hydroxypentyl)oxy]propionitrile

[0778]

[0779] Pentan-1,5-diol (2.98 g, 28.6 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 820 mg, 34.2 mmol) in THF (50 mL). After the mixture was stirred at room temperature for 20 minutes, it 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 vacuum, 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 in vacuo. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with MeOH / DCM (0:100 to 3:97) to give 3-[(5-hydroxypentyl)oxy]propionitrile (635 mg, 18% yield). 1 H NMR (400MHz, CDCl3) δ3.60-3.73(m,4H),3.45-3.55(m,2H),2.60(dt,J=4.1,6.4Hz,2H),2.06(d,J=3.9Hz,1H),1.57-1.69(m,4H),1.43-1.50(m,2H).

[0780] Step 2: tert-Butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate

[0781]

[0782] To 3-[(5-hydroxypentyl) oxy] propionitrile (400mg, 2.54mmol) in MeOH (12mL) and H2O (2.0mL) solution in nickel (II) chloride (393mg, 3.04mmol) was added, followed by portionwise addition of sodium borohydride (360mg, 9.52mmol). The mixture was stirred at room temperature for 3 hours, then quenched with MeOH (12mL). The mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated in vacuo. To the above crude product in THF (5mL) solution, 6M NaOH aqueous solution (0.5mL) and di-tert-butyl dicarbonate (831mg, 3.81mmol) were added, and the resulting mixture was stirred at room temperature for 3 hours, then concentrated in vacuo. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with MeOH / DCM (0:100 to 4:96) to afford tert-butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate (366 mg, 55% yield). 1 H NMR (400MHz, CDCl3) δ4.91(br.s.,1H),3.66(br.s.,2H),3.49(t,J=5.9Hz,2H),3.43(t,J=6.3 Hz, 2H), 3.24 (q, J = 5.9Hz, 2H), 1.75 (quintet, J = 6.2Hz, 2H), 1.57-1.65 (m, 5H), 1.41-1.52 (m, 11H).

[0783] Step 3: tert-Butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate

[0784]

[0785] To a solution of tert-butyl (3-((5-hydroxypentyl)oxy)propyl)carbamate (300 mg, 3.88 mmol) in DCM (10 mL) was added DIPEA (599.3 μL, 3.44 mmol), tosyl chloride (262.3 mg, 1.38 mmol) and 4-dimethylaminopyridine (14.0 mg, 0.115 mmol). The resulting mixture was stirred at room temperature for 20 hours. The reaction was quenched with half-saturated sodium bicarbonate, extracted with DCM (2×), filtered through a Biotage universal phase separator, and concentrated in vacuo. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with EtOAc / heptane (0:100 to 30:70) to give tert-butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate (914 mg, 26% yield). 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H),4.02(t,J=6.5Hz,2H),3.44(t,J=6.1Hz,2H),3.35(t, J=6.3Hz,2H),3.19(q,J=5.9Hz,2H),2.44(s,3H),1.64-1.74(m,5H),1.49-1.54(m,2H),1.42(s,9H),1.33-1.40(m,2H). LC-MS(ES + ):m / z 438.19[MNa + ], t R =2.65min.

[0786] Step 4: Methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate

[0787]

[0788] 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), potassium carbonate (203 mg, 1.47 mmol) in MeCN (10 mL) was stirred at 80 ° C for 24 hours. The reaction mixture was diluted with EtOAc, washed with half-saturated sodium bicarbonate solution (1×), water (2×), brine (1×), and then filtered through a Biotage universal phase separator. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with EtOAc / heptane (0:100 to 50:50) to give methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (300 mg, 93% yield). LC-MS(ES + ):m / z 418.21[MNa + ], t R =2.74min.

[0789] Step 5: 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid

[0790]

[0791] To a solution of methyl 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate (150 mg, 0.38 mmol) in 1:1:1 THF / water / MeOH (6.0 mL, v / v / v) was added lithium hydroxide (81.6 mg, 3.41 mmol). The resulting mixture was stirred at room temperature overnight and then acidified to pH 2-3 with 6N aqueous HCl. The mixture was concentrated in vacuo to remove most of the solvent and then diluted with EtOAc, washed with water (2×), brine (2×), filtered through a Biotage universal phase separator, and concentrated in vacuo. The crude product was taken to the next step without further purification (123 mg). LC-MS (ES) + ):m / z 404.20[MNa + ], t R =2.40min.

[0792] 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

[0793]

[0794] To a solution of 4-{[5-(3-{[(tert-butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid (124 mg, 0.322 mmol), 2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile (89.8 mg, 0.322 mmol) in DMF (5 mL) was added DIPEA (112 μL, 0.65 mmol) and TBTU (155 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 1 hour, then diluted with EtOAc, washed with water (3×), brine (1×), filtered through a Biotage universal phase separator, and concentrated in vacuo. The residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with MeOH / DCM (0:100 to 5:95) to give tert-butyl N-(3-{[5-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxy}propyl)carbamate (169 mg, 82% yield). LC-MS (ES) + ):m / z 643.32 / 645.31(3:1)[MH + ], t R =3.04min.

[0795] 12. 4-{[5-(3-aminopropoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0796]

[0797] To a solution of tert-butyl N-(3-{[5-(4-{[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenoxy)pentyl]oxy}propyl)carbamate (124 mg, 0.192 mmol) in DCM (5 mL) was added trifluoroacetic acid (372 μL, 4.86 mmol) and heated at 45 °C for 1 hour until completion. The reaction was then concentrated in vacuo to a solid and carried to the next step without further purification (104 mg, 99% yield). LC-MS (ES) + ):m / z 543.27 / 545.26(3:1)[MH + ], t R =2.26min.

[0798] 13. 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0799]

[0800] (Compound structure No. 11 shown in Table 1)

[0801] To a solution of 4-{[5-(3-aminopropoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (30.0 mg, 0.0553 mmol) in 1,4-dioxane (2 mL) was added diisopropylethylamine (384 μL, 2.21 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (18.3 mg, 0.0664 mmol). The resulting mixture was refluxed for 16 h, then diluted with EtOAc, washed with half-saturated brine solution (2×), filtered through a Biotage universal phase separator, and concentrated in vacuo. The residue was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with MeOH / DCM (0:100 to 7:93) to give 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (12 mg, 28% yield). LC-MS (ES) + ):m / z 799.31 / 801.31(3:1)[MH + ], t R =2.97min. 1H NMR (400MHz, CDCl3) δ8.03(s,1H),7.72(d,J=9.0Hz,2H),7.58(d,J=8.6Hz,1H),7.48(dd,J=7.2,8.4Hz,1H),7.07(d,J=7.0Hz,1H),6.98(d,J=2. 3Hz,1H),6.89-6.96(m,3H),6.82(dd,J=2.5,8.8Hz,1H),6.18(d,J=8.2Hz,1H),4.89(dd,J=5.1,12.1Hz,1H),4.16(d,J=7.8Hz,1H),4.06(s,1H), 4.02 (t, J = 6.7 Hz, 2H), 3.56 (t, J = 5.9 Hz, 2H), 3.50 (s, 2H), 3.46-3.48 (m, 1H), 3.41 (t, J = 6.5 Hz, 2H), 2.82-2.90 (m, 1H), 2.76-2.81 (m, 1H), 2.67-2.75 (m, 1H), 2.07-2.14 (m, 1H), 1.94 (quintet, J = 6.1 Hz, 2H), 1.82-1.87 (m, 2H), 1.67-1.73 (m, 2H), 1.53-1.59 (m, 2H), 1.28 (s, 6H), 1.20-1.25 (m, 6H).

[0802] C. Protein Degradation Bioassay:

[0803] The following bioassays were performed using representative compounds disclosed herein to assess the level of protein degradation observed in various cell types.

[0804] In each bioassay, cells were treated with varying amounts of compounds encompassed by the present disclosure, as shown in Table 1. Degradation of the following proteins was assessed in this study: TANK binding kinase 1 (TBK1), estrogen receptor alpha (ERα), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc.

[0805] 1. TBK1 Western protocol

[0806] Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco) supplemented with 15% FBS (ATCC) and 10U / mL human recombinant insulin (Gibco). DMSO control and compound treatment (0.1 μM, 0.3 μM and 1 μM) were carried out in 12-well plates for 16 hours. TLR3 agonist poly I: C (Invivogen; tlrl-pic) was added for the final 3 hours. Cells were collected and lysed in RIPA buffer (50mM Tris pH 8, 150mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysate was clarified at 16,000g for 10 minutes, and supernatant was separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were TBK1 (Cell Signaling No. 3504), pIRF3 (abcam No. ab76493) and GAPDH (Cell Signaling No. 5174). Bands were quantified using the Biorad ChemiDoc MP imaging system.

[0807] 2. ERRα Western Blot

[0808] 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 carried out in 24-well plates for 16 hours. Cells were collected and lysed with cell lysis buffer (Cell Signaling Technologies) containing protease inhibitors (Thermo Scientific). Lysates were clarified for 10 minutes at 16,000 g, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were ERRα (Cell Signaling No. 8644) and GAPDH (Cell Signaling No. 5174). Bands were quantified using the Bio-rad ChemiDoc MP imaging system.

[0809] 3. BRD4 Western Protocol

[0810] VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle's Medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatment (0.003 μM, 0.01 μM, 0.03 μM and 0.1 μM) were performed in 12-well plates for 16 hours. Cells were collected 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 lysate was clarified at 16,000 g for 10 minutes and the protein concentration was determined. Equal amounts of protein (20 μg) were subjected to SDS-PAGE analysis and subsequent immunoblotting according to standard protocols. The antibodies used were BRD4 (Cell Signaling No. 13440) and actin (Sigma No. 5441). The detection reagent was Clarity Western ECL substrate (Bio-rad No. 170-5060).

[0811] 4.AR ELISA protocol

[0812] VCaP cells were purchased from ATCC and cultured in Dulbecco's modified Eagle's medium (ATCC) supplemented with 10% FBS (ATCC) and penicillin / streptomycin (Life Technologies). DMSO control and compound treatment (0.0001 μM-1 μM) were performed in 96-well plates for 16 hours. The cells were collected and lysed with cell lysis buffer (Cat. No. 9803) (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 B-glycerophosphate, 1 mM Na3VO4, 1 ug / ml leupeptin). The lysate was clarified at 16,000 g for 10 minutes and loaded into PathScan AR ELISA (Cell Signaling Cat. No. 12850). The total androgen receptor sandwich ELISA kit is a solid phase sandwich enzyme-linked immunosorbent assay (ELISA) that detects endogenous levels of total androgen receptor protein. Androgen receptor rabbit mAb has been coated on microwells. After incubation with cell lysate, androgen receptor protein is captured by the coated antibody. After large-scale washing, androgen receptor mouse detection mAb is added to detect the captured androgen receptor protein. Anti-mouse IgG (HRP-coupled antibody) is then used to identify the bound detection antibody. HRP substrate TMB is added to develop color. The magnitude of the absorbance developed is proportional to the amount of total androgen receptor protein.

[0813] The antibodies in the kit are of a customary formulation specific to the kit.

[0814] 5.c-Myc ELISA Assay Protocol

[0815] 22RV-1 cells were purchased from ATCC and cultured in RPMI+10% FBS medium. Cells were collected using trypsin (Gibco No. 25200-114), counted, and seeded in RPMI+10% FBS medium in a 96-well plate at 30,000 cells / well at a volume of 75 μL / well. Cells were administered with compounds diluted in 0.1% DMSO, incubated for 18 hours, then washed and lysed in 50uL RIPA buffer (50mMTris pH 8, 150mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 4000rpm for 10 minutes at 4°C, and then aliquots were added to 96-well ELISA plates of Novex human c-myc ELISA kit from Life Technologies catalog number KHO2041. Add 50ul c-Myc detection antibody to each well, incubate the plate at room temperature for 3 hours, then wash with ELISA wash buffer. Add 100uL anti-rabbit IgG-HRP secondary antibody to each well and incubate at room temperature for 30 minutes. Wash the plate with ELISA wash buffer, add 100μL TMB to each well, and then monitor the color change every 5 minutes. Add 100μL stop solution and read the plate at 450nm.

[0816] D. Results

[0817] Table 1 provides the results of experimental data obtained from a variety of representative compounds encompassed by the present disclosure. Specifically, various cell types were treated with the compounds listed in Table 1, which were identified by chemical structure, mass spectrometric characterization, and compound name.

[0818] Table 1 shows that (A) 10-30% degradation was achieved in cells treated with 1 uM compounds 1, 6-9, 12, and 17; (B) 31-50% degradation was achieved in cells treated with 1 uM compounds 2-5, 10, and 20; and (C) >50% degradation was achieved in cells treated with 1 uM compounds 11, 13-16, 18-19, 21, and 22. Table 1 also shows that (D) IC values ​​of compounds 24 and 26-35 were 50 <50 nM, while (E) IC of compounds 23 and 25 50 >50nM.

[0819] The contents of all references, patents, pending patent applications, and published patents cited throughout this application are hereby expressly incorporated by reference.

[0820] Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using only routine experiments. Such equivalents are intended to be covered by the following claims. It should be understood that the detailed embodiments and embodiments described herein are given for illustrative purposes only by way of example and are by no means considered to limit the present invention. Various modifications or changes thereto will be thought of by those skilled in the art, and are included in the spirit and scope of the present application, and are considered to be within the scope of the appended claims. For example, the relative amounts of the ingredients may be changed to optimize the desired effect, additional ingredients may be added, and / or one or more of the described ingredients may be replaced with similar ingredients. Other advantageous features and functionality associated with the systems, methods and processes of the present invention will be apparent from the appended claims. In addition, those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein using only routine experiments. Such equivalents are intended to be covered by the following claims.

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

Claims

1. A compound having a chemical structure comprising: L-CLM or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein L is a linker group; and CLM is the E3 ubiquitin ligase binding part of cerebellum protein. wherein the linker group is chemically linked to the CLM.

2. The compound of claim 1, wherein the compound has a chemical structure comprising: PTM-L-CLM in PTMs are protein target moieties that bind to target proteins or target peptides. wherein the PTM is chemically linked to the CLM via the linker group.

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

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

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

6. The compound of claim 1, wherein the compound further comprises a ULM, a second CLM, a CLM', or a plurality or combination thereof, wherein ULM is the E3 ubiquitin ligase binding part. The second CLM has the same chemical structure as the CLM, CLM' is a cerebellar protein E3 ubiquitin ligase binding portion that is structurally distinct from the CLM. wherein the ULM, the second CLM, the CLM', or a plurality thereof, or a combination thereof, are optionally coupled to another linker group.

7. The compound of claim 1, wherein the CLM has a chemical structure represented by: in 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-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z is selected from the group consisting of: O, S and H2; G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from R', N or N-oxide; A is independently selected from the groups alkyl, cycloalkyl, Cl and F; R includes -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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 the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl; represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R n including functional groups or atoms, Where n is an integer from 1 to 4, and When n is 1, Rn is modified to be covalently linked to the linker group (L), and When n is 2, 3, or 4, then an R n is modified to be covalently attached to the linker group (L), and any other R n Optionally modified to be covalently linked to a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

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

9. The compound of claim 1, wherein the linker group (L) comprises a chemical structural unit represented by the following formula: -A q - in q is an integer greater than 1; and A is independently selected from the group consisting of: a bond, CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 ,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 , optionally through 0-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally with 0-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally 0-6 R L1 and / or R L2 The aryl group substituted by a group, optionally substituted by 0-6 R L1 and / or R L2 A heteroaryl group substituted with a group; wherein R L1 , R L2 , R L3 , R L4 and R L5 are each independently selected from the group consisting of: H, halogen, 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 Heterocyclic group, 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)(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 and NHSO2NH2; and wherein When q is greater than 1, R L1 or R L2 Each independently can be linked to another A group to form a L5 The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

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

11. The compound of claim 2, wherein the PTM group is a moiety that binds to a target protein, wherein the target protein is selected from the group consisting of B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other chaperones in apoptosis pathways, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and analogs, 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-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras / Raf / ME / ERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGFβ-activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, estrogen receptor, estrogen-related receptor, focal adhesion kinase, Src, endothelin receptor, neuropeptide Y and receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA of NGF a receptor, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase.Other protein targets include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel. Other target proteins include acetyl-CoA carboxylase, adenylo-succinate synthetase, protoporphyrinogen oxidase and enolpyruvylshikimate-phosphate synthase.

12. The compound of claim 2, wherein the PTM group is an Hsp90 inhibitor; a kinase inhibitor; a phosphatase inhibitor, a HDM2 / MDM2 inhibitor, a compound targeting a human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting a 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 HIV protease, a compound targeting HIV integrase, a compound targeting HCV protease, or a compound targeting acyl protein thioesterase 1 and / or 2.

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

14. A composition comprising the compound of claim 2.

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

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

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

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

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

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

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

22. The pharmaceutical composition of claim 16, wherein the bioactive agent is an anticancer agent.

23. The composition of claim 22, wherein the anticancer agent is selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint-1 or 2 inhibitors, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalimumab, etakalim, tetrandrine, rubitecan, tesmilifen, oblimersen, tesilitumumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1, KRX-0402, Lucanthone, LY 317615, Nudi, Vitspan, Rta744, Sdx 102, Talanpanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliciclib, PD0325901, AZD-6244, Capecitabine, L-glutamic acid, N-[4-[2-(2-amino [4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,);3-[5-(Methylsulfonylpiperidinylmethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, acetate of [D-Ser(But)6,Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C; 59 H 84 N 18 Oi4-(C2H4O2) x , where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, yonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU112 48. Sorafenib, KRN951, aminoglutethimide, amitriptyline, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate), cyproterone acetate, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, dichloromethane, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone Tan, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neivastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitacin, droloxifene, iodoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, episeron B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipenoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L- 779,450, PEG-filgrastim, darbepoietin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrogenated Cortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immunoglobulin, nitrogen mustard, methylprednisolone, tentan isobetumomab, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, adipronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, casopitant, naphthalene Topitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabitol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

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

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

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

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

28. A method for treating a disease state or condition in a patient wherein deregulated protein activity is responsible for the disease state or condition, the method comprising administering an effective amount of a compound according to claim 2.

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

30. The method of claim 28, wherein the disease state or condition is 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, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, vasculitis.

31. The method of claim 28, wherein the disease state or condition is aceruloplasminosis, achondroplasia type II, achondroplasia, pointed head, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenyloylsuccinate lyase deficiency, adrenal reproductive syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocher, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alstrom syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insufficiency Sensitive syndrome, anemia, diffuse body angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider feet (Marfan syndrome), Stickler syndrome, congenital multiple achalasia (Ehlers-Danlos syndrome # achalasia type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Bill-Stevensson skin gyroscope syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberg syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastoma cytotoxic anemia, Bonneville-Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Bert-Hoeg-Dub syndrome, brittle bone disease (osteogenesis imperfecta), pan-thump-big toe syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronze cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy's disease), Berg-Grutz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disease, camptomelia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat cry syndrome, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital thyrotoxicosis Hypothyroidism, chondrodystrophy syndrome (achondroplasia), aurispondyloepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, cone abnormal face syndrome, Wenkuli's anemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint deformity (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease),Cockayne syndrome, Cowden syndrome, Kirshman-Batten-Steinert syndrome (myotonic dystrophy), Bill-Stevensson skin gyration syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Stradwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, degenerative neurological diseases (including deGrown syndrome and DeGeliner-Sotas syndrome), developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globuloid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocyte 5-aminolevulinic acid synthetase deficiency, erythropoiesis Porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosemia, inherited brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grunblad-Standberg syndrome (pseudoxanthoma elasticum), Genda disease (congenital erythropoietic porphyria), hemochromatosis, Holgren syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria) , hyperandrogenism, chondrodysplasia, 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 disease (including hyperoxaluria), Klinefelter syndrome, Knister dysplasia, intermittent dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knister dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Mink syndrome, neurofibromatosis, Nance-Insley syndrome Syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Lundy disease, Piots-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Piots-Jeghers syndrome, Prader-Labatt-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension,PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS Type 3, Lake syndrome, Riley-Day syndrome, Lucey-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma of the breast, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tubercular sclerosis), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Stradwick SED (spondyloepiphyseal dysplasia type), SEDc (spondyloepiphyseal dysplasia congenita), SEMD, Stradwick type (spondyloepiphyseal dysplasia type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemley-Opitz syndrome, South African hereditary porphyria (variant porphyria), hereditary spastic paralysis of infantile-onset ascending type paralysis, speech and communication disorders, neurolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, dactylyx neuropathy (hereditary neuropathy with a tendency to pressure paralysis), Treacher Collins syndrome, trisomy X syndrome (triple X syndrome), triploidy 21 (Down syndrome), triploidy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frohlich's disease, Waardenburg syndrome, Warburg-St. Joseph-Frederick syndrome, Weissenbacher-Zawie-Muller syndrome, Wolff-Hirshhorn syndrome, Wolff periodic disease, Weissenbacher-Zawie-Muller syndrome and xeroderma pigmentosum.

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

33. The method of claim 32, wherein the cancer is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; multiple myeloma, sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratoma.

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

35. A compound library comprising more than one compound of claim 1.

36. A method for identifying a compound containing an E3 ubiquitin ligase binding moiety that recognizes cerebellin (CRBN), comprising: The test compound is incubated with the CRBN protein; The amount of the test compound bound to the CRBN protein is determined.

37. A cerebellin E3 ubiquitin ligase binding moiety (CLM) having a chemical structure represented by: in 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-heteroaryl, N-cycloalkyl, N-heterocyclyl, O and S; Z is selected from the group consisting of: O, S and H2; G and G' are independently selected from the group consisting of H, alkyl, OH, CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from R', N or N-oxide; A is independently selected from the groups alkyl, cycloalkyl, Cl and F; R includes -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'NR'R"-, -aryl, -heteroaryl, -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 the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl; represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and R n including functional groups or atoms, Where n is an integer from 1 to 4.

38. The CLM of claim 1, wherein the R n Included are functional groups or atoms covalently linked to a linker group (L), a protein targeting moiety (PTM), an E3 ubiquitin ligase binding moiety (ULM), or any multiple or combination thereof.

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

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