Imide-based proteolysis modulators and related methods of use

Abstract

The present invention relates to imide-based compounds, including bifunctional compounds containing the same, which are useful as modulators of targeted ubiquitination, particularly inhibitors of a variety of polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds according to the present invention. Specifically, compounds are described that contain a ligand on one end that binds to the cerebellum protein E3 ubiquitin ligase and a moiety on the other end that binds to a target protein, positioning the target protein in proximity to the ubiquitin ligase to achieve degradation (and inhibition) of the protein. Compounds can be synthesized that exhibit a wide range of pharmacological activities consistent with the degradation / inhibition of virtually any type of targeted polypeptide.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is an International PCT application claiming the benefit of and priority to U.S. Provisional Application No. 61 / 979,351, filed April 14, 2014, entitled “IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE,” which is incorporated herein by reference in its entirety.

[0003] Incorporated by reference

[0004] Pursuant to 37 CFR §1.52(e), the computer-readable sequence listing information is submitted herewith in .txt format, file name: Sequence_Listing_ST25.txt; size 2 KB; generated using PatentIn-3.5 on April 14, 2015, which is incorporated herein by reference in its entirety. Field of the Invention

[0005] 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, particularly with respect to various polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds according to the present invention.

[0006] background

[0007] 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.

[0008] One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor. VHL comprises 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 for von Hippel-Lindau (VHL) was generated from a novel small-molecule ligand (Schmidt et al., 2002), and the crystal structure was obtained, demonstrating that the compound mimics the binding mode of the transcription factor HIF-1α, the main substrate of VHL.

[0009] Cerebellin is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Cerebellin forms an E3 ubiquitin ligase complex with damage DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates a variety of other proteins. Through mechanisms that have not yet been fully elucidated, cerebellin ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates various developmental processes, such as limb and otic vesicle formation. The net result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cerebellin, DDB1 forms a complex with DDB2, a DNA damage binding protein.

[0010] 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 anti-tumor 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).

[0011] Notably, thalidomide and its analogs (e.g., pomalidomide and lenalinomide) are known to bind to cerebellum. These agents bind to cerebellum and alter 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 cerebellum correlates with increased efficacy of imide drugs in treating multiple myeloma.

[0012] 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 are simultaneously "tunable" to specifically target and modulate a wide variety of protein classes would be highly useful as therapeutic agents. Summary of the Invention

[0013] The present disclosure describes bifunctional compounds that act to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. Specifically, the present invention provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that 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 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 a compound as described herein.

[0014] Thus, in one aspect, the present disclosure provides novel imide-based compounds as described herein.

[0015] In another aspect, the present disclosure provides bifunctional or PROTAC compounds comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for the E3 ubiquitin ligase or "ULM" group) and a moiety that binds to a target protein so that the target protein / polypeptide is positioned proximal 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:

[0016]

[0017] The corresponding positions of the PTM and CLM moieties as described herein, as well as 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 described herein can be synthesized such that the number and position of the corresponding functional moieties can be varied as desired.

[0018] 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:

[0019]

[0020] where PTM is the protein / peptide targeting moiety, L is the linker, and CLM is the cerebellum E3 ubiquitin ligase binding moiety.

[0021] In certain preferred embodiments, the E3 ubiquitin ligase is cerebellin. Thus, in certain other embodiments, the CLM of the bifunctional compound comprises a chemical species such as an imide, amide, thioamide, or 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 analogs or derivatives thereof.

[0022] In certain embodiments, the compounds as described herein comprise multiple CLMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0023] 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 proteins of interest for treating or improving diseases (e.g., cancer). On the other hand, the present invention provides a method for ubiquitination / degradation of target proteins in cells. 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 group as further 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 cerebellum proteins), 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 degradation / inhibition of the effects of the target protein and control of protein levels. The control of protein levels achieved by the present invention provides for the treatment of disease states or conditions that are modulated by targeting a protein by reducing the levels of that protein in the patient's cells.

[0024] In another aspect, the present invention provides a method for evaluating (i.e., determining and / or measuring) the binding affinity of CLM. In certain embodiments, the method comprises providing a test agent or compound of interest, such as an agent or compound having an imide moiety (e.g., phthalimido, phthalimido-glutarimidyl, derivatized thalidomide, derivatized lenalidomide, or derivatized pomalidomide); and comparing the cerebellum binding affinity and / or inhibitory activity of the test agent or compound with that of an agent or compound known to bind to cerebellum and / or inhibit cerebellum activity.

[0025] 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.

[0026] In another aspect, the present invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the present invention.

[0027] The above general application areas are given by way of example only 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 objects and advantages associated with the compositions, methods, and processes of the present invention in light of the present claims. For example, various aspects and embodiments of the present invention can be used in numerous combinations, all of which are clearly encompassed by the present invention. These other advantages, objects, and embodiments are clearly included within the scope of the present invention. Publications and other materials herein that illustrate the background of the invention and, in specific cases, provide additional details about practice are incorporated by reference.

[0028] Brief description of the diagram

[0029] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present invention and, together with the present invention, serve to explain the principles of the invention. The drawings are for the purpose of illustrating the embodiments of the present invention only 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 detailed description taken in conjunction with the accompanying drawings showing illustrative embodiments of the present invention, in which:

[0030] Figure 1 . Illustrate 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) Illustrate the functional use 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 is complexed 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 proteasomal machinery.

[0031] Details

[0032] The following are provided to help those skilled in the art to practice the present invention. Those skilled in the art may make modifications and variations 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.

[0033] 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 positioned in proximity to the target protein via bifunctional or chimeric constructs that bind 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.

[0034] 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 this invention belongs. The terminology used in the present invention is for describing particular embodiments only and is not intended to be limiting of the invention.

[0035] Where a range of values ​​is provided, it is understood that unless the context clearly indicates otherwise (such as in the case of a group containing multiple carbon atoms, in which case the number of each carbon atom falling within the stated range is provided), every intervening value (to one-tenth of the lower limit) between the upper and lower limits of the stated range, and any other stated or intervening value in the stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in smaller ranges also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where a 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.

[0036] 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 those skilled in the art as the term is applied to the present invention in the context.

[0037] 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.

[0038] 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"), a 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.

[0039] 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 a list 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 a list of elements. In general, as used herein, the term "or" when preceded by an exclusive term (such as "one of...", "only one of..." or "exactly one of...") should only be interpreted as indicating an exclusive alternative (i.e., "one or the other but not both").

[0040] In the claims and the foregoing description, all transitional phrases (e.g., "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," etc.) are to be understood as open-ended, i.e., meaning including, but not limited to, including. Only the transitional phrases "consisting of" and "consisting essentially of" are to 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.

[0041] 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") can refer to at least one, optionally including more than one A, with no B (and optionally including elements other than B) in one embodiment; at least one, optionally including more than one B, with no 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.

[0042] It will 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 are not necessarily limited to the order in which the steps or actions of the method are listed unless the context dictates otherwise.

[0043] The terms "co-administration" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and chronotropic administration (administration of 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 an effective amount). 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 an anticancer agent. In particularly preferred aspects, the co-administration of the compounds results in synergistic activity and / or therapy, including anticancer activity.

[0044] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, where the context is applicable, and includes its tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers (including optical isomers (enantiomers) and other stereoisomers (diastereomers)), as well as pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When used in this context, the term compound generally refers 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 this 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, numerous substituents and variables associated therewith are described, among others. One of ordinary skill will understand that the molecules described herein are stable compounds as generally described below. When bonds are shown, both double and single bonds are represented in the context of the compounds shown.

[0045] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, cerebellin is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to a lysine on a target protein and subsequently targets the specific protein substrate for degradation via the proteasome. Thus, E3 ubiquitin ligases, alone or in complex with an E2 ubiquitin-conjugating enzyme, are responsible for the transfer of ubiquitin to target proteins. Generally speaking, ubiquitin ligases participate in polyubiquitination, where 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 via the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead alter their cellular location or function, for example, through binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by the E3 for chain preparation. The most common lysine is Lys48 in the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.

[0046] 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 purpose of treating those infections, conditions, or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domestic animals such as dogs or cats; or farm animals such as horses, cows, sheep, etc. Generally speaking, in the present invention, the term patient refers to a human patient unless otherwise stated or implied from the context in which the term is used.

[0047] 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.

[0048] Compounds and compositions

[0049] In one aspect, the present 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:

[0050] (I)L-CLM

[0051] 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.

[0052] 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 cerebellum (i.e., CLMs). Furthermore, the term CLM includes all possible cerebellum E3 ubiquitin ligase binding moieties.

[0053] 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 that is 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, the CLM is connected or coupled to the PTM via a chemical linker (L). The CLM recognizes the cerebellum protein E3 ubiquitin ligase and the PTM recognizes the target protein, and the interaction of the corresponding portion with its target promotes the degradation of the target protein by positioning the target protein close to the ubiquitin ligase protein. Exemplary bifunctional compounds can be depicted as:

[0054] (II) PTM-CLM

[0055] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be depicted as:

[0056] (III)PTM-L-CLM

[0057] where PTM is the protein / peptide targeting moiety, L is the linker, and CLM is the cerebellum E3 ligase binding moiety.

[0058] In certain embodiments, the compounds described herein comprise multiple PTMs (targeting the same or different protein targets), multiple CLMs, one or more ULMs (i.e., a moiety 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 can 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 can be for the same E3 ubiquitin ligase or each corresponding ULM can specifically bind to a different E3 ubiquitin ligase. In yet other embodiments, when a compound has multiple PTMs, the PTMs can bind to the same target protein or each corresponding PTM can specifically bind to a different target protein.

[0059] In another embodiment, the present invention provides a compound comprising multiple CLMs coupled directly or via a chemical linker moiety (L). For example, a compound with two CLMs can be depicted as:

[0060] (IV)CLM-CLM or

[0061] (V)CLM-L-CLM

[0062] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are identical. In other embodiments, a compound comprising multiple CLMs further comprises at least one PTM coupled to the CLM directly, 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 identical or optionally different. In yet other embodiments, where the PTMs are different, the respective PTMs may bind to the same protein target or specifically bind to different protein targets.

[0063] In other embodiments, the present 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 having two different CLMs can be depicted as:

[0064] (VI) CLM-CLM' or

[0065] (VII)CLM-L-CLM'

[0066] wherein CLM' represents a cerebellum protein 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 the CLM or CLM' directly, via a chemical linker, or both. In any of the embodiments 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 ULM' or CLM').

[0067] 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.

[0068] 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.

[0069] New imide compounds

[0070] In one aspect, the present 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:

[0071]

[0072] in

[0073] W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0074] X is independently selected from the group consisting of O, S, and H2;

[0075] Y is independently selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0076] Z is independently selected from the group consisting of O and S or H2, but wherein both X and Z cannot be H2;

[0077] 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';

[0078] Q1-Q4 represents a carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0079] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0080] 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

[0081] R' and R" are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl

[0082] n is an integer from 1 to 4;

[0083] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0084] R n Includes 1-4 independent functional groups or atoms.

[0085] Exemplary CLM

[0086] In any of the compounds described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0087]

[0088] in

[0089] W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl;

[0090] X is independently selected from the group consisting of O, S, and H2;

[0091] Y is independently selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0092] Z is independently selected from the group consisting of O and S or H2, but wherein both X and Z cannot be H2;

[0093] 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';

[0094] Q1-Q4 represents a carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0095] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0096] 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

[0097] R' and R" are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl

[0098] n is an integer from 1 to 4;

[0099] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0100] 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.

[0101] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0102] 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 groups are, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, the alkyl group is 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 a side chain (often linked via a polyethylene glycol group) terminated with an alkyl group having a halogen substituent (often chlorine or bromine) at its terminus, which results in the compound containing such a moiety being covalently bound to a protein.

[0103] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0104] The term "alkynyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0105] The term "alkylene" when used herein refers to -(CH2) n- group (n is an integer typically 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 halo groups, preferably 1 to 3 halo 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, and often 1 to 4 ethylene glycol units), which is substituted with an alkyl chain substituted with a single halo group, preferably a chloro group (preferably, but not exclusively, at the terminus 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.

[0106] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A carbon atom range including CO means that the carbon is absent and 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.

[0107] 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 a moiety in a compound according to the invention, and which may themselves be further substituted), and includes as substituents: hydroxy, 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-C1-C2), ...1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1 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 ester (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 ring alkylene amine, Further included are C1-C6 alkylamines or C1-C6 dialkylamines, the alkyl groups being 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 carboxamides 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 context are C1-C3 alkyl (including isopropyl or tert-butyl). 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 substituents described above. As defined above, alkylene -(CH2) m -or-(CH2) n-groups or other chains, such as ethylene glycol chains, can be substituted anywhere along the chain. Preferred substituents on the alkylene group 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 can be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl, or amino acid side chains as otherwise described herein. In the present invention, moieties in the molecule can be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present invention, substituted moieties are substituted with one or two substituents.

[0108] The term "substituted" (each substituent being independent of any other substituent) shall also mean, within the context of its use, 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 amines, 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 in this context 1, 2, 3, 4, 5 or 6), -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, -(C H2O) 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). 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 group as described above, or a carbamate group OC(O)-NR1R2 group (wherein R1 and R2 are as otherwise described herein), but numerous other groups may also be used as substituents. 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 in a compound is desired (primarily for reasons of valence), but no substitution is indicated, then the substituent is interpreted or understood to be H unless the context of the substitution implies otherwise.

[0109] 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, phenanthrenyl, etc.), and can be bound to the compounds according to the present 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 include, inter alia, 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 can be optionally substituted as described above. Among the heteroaryl groups that may be mentioned are especially nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthylidine, 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 two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, all of which may be optionally substituted.

[0110] 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, an aryl group may contain a substituent selected from: -(CH2) n OH, -(C H2) 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 bis-(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 oxadiazolyl, including methyloxadiazolyl; 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.

[0111] "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 those defined herein.

[0112] The term "heteroaryl" may mean, 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:

[0113]

[0114] in

[0115] S c It is CHR SS NR URE or O;

[0116] 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);

[0117] 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);

[0118] 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

[0119] 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).

[0120] The terms "aralkyl" and "heteroarylalkyl" refer to groups that contain both an aryl or respectively heteroaryl group as defined above and an alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring system.

[0121] As used herein, the term "arylalkyl" refers to an aryl group as defined above attached to an alkyl group as defined above. The arylalkyl group is attached to the parent moiety through the alkyl group, wherein the alkyl group has one to six carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0122] 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.

[0123] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, 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, cyclopentylsulfide.

[0124] The heterocyclic group may be optionally substituted with a member selected from the group consisting of an alkoxy group, a substituted alkoxy group, a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted cycloalkenyl group, an acyl group, an acylamino group, an acyloxy group, an amino group, a substituted amino group, an aminoacyl group, an aminoacyloxy group, an oxaminoacyl group, an azido group, a cyano group, a halogen group, a hydroxyl group, a keto group, a thioketo group, a carboxyl group, a carboxylalkyl group, a thioaryloxy group, a thioheteroaryloxy group, a thiol group, a thioalkoxy group, a substituted thioalkoxy group, an aryl group, an aryloxy group, a heteroaryl group, a heteroaryloxy group, a heterocycle, a heterocycle group, a heterocycle group, a hydroxyamino group, an alkoxyamino group, a nitro group, a —SO-alkyl group, a —SO-substituted alkyl group, a —SO-aryl group, a —SO-heteroaryl group, a —SO2-alkyl group, a —SO2-substituted alkyl group, a —SO2-aryl group, an oxo (=O) group, and a —SO2-heteroaryl group. 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, and the like, as well as 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, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, etc.).

[0125] The term "cycloalkyl" may refer to, but is in no way limited to, a monovalent group derived from a monocyclic or polycyclic alkyl group 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 refer to, but is in no way limited to, a monocyclic or polycyclic alkyl group and is substituted with one or more substituents such as amino, halogen, alkyl, substituted alkyl, divalent carbonyloxy, divalent carbonyl mercapto, aryl, nitro, mercapto, or sulfo, and these general substituents have the same meanings as those of the corresponding groups defined in this example.

[0126] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the cyclic 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 cyclic 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 carbonyloxy, divalent carbonylthiol, aryl, nitro, thiol or sulfo, and these general substituents have the same meanings as those of the corresponding groups defined in this example.

[0127] 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.

[0128] 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.

[0129] More specifically, non-limiting examples of CLMs include those shown below as well as those 'hybrid' molecules resulting from the combination of one or more of the different features shown in the following molecules.

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] Exemplary linkers

[0136] 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 comprising one or more covalently linked units 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 A1. q Indirectly connected to another ULM, PTM, or a combination thereof.

[0137] 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 substituted with 0-6 R L1 and / or R L2 C 3-11 Heterocyclyl, optionally substituted with 0-6 R L1 and / or R L2 The aryl group substituted by the 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 a further 0-4 R L5 a cycloalkyl and / or heterocyclyl moiety substituted by a group; wherein

[0138] 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.

[0139] 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.

[0140] 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 (number of such structural units A: q-2).

[0141] In certain embodiments, for example when q is 2, A q is a group connected to A1 and the ULM or ULM' moiety.

[0142] 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.

[0143] 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.

[0144] In certain embodiments, the linker (L) is selected from the group consisting of:

[0145]

[0146]

[0147] 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, 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 an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclyl group. In certain embodiments, the linker can be asymmetric or symmetric.

[0148] 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, about 2 to about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, or between about 2 and 4 ethylene glycol units.

[0149] Although the CLM (or ULM) group and the PTM group can be covalently linked to the linker group through any group that is suitable and stable for the chemical properties 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 through amide, ester, thioester, ketone, carbamate (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.

[0150] Exemplary PTMs

[0151] 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 that are 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 present 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 present invention. The target protein is preferably a eukaryotic protein. In certain aspects, the protein binding moiety is a haloalkane, preferably a C1-C1-C2-substituted alkyl group substituted with at least one halo, preferably at the end of the alkyl group (i.e., away from the linker or CLM group). 10 An alkyl group that can be covalently bound to a dehalogenase in a patient or subject or in a diagnostic assay.

[0152] 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 moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), as well as numerous others. The compositions described below illustrate some members of these nine 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, as well as other small molecules that can target the protein of interest. These binding moieties are preferably linked to the ubiquitin ligase binding moiety via a linker so that the target protein (to which the protein target moiety is bound) is present in close proximity to the ubiquitin ligase for ubiquitination and degradation.

[0153] 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.

[0154] In yet other embodiments, the PTM group is a haloalkyl group, wherein the alkyl group typically ranges in size from about 1 or 2 carbons to about 12 carbons, often from about 2 to 10 carbons, often from about 3 carbons to about 8 carbons, and more often from about 4 carbons to about 6 carbons. The haloalkyl group is typically a straight chain alkyl group (although branched chain alkyl groups may be used) and terminates with at least one halogen group, preferably a single halogen group, often a single chloro group. The haloalkyl PT group used in the present invention preferably has the chemical structure -(CH2) v -halo represents 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 bromo, more often Cl.

[0155] In another embodiment, the present invention provides a library of compounds. The library comprises more than one compound, wherein each composition has the formula AB, wherein A is a ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin ligase moiety as further disclosed herein) and B is a protein binding member of a molecular library, wherein A is coupled (preferably via a linker moiety) to B, and wherein the ubiquitin pathway protein binding moiety recognizes ubiquitin pathway proteins, particularly E3 ubiquitin ligases, such as cerebellum. In a specific embodiment, the library contains specific cerebellum E3 ubiquitin ligase binding moieties (e.g., a chemical compound library) bound to random target protein binding elements. Thus, the target protein is not determined a priori, and the method can be used to determine the activity of putative protein binding elements and their pharmacological value as targets after degradation by ubiquitin ligases.

[0156] 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.

[0157] On the other hand, the present invention provides therapeutic compositions 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 compositions regulate protein degradation in patients or subjects (e.g., animals, such as humans), and can be used to treat or improve disease states or conditions regulated by the degraded proteins. In certain embodiments, the therapeutic compositions as described herein can be used to practice degradation of proteins of interest for treating or improving diseases (e.g., cancer). In certain other embodiments, the disease is multiple myeloma.

[0158] In an alternative aspect, the present invention relates to a method for treating a disease state or improving the symptoms of a disease or condition in a subject in need thereof 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 in treating or improving the subject's disease or condition or its symptoms. The methods 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 overexpression of a protein (which leads to a disease state and / or condition).

[0159] In another aspect, the present invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the present invention.

[0160] The term "target protein" is used below to describe a protein or polypeptide that is bound to a compound according to the present 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, as well as 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.

[0161] Target proteins that can be bound to a protein targeting moiety and degraded by the ligase bound by the ubiquitin ligase binding moiety include any protein or peptide, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides with 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 involved in 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 microorganisms, viruses, fungi, and parasites, among many others, including humans, microorganisms, viruses, fungi, and parasites as targets for drug therapy, other animals (including domestic animals), microorganisms used as targets for testing antibiotics and other antimicrobials, and plants and even viruses, among many others.

[0162] More specifically, various drug targets of human therapeutics represent protein targets to which protein target moieties can bind and be incorporated into compounds according to the present invention. It includes proteins that can be used to restore function in a variety of polygenic diseases, including, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, 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, tryptase-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 p56lck, 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 receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA of NGF α receptor, β-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, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0163] Haloalkane dehalogenase is another target of certain compounds according to the present invention. Compounds according to the present 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 December 6, 2011, and published as WO 2012 / 078559 on June 14, 2012, the contents of which are incorporated herein by reference.

[0164] 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 with a view to a therapeutic end result.

[0165] 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 localizes / 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.

[0166] 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).

[0167] 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.

[0168] I. Heat shock protein 90 (HSP90) inhibitors:

[0169] HSP90 inhibitors as used herein include but are not limited to:

[0170] 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]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide):

[0171]

[0172] derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via a terminal amide group;

[0173] 2. HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfonyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

[0174]

[0175] wherein the linker group L or -(L-CLM) group is attached, for example, via a terminal ethynyl group;

[0176] 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:

[0177]

[0178] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via an amide group (at the amine or an alkyl group on the amine);

[0179] 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:

[0180]

[0181] wherein the linker group L or -(L-CLM) is attached, for example, via a butyl group; and

[0182] 5. The HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] (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).

[0183] II. Kinase and phosphatase inhibitors:

[0184] Kinase inhibitors as used herein include but are not limited to:

[0185] 1. Erlotinib derivative tyrosine kinase inhibitors:

[0186]

[0187] wherein R is a linker group L or a -(L-CLM) group, for example, linked via an ether group;

[0188] 2. Kinase inhibitor sunitinib (derivative):

[0189]

[0190] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, a pyrrole moiety);

[0191] 3. Kinase inhibitor sorafenib (derivative):

[0192]

[0193] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, an amide moiety);

[0194] 4. Kinase inhibitor desatinib (derivative):

[0195]

[0196] (derivatized, where R is a linker group L or -(L-CLM) attached to, for example, pyrimidine);

[0197] 5. Kinase inhibitor lapatinib (derivative):

[0198]

[0199] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via the terminal methyl group of a sulfonylmethyl group);

[0200] 6. Kinase inhibitor U09-CX-5279 (derivative):

[0201]

[0202] 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;

[0203] 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:

[0204]

[0205] YIX(1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfonyl}benzyl)urea)

[0206] Derivatized, wherein the linker group L or -(L-CLM) group is for example via i Propyl linker;

[0207]

[0208] 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

[0209] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, preferably via an isopropyl or tert-butyl group;

[0210] 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:

[0211]

[0212] 4-amino-2-[4-(tert-butylsulfamoyl]phenyl)-N-methylthieno[3,2-c]pyridine-7-carboxamide thienopyridine 19

[0213] 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;

[0214]

[0215] 4-amino-N-methyl-2-[4-(morpholin-4-yl]phenyl)thieno[3,2-c]pyridine-7-carboxamidethienopyridine 8

[0216] 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;

[0217] 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 the kinase inhibitor 07U having the following structure:

[0218]

[0219] 2-Methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine

[0220] derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a secondary amine or a terminal amino group;

[0221] 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:

[0222]

[0223] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via either terminal hydroxyl group;

[0224] 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 the kinase inhibitors XK9 and NXP (derivative) having the following structures:

[0225]

[0226] N-{4-[(1E)-N-(N-hydroxycarbamoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide;

[0227]

[0228] N-{4-[(1E)-N-aminocarboximidoylethanehydrazonoyl]PHENYL}-1H-indole-3-carboxamide

[0229] 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);

[0230] 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);

[0231] 13. The kinase inhibitor fostamatinib (derivatized) ([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 phosphate hexahydrate) (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a methoxy group);

[0232] 14. Kinase inhibitor gefitinib (derivative) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

[0233]

[0234] (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a methoxy or ether group);

[0235] 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);

[0236] 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);

[0237] 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);

[0238] 18. Kinase inhibitor Gleevec (derivative):

[0239]

[0240] (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);

[0241] 19. Kinase inhibitor pazopanib (derivative) (VEGFR3 inhibitor):

[0242]

[0243] (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);

[0244] 20. Kinase inhibitor AT-9283 (derivative) Aurora kinase inhibitor

[0245]

[0246] (wherein R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0247] 21. Kinase inhibitor TAE684 (derived) ALK inhibitor

[0248]

[0249] (wherein R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0250] 22. Kinase inhibitors Nilotanib (derivative) Abl inhibitors:

[0251]

[0252] (derivatized, where R is a linker group L or a -(L-CLM) group, for example, attached to a phenyl moiety or an aniline amine group);

[0253] 23. Kinase inhibitor NVP-BSK805 (derived) JAK2 inhibitor

[0254]

[0255] (derivatized, where R is a linker group L or a -(L-CLM) group, for example, attached to a phenyl moiety or an oxadiazole group);

[0256] 24. Alk inhibitors derived from the kinase inhibitor crizotinib

[0257]

[0258] (derivatized, where R is a linker group L or a -(L-CLM) group, for example, attached to a phenyl moiety or an oxadiazole group);

[0259] 25. Kinase inhibitors JNJ FMS (derived) inhibitors

[0260]

[0261] (derivatized, where R is a linker group L or a -(L-CLM) group attached to, for example, a phenyl moiety);

[0262] 26. Kinase inhibitors Foretinib (derivative) Met inhibitors

[0263]

[0264] (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);

[0265] 27. Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivative):

[0266]

[0267] derivatized, wherein a linker group L or a -(L-CLM) group is attached as indicated, e.g., at R;

[0268] 28. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatives):

[0269]

[0270] Derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, at R; 29. ​​BRAF (BRAF V600E ) / MEK inhibitors (derivatives):

[0271]

[0272] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R;

[0273] 30. Inhibitors of tyrosine kinase ABL (derivatives)

[0274]

[0275] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R;

[0276] 31. Kinase inhibitor OSI-027 (derived) mTORC1 / 2 inhibitor

[0277]

[0278] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R;

[0279] 32. Kinase inhibitor OSI-930 (derivative) c-Kit / KDR inhibitor

[0280]

[0281] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R; and

[0282] 33. Kinase inhibitor OSI-906 (derived) IGF1R / IR inhibitor

[0283]

[0284] Derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at R;

[0285] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group on the piperazine moiety).

[0286] III. HDM2 / MDM2 inhibitors:

[0287] As used herein, HDM2 / MDM2 inhibitors include but are not limited to:

[0288] 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 (derivatives) as described below, and all derivatives and analogs thereof:

[0289]

[0290] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at a methoxy or hydroxyl group);

[0291]

[0292] (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, at a methoxy or hydroxyl group);

[0293]

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

[0295] 2. trans-4-iodo-4'-boryl-chalcone

[0296]

[0297] (derivatized, wherein the linker group L or -(L-CLM) group is attached, for example, via a hydroxyl group).

[0298] IV. Compounds Targeting Human BET Bromodomain-Containing Proteins:

[0299] Compounds targeting human BET bromodomain-containing proteins include, but are not limited to, compounds related to the targets described below, where "R" indicates the site for attachment of a linker group L or -(L-CLM) group, for example:

[0300] 1.JQ1, Filippakopoulos et al. Selective inhibition of BETbromodomains. Nature (2010):

[0301]

[0302] 2. I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic HistoneMimic. Nature (2010). Chung et al. Discovery and Characterization of Small MoleculeInhibitors of the BET Family Bromodomains. J. Med Chem. (2011):

[0303]

[0304] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.

[0305]

[0306] 4.I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia. Nature (2011):

[0307]

[0308] (wherein R in each case indicates the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0309] V.HDAC inhibitors:

[0310] HDAC inhibitors (derivatives) include but are not limited to:

[0311] 1. Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999).

[0312]

[0313] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group); and

[0314] 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);

[0315] VI. Human lysine methyltransferase inhibitors:

[0316] Human lysine methyltransferase inhibitors include but are not limited to:

[0317] 1. Chang et al. Structural Basis for G9a-Like protein LysineMethyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16 (3) 312.

[0318]

[0319] (derivatized, where "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group);

[0320] 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.

[0321]

[0322] (derivatized, where "R" indicates a potential site for attachment, e.g., a linker group L or a -(L-CLM) group);

[0323] 3. azacitidine (derivatized) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (derivatized wherein a linker group L or a -(L-CLM) group is attached, for example, via a hydroxyl or amino group); and

[0324] 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (derivatized, wherein a linker group L or a -(L-CLM) group is attached, for example, via either the hydroxyl group or at the amino group).

[0325] VII. Angiogenesis Inhibitors:

[0326] Angiogenesis inhibitors include but are not limited to:

[0327] 1. GA-1 (derivative) and its derivatives and analogs having a structure and conjugated to a linker group 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;

[0328] 2. Estradiol (derivatized), which can 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;

[0329] 3. Estradiol, testosterone (derived) and related derivatives, including but not limited to DHT and its derivatives and analogs, having the structure and conjugated to a linker group L or a -(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

[0330] 4. Ovalicin, fumagillin (derivatives) and derivatives and analogs thereof having the structure 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.

[0331] VIII. Immunosuppressive compounds:

[0332] Immunosuppressive compounds include, but are not limited to:

[0333] 1. AP21998 (derivatized) having the structure and conjugated to a linker group L or a -(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;

[0334] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (derivatized wherein the linker group L or the -(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);

[0335] 3. methotrexate (derivatized, wherein a linker group or a -(L-CLM) group may be attached, for example, to either of the terminal hydroxyl groups);

[0336] 4. ciclosporin (derivatized, wherein a linker group or a -(L-CLM) group can be attached, for example, at either of the butyl groups);

[0337] 5. Tacrolimus (FK-506) and rapamycin (derivatized wherein a linker group L or a -(L-CLM) group may be attached, for example, at one of the methoxy groups); and

[0338] 6. Actinomycin (derivatized wherein a linker group L or a -(L-CLM) group may be attached, for example, at one of the isopropyl groups).

[0339] IX. Compounds targeting the aryl hydrocarbon receptor (AHR):

[0340] Compounds targeting the aryl hydrocarbon receptor (AHR) include, but are not limited to:

[0341] 1. apigenin (derivatized by conjugation to a linker group L or a -(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

[0342] 2. SR1 and LGC006 (derivatized so as to incorporate a linker group L or -(L-CLM)) as described in Boitano et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 2010 Sep 10: Vol. 329 No. 5997 pp. 1345-1348.

[0343] X. Compounds targeting RAF receptor (kinase):

[0344]

[0345] PLX4032

[0346] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0347] XI. Compounds targeting FKBP:

[0348]

[0349] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0350] XII. Compounds Targeting Androgen Receptor (AR)

[0351] 1. RU59063 ligand for androgen receptor (derivative)

[0352]

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

[0354] 2. SARM ligands for androgen receptor (derivatives)

[0355]

[0356] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0357] 3. Androgen receptor ligand DHT (derived)

[0358]

[0359] (derivatized, wherein "R" indicates a site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0360] 4.MDV3100 ligand (derivative)

[0361]

[0362] 5.ARN-509 ligand (derivatized)

[0363]

[0364] 6. Hexahydrobenzisoxazole

[0365]

[0366] 7. Tetramethylcyclobutane

[0367]

[0368] XIII. Compounds Targeting Estrogen Receptor (ER) ICI-182780

[0369] 1. Estrogen receptor ligand

[0370]

[0371] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group).

[0372] XIV. Compounds Targeting Thyroid Hormone Receptor (TR)

[0373] 1. Thyroid hormone receptor ligand (derivative)

[0374]

[0375] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group and MOMO indicates methoxymethoxy).

[0376] XV. Compounds Targeting HIV Protease

[0377] 1. HIV protease inhibitors (derivatives)

[0378]

[0379] (Derivatized, where "R" indicates the site for attachment of the linker group L or -(L-CLM) group.) See J. Med. Chem. 2010, 53, 521-538.

[0380] 2. HIV protease inhibitors

[0381]

[0382] (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.

[0383] XVI. Compounds Targeting HIV Integrase

[0384] 1. HIV integrase inhibitors (derivatives)

[0385]

[0386] (Derivatized, where "R" indicates the site for attachment of the linker group L or -(L-CLM) group.) See J. Med. Chem. 2010, 53, 6466.

[0387] 2. HIV integrase inhibitors (derivatives)

[0388]

[0389] 3. HIV integrase inhibitor Isetntress (derivative)

[0390]

[0391] (Derivatized, where "R" indicates the site for attachment of the linker group L or -(L-CLM) group.) See J. Med. Chem. 2010, 53, 6466.

[0392] XVII. Compounds Targeting HCV Protease

[0393] 1. Inhibitors of HCV protease (derivatives)

[0394]

[0395] (derivatized, wherein "R" indicates the site for attachment of a linker group L or a -(L-CLM) group).

[0396] XVIII. Compounds Targeting Acyl-Protein Thioesterases 1 and 2 (APT1 and APT2)

[0397] 1. Inhibitors of APT1 and APT2 (derivatives)

[0398]

[0399] (derivatized, wherein "R" indicates the 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.

[0400] Therapeutic compositions

[0401] The following pharmaceutical compositions represent another aspect of the present disclosure and comprise an effective amount of at least one bifunctional compound as described herein in combination with one or more of the compounds further described herein (all in effective amounts), and a pharmaceutically effective amount of a carrier, additive, or excipient.

[0402] The present disclosure includes, where applicable, compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. The acids used to prepare the 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, saccharates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates [i.e., 1,1'-methylenebis-(2-hydroxy-3-naphthoate)], as well as many others.

[0403] 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-(meglumine); and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines.

[0404] 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 drip) 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 routes of administration. 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. The administration of compounds according to the present disclosure can also be used, 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 a pharmaceutically acceptable carrier, additive or excipient. 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 the form of 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.

[0405] 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.

[0406] The compositions 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.

[0407] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally used as solvents or suspending media. For this purpose, any bland, non-volatile oil may be used, including synthetic mono- or diglycerides. Fatty acids (such as oleic acid) and their glyceride derivatives may be used to prepare injectables, as may natural, pharmaceutically acceptable oils such as olive oil or castor oil, particularly in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0408] The pharmaceutical compositions 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.

[0409] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent 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.

[0410] The pharmaceutical compositions described herein can also be administered topically. Suitable topical formulations are readily prepared for use in each of these areas or organs. Topical administration to the lower intestinal tract can be achieved with a rectal suppository formulation (see above) or with a suitable enema formulation. Topically acceptable transdermal patches can also be used.

[0411] For topical administration, the pharmaceutical composition can be formulated in the form of a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred aspects of the present invention, the compound can be applied to a stent surgically implanted in a patient to inhibit or reduce the likelihood of occlusion of the stent in the patient.

[0412] 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.

[0413] 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.

[0414] The pharmaceutical compositions 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 normal saline using benzyl alcohol or other suitable preservatives, absorption promoters (to enhance bioavailability), fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0415] 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, and the composition should preferably be formulated to contain between about 0.05 mg and 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.

[0416] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound 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.

[0417] A patient or subject in need of therapy using a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present 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 stimulating agents as otherwise identified herein.

[0418] The 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.

[0419] 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 patient being treated. 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.

[0420] The compound is preferably administered in any suitable unit dosage form, including but not limited to unit dosage forms 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.

[0421] 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 physiological saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0422] 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, the 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 merely exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once; or it can be divided into multiple smaller doses administered at different time intervals.

[0423] Oral compositions will typically include an inert diluent or edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, buccal tablets or capsules. Pharmaceutically compatible binding agents and / or adjuvant substances can be included as part of the composition.

[0424] Tablets, pills, capsules, lozenges, and the like 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 sterote; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor. When the unit dosage form is a capsule, it may contain, in addition to substances of the types mentioned above, a liquid carrier such as a fatty oil. In addition, the unit dosage form may contain various other substances that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.

[0425] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0426] 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 stimulating agents, 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 stimulating agent or a wound healing agent, including an antibiotic.

[0427] 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 oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; 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.

[0428] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0429] 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 microencapsulated 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.

[0430] Liposomal suspensions can also be pharmaceutically acceptable carriers. They 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 stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidylphosphatidylcholine 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.

[0431] Treatment

[0432] 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 modulates protein degradation in a patient or subject (e.g., an animal, such as a human) and can be used to treat or ameliorate a disease state or condition modulated by the degraded protein.

[0433] As used herein, the term "treat / treating / treatment" refers to any effect that provides a benefit to a patient to whom the compounds of the present invention can be administered, including any disease state or condition to which the compounds of the present invention bind. Disease states or conditions that can be treated using the compounds of the present invention are described above, including cancer.

[0434] The present invention provides therapeutic compositions 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 comprises administering a bifunctional compound as described herein, the bifunctional compound comprising a CLM and a PTM preferably connected by a linker moiety as further 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, thereby resulting in degradation / inhibition of the effect of the target protein and control of protein levels. The control of protein levels 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 the cell (e.g., patient's cell). In certain embodiments, the methods comprise administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another biologically active agent, or a combination thereof.

[0435] In other embodiments, the present invention provides a method for treating or ameliorating 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 ameliorating the disease, disorder, or symptom thereof in the subject.

[0436] In another aspect, the present invention provides methods of identifying the effects of degradation of a protein of interest in a biological system using the compounds according to the present invention.

[0437] In another embodiment, the present invention relates to a method of treating a disease state or condition regulated by a protein in a human patient in need thereof, wherein degradation of the protein produces 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 present invention, optionally in combination with another biologically active agent. The disease state or condition may be caused by a microbial agent or other exogenous agent (such as a virus, bacteria, fungus, protozoa or other microorganism), or may be caused by overexpression of a protein that results in the disease state and / or condition.

[0438] The term "disease state or condition" is used to describe any disease state or condition in which protein dysregulation (i.e., elevated levels of a protein expressed in a patient) occurs and in which degradation of one or more proteins in the patient can provide beneficial therapy or relief of symptoms to the patient in need thereof. In some cases, the disease state or condition can be cured.

[0439] Disease states or conditions that can be treated using the compounds according to the present 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.

[0440] 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.

[0441] Still other disease states or conditions that can be treated by the compounds according to the present invention include, inter alia, ceruloplasminemia, achondroplasia type II, achondroplasia, apico, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, 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 digits (Marfan syndrome), Stickler syndrome, arthrogryposis multiplex congenita (Ehlers-Danlossyndrome, arthrogryposis type), ataxia-telangiectasia, Rett syndrome, essential pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Beare-Stevenson cutis gyrata syndrome, familial Mediterranean fever, Benjamin syndrome 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 (tubercular sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), pan-hallucinoma syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronzin cirrhosis (hemochromatosis), bulbar muscular dystrophy (Kennedy's disease), Burger-Grutz syndrome 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), otospondyloepiphyseal 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-dysfacial syndrome, Cooley's anemia (beta-thalassemia), copper storage diseases (Wilson's disease), 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-Stevens 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 (pseudoxanthoma elasticum), Gunther disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren syndrome syndrome), sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, achondroplasia, hypochromic anemia, immune system disorders (including X-linked severe combined immunodeficiency), Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney 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 Knisster dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insley syndromesyndrome), Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome syndrome), hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary Alzheimer's disease, 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 1), relapsing 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 syndrome), Breast Sarcoma, Leukemia, and Adrenal (SBLA) syndrome, Tuberous Sclerosis (Tuberous Sclerosis), SDAT, Congenital SED (Spondyloepiphyseal Dysplasia Congenita), Stradwick SED (Spondyloepiphyseal Dysplasia Congenita), SEDc (Spondyloepiphyseal Dysplasia Congenita), SEMD, Stradwick type (Spondyloepiphyseal Dysplasia Congenita), Shprintzen syndrome, Skin Pigmentation Disorders, Smith-Lemli-Opitz Syndromesyndrome), South African hereditary porphyrias (variant porphyrias), 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, schwannoid neuropathy (a 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-Zawrey-Müller syndrome, and xeroderma pigmentosum.

[0442] 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 generally 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, unless appropriately treated, lead to the death of the patient. 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 can be treated by the compounds of the present 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; myeloproliferative 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.

[0443] The term "biologically active agent" is used to describe an agent other than a compound 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 (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 administered, and include, for example, anticancer agents, antiviral agents (especially including anti-HIV agents and anti-HCV agents), antimicrobial agents, antifungal agents, and the like.

[0444] The term "another anticancer agent" is used to describe an anticancer agent that can be used in combination with a compound 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 (BCG) 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, epithelione 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, immune globulin white, nitrogen mustard, methylprednisolone, ibritigumomab tiuxetan, androgens, 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.

[0445] The term "anti-HIV agent" or "another anti-HIV agent" includes, inter alia, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., those not representing the present invention), protease inhibitors, fusion inhibitors, where exemplary compounds may include, inter alia, 3TC (Lamivudine), AZT (Zidovudine), (-)-FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Raci HIV, including but not limited to: HIV, 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), fusions and mixtures thereof, including anti-HIV compounds in clinical trials or development.

[0446] Other anti-HIV agents that can be co-administered with the compounds according to the present invention include, for example, other NNRTIs (i.e., in addition to the NNRTIs according to the present 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)-2-thiazolinone]-1-yl]piperazine, piperazine, 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)thymidine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymidine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymidine) ), 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-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivatives), N-[2-(3-fluorofuryl)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-methylpyridine-2(1H)-thione (2-pyridone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methylpyridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, Suramin Sodium, TBZ (thiazolinone benzimidazole, NSC 625487), thiazolidinol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38, and UC-84.

[0447] 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 that is present to increase the solubility of the compound in the gastrointestinal fluid of the patient's gastrointestinal tract so as to promote dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, salts derived from pharmaceutically acceptable inorganic or organic bases and acids. 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 art. Sodium and potassium salts are particularly preferred as neutralized salts of the phosphates according to the present invention.

[0448] 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.

[0449] General synthetic method

[0450] The synthesis of bifunctional molecules as described herein is realized and optimized and can be carried out in a step-by-step or modular manner. For example, if no suitable ligand is immediately available, then identifying compounds that are bound to the target molecule can involve high or medium yield screening activities. It is common that the initial ligand requires iterative design and optimization cycles to improve the suboptimal aspects as identified by data from suitable in vitro and pharmacological and / or ADMET analyses. A part of the optimization / SAR activity will be to detect the tolerated substitution of the ligand and can be the position of the suitable position for connecting the linker chemicals previously mentioned herein. When crystallization or NMR structural data are available, it can be used to focus on such synthesis attempts.

[0451] Ligands for E3 ligases, ie ULM / CLM, can be identified and optimized in a very similar manner.

[0452] Using PTMs and ULMs (e.g., CLMs), one skilled in the art can apply known synthetic methods to their combination with or without a linker moiety. The linker moiety can be synthesized with 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 resulting bifunctional molecules can undergo iterative design and optimization cycles to identify molecules with desirable properties.

[0453] Some non-limiting exemplary methods for producing CLMs as described herein are summarized below.

[0454]

[0455]

[0456]

[0457]

[0458]

[0459] 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.

[0460] Alternatively, as shown in Representative Reaction 2, 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. The same type of intermediate phthalimide can also be reacted with Lawesson's reagent, followed by a dehydration step, to provide the thio analogue, as shown in Representative Reactions 8 and 9.

[0461] Examples of protected 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivatives (such as N- 1 -BOC species) can be deprotected by using a reagent such as TFA or silica in this case to afford the target 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione derivative.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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 combination with a rhodium(II) catalyst and silver carbonate to provide the desired product.

[0466] 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 products.

[0467] 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.

[0468] 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.

[0469] 3-(2,6-Dioxopiperidin-3-yl)-3,4-dihydro-2H-1,3-benzoxazine-2,4-dione analogs can be prepared by activation of salicylic acid with chloroformic acid followed by condensation with 3-aminopiperidine-2,6-dione, as shown in Representative Reaction 17.

[0470] As shown in Representative Reaction 18, 3,3-dichloro-2,1λ 6 -Benzothiolene-1,1-diones 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.

[0471] 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.

[0472] 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).

[0473] 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.

[0474] N 1 Preparation of -substituted compounds such as 2-[1-(benzyloxy)-2,6-dioxopiperidin-3-yl]-2,3-dihydro-1H-isoindole-1,4-dione (Representative Reaction 22) can be achieved by reacting 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)glutaric acid with N-benzylhydroxylamine and trifluoroacetic anhydride.

[0475] 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.

[0476] 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.

[0477] 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 taken to full cyclization by using a dehydrating agent.

[0478] 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.

[0479] 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 through 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.

[0480] In some cases, protecting group strategies and / or functional group interconversion (FGI) may be required to facilitate the preparation of the desired substance. 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 G.M. Wuts and Theodora W. Greene (Wiley) and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley).

[0481] Protein level control

[0482] 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.

[0483] The following examples are provided to help describe the present invention but should not be construed as limiting the invention in any way.

[0484] Specific embodiments of the present disclosure

[0485] The present disclosure encompasses the following specific embodiments. These following embodiments may include all of the features enumerated in the preceding embodiments as specified. Where applicable, the following embodiments may also include any of the features enumerated inclusively or alternatively in the preceding embodiments (e.g., embodiment (8) may include the features enumerated in embodiment (1) and / or the features of any of embodiments (2) to (7)).

[0486] (1) A compound having a chemical structure comprising:

[0487] L-CLM

[0488] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein

[0489] L is a linker group; and

[0490] CLM is the E3 ubiquitin ligase binding moiety of cerebellum protein.

[0491] wherein the linker group is chemically linked to the CLM.

[0492] (2) The compound according to (1), wherein the compound has a chemical structure comprising:

[0493] PTM-L-CLM

[0494] in

[0495] PTMs are protein-targeting moieties that bind to target proteins or peptides.

[0496] wherein the PTM is chemically linked to the CLM via the linker group.

[0497] (3) The compound according to (1), wherein the CLM comprises a chemical group derived from imide, thioimide, amide or thioamide.

[0498] (4) The compound according to (1), wherein the chemical group is a phthalimido group or an analogue or derivative thereof.

[0499] (5) The compound according to (1), wherein the CLM is thalidomide, lenalidomide, pomalidomide, an analog thereof, an isostere thereof, or a derivative thereof.

[0500] (6) The compound of (1), wherein the compound further comprises a ULM, a second CLM, a CLM′, or a plurality thereof or a combination thereof, wherein

[0501] ULM is the binding part of E3 ubiquitin ligase,

[0502] The second CLM has the same chemical structure as the CLM,

[0503] CLM' is a cerebellar protein E3 ubiquitin ligase binding portion that is structurally distinct from the CLM.

[0504] wherein the ULM, the second CLM, the CLM', or a plurality thereof, or a combination thereof, are optionally coupled to another linker group.

[0505] (7) The compound according to (1), wherein the CLM has a chemical structure represented by:

[0506]

[0507] in

[0508] W is selected from the group consisting of: CH2, CHR, C=O, SO2, NH and N-alkyl;

[0509] Each X is independently selected from the group consisting of: O, S and H2;

[0510] Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0511] Z is selected from the group consisting of: O, S and H2;

[0512] 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';

[0513] Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0514] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0515] 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;

[0516] R' and R" are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0517] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0518] R n including functional groups or atoms,

[0519] Where n is an integer from 1 to 4, and

[0520] When n is 1, R n is modified to be covalently attached to the linker group (L), and

[0521] 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 is optionally modified to be covalently attached to a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0522] (8) The compound according to (1), wherein the CLM is selected from the group consisting of:

[0523] 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;

[0524] 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;

[0525] 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;

[0526] 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;

[0527] 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;

[0528] 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;

[0529] 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;

[0530] 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;

[0531] 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;

[0532] 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;

[0533] 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;

[0534] 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;

[0535] 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;

[0536] 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-[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)acetamide;

[0537] 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-[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;

[0538] 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-(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;

[0539] 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;

[0540] 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;

[0541] 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;

[0542] 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;

[0543] 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;

[0544] 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;

[0545] 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-[(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;

[0546] 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-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)propyl]acetamide;

[0547] 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-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propyl)acetamide;

[0548] 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-[(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;

[0549] 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-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethyl]acetamide;

[0550] 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-[(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;

[0551] 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-[(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;

[0552] 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-[(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;

[0553] 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;

[0554] 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-{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;

[0555] 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-{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;

[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-{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

[0557] 2-[(9R)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0 2 , 6 ]Tridec-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-azadodec-12-yl}oxy]phenyl)acetamide.

[0558] (9) The compound according to (1), wherein the linker group (L) comprises a chemical structural unit represented by the following formula:

[0559] -A q -

[0560] in

[0561] q is an integer greater than 1; and

[0562] 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 substituted with 0-6 R L1 and / or R L2 C 3-11 Heterocyclyl, optionally substituted with 0-6 R L1 and / or R L2 The aryl group substituted by the group, optionally substituted by 0-6 R L1 and / or R L2 a heteroaryl group substituted with a group; wherein

[0563] R L1 、R L2 、R L3 、R L4 and R L5 are 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

[0564] When q is greater than 1, R L1 or R L2 Each independently can be linked to another A group to form a further R L5 The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0565] (10) The compound according to (2), wherein the PTM is a protein target portion that binds to a target protein, 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.

[0566] (11) A compound according to (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, 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, trypanosome 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 p56lck, 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-1), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, c-Kit, TGF-β-activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, 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 α receptor, β-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytoplasmic 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, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0567] (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 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.

[0568] (13) The compound 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.

[0569] (14) A composition comprising the compound described in (2).

[0570] (15) A pharmaceutical composition comprising the compound described in (2), and a pharmaceutically acceptable carrier, additive and / or excipient.

[0571] (16) The pharmaceutical composition as described in (15), further comprising a bioactive agent.

[0572] (17) The pharmaceutical composition according to (16), wherein the bioactive agent is an antiviral agent.

[0573] (18) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HIV agent.

[0574] (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.

[0575] (20) The pharmaceutical composition according to (17), wherein the antiviral agent is an anti-HCV agent.

[0576] (21) The pharmaceutical composition according to (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.

[0577] (22) The pharmaceutical composition according to (16), wherein the bioactive agent is an anticancer agent.

[0578] (23) The composition according to (22), wherein the anticancer agent is selected from the group consisting of: everolimus, trabectedin, abraxine, 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, IPdR1KRX-0402, Lucanthone, LY 317615, Newdi, Vitspan, Rta744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib, PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, 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, where x = 1 to 2.4], goserelin acetate, leuprorelin 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, jonafarnib, BMS-214662, tipifarnib, amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, so Rafenib, KRN951, amineglutethimide, aminebenzimidazole, 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, leuprorelin, levamisole, lomustine, dichloromethane, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nivolumab Amitraz, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, 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, vitaxine, 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, zoledronic acid, 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, isoflurane, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, adipronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium 89, carboplatin Sopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, dalperidol, dronabilol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0579] (24) A method for inducing degradation of a target protein in a cell, comprising:

[0580] An effective amount of the compound described in (2) is administered to the cells.

[0581] (25) A method for inducing degradation of a target protein in a cell, comprising:

[0582] An effective amount of the compound described in (10) is administered to the cells.

[0583] (26) A method for inducing degradation of a target protein in a cell, comprising:

[0584] An effective amount of the compound described in (11) is administered to the cells.

[0585] (27) A method of inducing degradation of a target protein in a patient, comprising

[0586] An effective amount of the compound described in (2) is administered to the patient.

[0587] (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

[0588] An effective amount of the compound according to (2) is administered.

[0589] (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 error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Duce 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.

[0590] (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.

[0591] (31) The method of (28), wherein the disease state or condition is ceruloplasminemia, achondroplasia type II, achondroplasia, apico, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuria ocheropathy, 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. Symptoms include: inflammatory bowel syndrome, anemia, diffuse angiokeratoma of the corpus, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, spider digits (Marfan syndrome), Stickler syndrome, arthrogryposis multiplex congenita (Ehlers-Danlos syndrome with arthrogryposis type), ataxia-telangiectasia, Rett syndrome, essential 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 sideroblastic anemia, and Bonavi Ulrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion disease, Burt-Hoeg-Dub syndrome, brittle bone disease (osteogenesis imperfecta), pan-thumb-bigtoe syndrome (Rubinstein-Taybi syndrome), bronze diabetes / bronz cirrhosis (hemochromatosis), bulbar muscular atrophy (Kennedy disease), Berger-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous granulomatous disease (CGD), camptomelia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cry-a-cat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, soft tissue dysplasia 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 anomaly syndrome, Wencure'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-Stevens syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Stradwick type), Duchenne-Becker muscular dystrophy (DBMD), Ussher syndrome, degenerative neurological diseases (including deGrown syndrome and DeGelis-Sotas syndrome), developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse glomerulosclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythrocytic 5-aminolevulinic acid synthetase deficiency, erythropoietic porphyria, red blood cells 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, Hollgren 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 malformations. Bone dysplasia, 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, Knistedt dysplasia, intermittent dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders (including Knistedt dysplasia), Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Mink syndrome, neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney dysplasia 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-Rabat-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary Alzheimer's disease, 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 1), relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Reck 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-Lemli-Opitz syndrome, South Non-hereditary porphyrias (variant porphyrias), 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, leukoencephalopathy (a 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), Frohlich's disease, Waardenburg syndrome, Warburg-St. Joseph-Friedrich syndrome, Weissenbacher-Zawrey-Müller syndrome, Wolff-Hirschhorn syndrome, Wolff-Richhorn periodic disorder, Weissenbacher-Zawrey-Müller syndrome, and xeroderma pigmentosum.

[0592] (32) The method of (28), wherein the disease state or condition is cancer.

[0593] (33) The method of (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, 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.

[0594] (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 lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML.

[0595] (35) A compound library comprising more than one compound according to (1).

[0596] (36) A method for identifying a compound containing an E3 ubiquitin ligase binding moiety that recognizes cerebellin (CRBN), comprising:

[0597] The test compound was incubated with the CRBN protein;

[0598] The amount of the test compound bound to the CRBN protein is determined.

[0599] (37) A cerebellum protein E3 ubiquitin ligase binding moiety (CLM) having a chemical structure represented by:

[0600]

[0601]

[0602] in

[0603] W is selected from the group consisting of: CH2, CHR, C=O, SO2, NH and N-alkyl;

[0604] Each X is independently selected from the group consisting of: O, S and H2;

[0605] Y is selected from the group consisting of NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S;

[0606] Z is selected from the group consisting of: O, S and H2;

[0607] 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';

[0608] Q1, Q2, Q3 and Q4 represent carbon C substituted by a group independently selected from the group consisting of R', N or N-oxide;

[0609] A is independently selected from the groups alkyl, cycloalkyl, Cl and F;

[0610] 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;

[0611] R' and R" are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl;

[0612] represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

[0613] R n including functional groups or atoms,

[0614] Where n is an integer from 1 to 4.

[0615] (38) The CLM as described in (37), wherein the Rn Included are functional groups or atoms that are 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.

[0616] (39) The CLM of (38), wherein the ULM is a second CLM, a CLM′, or any combination or multiples thereof, wherein

[0617] The second CLM has the same chemical structure as the CLM, and

[0618] The CLM' is structurally different from the CLM. Example

[0619] A. Determination

[0620] 1. CRBN Assay - Cloning, Expression, and Purification of Human CRBN and DDB1

[0621] 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).

[0622] The cDNAs of the CRBN and DDB1 genes can be amplified by PCR using Pfusion (NEB) as the polymerase and the following primer sequences:

[0623]

[0624] CRBN can be cloned into pBV-ZZ-HT-LIC, pBV-GST-LIC, and pMA-HT-LIC using ligation-independent cloning, and DDB1 into pBV-notag-LIC. For cloning into the mammalian vector pMA-HT-LIC, the CRBN-Flag-reverse oligomer adds a C-terminal FLAG tag for immunodetection. DDB1-Rev adds a StrepTag. The ZZ-tag is required for high expression of soluble CRBN; without it, His-CRBN is expressed at low levels, while GST-CRBN causes protein aggregation. Recombinant baculoviruses expressing 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 using unsupplemented ESF921 medium from Expression Systems in 10 L wave bags at 27° C. Cells were harvested by centrifugation 48 hours after infection and the paste was resuspended in PBS plus 5× protease inhibitor cocktail (Roche, Indianapolis, IN).

[0625] All subsequent protein purification steps were carried out at 4 ° C. Frozen cells were 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 clear supernatant. Nickel-agarose and S200 Sephacryl chromatography were used to purify CRBN-DDB1 on an AKTA-xpress system (GE Healthcare). The complex was then further purified by a second pass on an 8ml MonoQ column using anion exchange chromatography and S-200 gel filtration. CRBN-DDB1 was identified by SDS-PAGE, and the fractions containing CRBN-DDB1 were pooled and stored at -70 ° C.

[0626] 2. Fluorescent Thermal Melting Assay to Measure Binding of Compounds to Recombinant CRBN

[0627] Assays are standard to those skilled in the art, as typified 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).

[0628] 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 according to Pantoliano et al. (Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E et al. High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 2001; 6: 429-440). 2 mg of protein 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 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.

[0629] 3. LCMS method

[0630] Analyses were performed on a Poroshell 120EC C18 column (50 mm x 3.0 mm id 2.7 μm packing diameter) at 45°C.

[0631] The solvents used were:

[0632] A = 0.1% v / v solution of formic acid in water.

[0633] B = 0.1% v / v solution of formic acid in acetonitrile.

[0634] The gradient used was as follows:

[0635]

[0636] UV detection was the average signal from wavelengths of 210 nm to 350 nm, and mass spectra were recorded on a mass spectrometer using positive ion mode electrospray ionization.

[0637] The mobile phases and gradients used when the compounds were subjected to preparative HPLC purification are described below.

[0638] 4. Preparative HPLC (Formic Acid Modifier)

[0639] HPLC analyses were performed on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0640] The solvents used were:

[0641] A = 0.1% v / v solution of formic acid in water.

[0642] B = acetonitrile.

[0643] 5. Preparative HPLC (ammonium bicarbonate modifier)

[0644] HPLC analyses were performed on an X Bridge RP18 OBD column (150 mm x 19 mm id, 5 μm packing diameter) at ambient temperature.

[0645] The solvents used were:

[0646] A = 10 mM ammonium bicarbonate aqueous solution.

[0647] B = acetonitrile.

[0648] For each preparative purification, regardless of the modifier used, the gradient used depended on the retention time of the particular compound undergoing purification as recorded in analytical LCMS.The flow rate was 20 mL / min.

[0649] UV detection is a signal from a wavelength of 254 nm or 220 nm.

[0650] Although preferred embodiments of the present invention have been shown and described herein, it will be understood that such embodiments are provided by way of example only. Those skilled in the art will appreciate numerous variations, modifications, and substitutions without departing from the spirit of the present invention. Therefore, it is intended that the appended claims encompass all such variations that fall within the spirit and scope of the present invention.

[0651] B. Synthesis:

[0652] The synthetic details of the examples included below represent general procedures for the syntheses of the broader example sets.

[0653] 1. 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione

[0654]

[0655] Step 1: 4-Fluoroisobenzofuran-1,3-dione

[0656]

[0657] 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 from 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).

[0658] Step 2: 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid

[0659]

[0660] 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).

[0661] Step 3: 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione

[0662]

[0663] 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-dioxopiperidine-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).

[0664] 2. N-(3-(5-bromo-2-chloropyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide

[0665]

[0666] Step 1: tert-Butyl N-{3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}-N-methylcarbamate

[0667]

[0668] 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.

[0669] Step 2: {3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl}(methyl)amine

[0670]

[0671] 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.

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

[0673]

[0674] 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 (ESI) + ):m / z=363.04 / 365.04[MH + ], t R =2.18min.

[0675] 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

[0676]

[0677] The title compound was prepared according to the procedure described in WO2011 / 143660.

[0678] 4. (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0679] The title compound was prepared according to the procedure described in Patch, RJ et al. J. Med. Chem. 2011, 54, 788-808.

[0680] 5. 4-[3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

[0681]

[0682] The title compound was prepared according to the procedure described in Jung, ME et al. J. Med. Chem. 2010, 53, 2779-2796.

[0683] 6. 2-Chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutyloxy)benzonitrile hydrochloride salt

[0684]

[0685] The title compound was prepared according to the procedure described in Guo, C. et al. J. Med. Chem. 2011, 54, 7693-7704.

[0686] 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]

[0687]

[0688] (Compound structure No. 17 shown in Table 1)

[0689] Step 1: 2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[0690]

[0691] A mixture of 2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (3 g, 5.96 mmol), 4-nitrophenol (813 mg, 5.84 mmol) and potassium carbonate (1.65 g, 11.94 mmol) in anhydrous N,N-dimethylformamide (20 mL) was stirred at 50 ° C overnight. The mixture was cooled to room temperature and poured into water (60 mL), then extracted with ethyl acetate (80 mL×3). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (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)

[0692] Step 2: [1-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene]

[0693]

[0694] 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-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)-4-nitrobenzene (865 mg) as a yellow oil.

[0695] Step 3: [2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethanamine]

[0696]

[0697]

[0146] 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 a nitrogen atmosphere for 14 hours. The volatiles were removed under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (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).

[0698] Step 4: tert-Butyl 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0699]

[0700] A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethanamine (661 mg, 2.1 mmol), triethylamine (449 mg, 4.43 mmol) and di-tert-butyl dicarbonate (505 mg, 2.31 mmol) in dichloromethane (25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (100 ml), washed with water (30 mL × 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).

[0701] Step 5: tert-Butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0702]

[0703] 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, and 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 provide tert-butyl 2-(2-(2-(2-(4-aminophenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate (512 mg, 67% yield) as a yellow oil.

[0704] Step 6: tert-Butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)ethoxy)ethoxy)ethylcarbamate

[0705]

[0706] 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.

[0707] Step 7: N-(3-(2-(4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide

[0708]

[0709] A mixture of tert-butyl 2-(2-(2-(2-(4-(5-bromo-4-(3-(N-methylcyclobutanecarboxamido)propylamino)pyrimidin-2-ylamino)phenoxy)ethoxy)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 (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)phenylamino)-5-bromopyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide (18 mg, 52% yield) as a yellow oil.

[0710] 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

[0711]

[0712] 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 and partitioned between ethyl acetate (100 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC to give N-(3-(5-bromo-2-(4-(2-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenylamino)pyrimidin-4-ylamino)propyl)-N-methylcyclobutanecarboxamide as a yellow solid (10.2 mg, 40% yield). 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).

[0713] 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

[0714]

[0715] (Compound structure No. 14 shown in Table 1)

[0716] Step 1: (2-(2,6-dioxopiperidin-3-yl)-4-(2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethylamino)isoindoline-1,3-dione

[0717]

[0718] A mixture of 2-(2-(2-(2-(4-nitrophenoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethanamine (128 mg, 0.41 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (112.5 mg, 0.41 mmol), and N-ethyl-N-isopropylpropan-2-amine (105 mg, 0.81 mmol) in 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-(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.

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

[0720]

[0721] 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 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.

[0722] 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

[0723]

[0724] To the reaction mixture of 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-tetramethyluronium hexafluorophosphate) (82 mg, 0.21 mmol). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 20 minutes. The mixture was poured into water (25 mL) and extracted with ethyl acetate (35 mL x 2). The combined organic phases were washed with water (20 mL) and brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by preparative TLC to give 2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(2-(2-(2-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-ylamino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)acetamide as a yellow solid (52 mg, 52% yield). 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).

[0725] 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

[0726]

[0727] (Compound structure No. 22 shown in Table 1)

[0728] 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

[0729]

[0730] A mixture of (Z)-4-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (1.0 g, 2.3 mmol), potassium carbonate (1.0 g, 6.9 mmol) and 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 flash column chromatography on silica gel (eluting with 10-30% ethyl acetate in hexanes) to afford (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.

[0731] Step 2: (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile

[0732]

[0733] 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.

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

[0735]

[0736] A mixture of the above (Z)-4-(4-((3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (130 mg, crude), triphenylphosphine (100 mg, 0.34 mmol) in water (0.2 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (eluting with 3-5% methanol in dichloromethane) to give (Z)-4-(4-((3-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-3-(trifluoromethyl)benzonitrile (60 mg, 8% yield over two steps) as a yellow oil. LC-MS(ES + ):m / z 552.1[MH + ], t R =2.15min.

[0737] 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

[0738]

[0739] 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- (2,6-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).

[0740] 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

[0741]

[0742] (Compound structure No. 1 shown in Table 1)

[0743] Step 1: 1,1,1,16-Tetraphenyl-2,5,8,11,15-pentaoxahexadecane

[0744]

[0745] 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) and extracted with ethyl acetate (60 mL x 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 silica gel flash chromatography eluting with 5-10% ethyl acetate in 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).

[0746] Step 2: 1-phenyl-2,6,9,12-tetraoxatetradecan-14-ol

[0747]

[0748] To a solution of 1,1,1,16-tetraphenyl-2,5,8,11,15-pentaoxahexadecane (4.8g 8.8mmol) in dichloromethane (10mL) and methanol (10mL) was added aqueous hydrochloric acid solution (37%, 2.5mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30mL) and extracted with dichloromethane (20mL×3). The combined organic phase was washed with aqueous sodium bicarbonate solution (1N, 50mL), water (30mL), 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-tetraoxatetradecane-14-ol (1.9g, 73% yield) as a colorless oil.

[0749] Step 3: 1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl 4-methylbenzenesulfonate

[0750]

[0751] 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).

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

[0753]

[0754] A mixture of 4-methylbenzenesulfonic acid 1-phenyl-2,6,9,12-tetraoxatetradecane-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-tetraoxatetradecane (1.4 g, thick) as a colorless oil, which was used in the next step without further purification.

[0755] Step 5: tert-Butyl (1-phenyl-2,6,9,12-tetraoxatetradec-14-yl)carbamate

[0756]

[0757] A mixture of the above 14-azido-1-phenyl-2,6,9,12-tetraoxatetradecane (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.

[0758] Step 6: tert-Butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate

[0759]

[0760] A mixture of tert-butyl (1-phenyl-2,6,9,12-tetraoxatetradecane-14-yl)carbamate (1.2 g, 3 mmol) and palladium on carbon (10%, 200 mg) in ethanol (50 mL) was stirred at room temperature under a hydrogen atmosphere (hydrogen balloon). Palladium on carbon was removed by filtration and washed with ethanol (20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)ethylcarbamate (900 mg, crude) as a colorless oil, which was used in the next step without further purification.

[0761] Step 7: 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl 4-methylbenzenesulfonate

[0762]

[0763] 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 phases were 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).

[0764] 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

[0765]

[0766] A mixture of 2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azaheptadecan-17-yl (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.

[0767] 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

[0768]

[0769] 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.

[0770] 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

[0771]

[0772] A solution of 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) was 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 layers were 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).

[0773] 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

[0774]

[0775] Step 1: 3-[(5-Hydroxypentyl)oxy]propionitrile

[0776]

[0777] 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 stirring the mixture 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) δ 3.60-3.73 (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).

[0778] Step 2: tert-Butyl N-{3-[(5-hydroxypentyl)oxy]propyl}carbamate

[0779]

[0780] To 3-[(5-hydroxypentyl) oxy] propionitrile (400mg, 2.54mmol) in MeOH (12mL) and H2O (2.0mL) in a solution of 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 a vacuum. To a solution of the above crude product in THF (5mL), a 6M NaOH aqueous solution (0.5mL) and tert-butyl dicarbonate (831mg, 3.81mmol) were added, and the resulting mixture was stirred at room temperature for 3 hours, then concentrated in a vacuum. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with MeOH / DCM (0:100 to 4:96) to give 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).

[0781] Step 3: tert-Butyl N-[3-({5-[(4-methylbenzenesulfonyl)oxy]pentyl}oxy)propyl]carbamate

[0782]

[0783] 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.

[0784] Step 4: Methyl 4-{[5-(3-{[(tert-Butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoate

[0785]

[0786] 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.

[0787] Step 5: 4-{[5-(3-{[(tert-Butoxy)carbonyl]amino}propoxy)pentyl]oxy}benzoic acid

[0788]

[0789] 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, 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 (ESI) + ):m / z 404.20[MNa + ], t R =2.40min.

[0790] 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

[0791]

[0792] 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.

[0793] 12. 4-{[5-(3-aminopropyloxy)pentyl]oxy}-N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide

[0794]

[0795] 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.

[0796] 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

[0797]

[0798] (Compound structure No. 11 shown in Table 1)

[0799] 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 hours, 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).

[0800] C. Protein Degradation Bioassay:

[0801] The following bioassays were performed using representative compounds disclosed herein to assess the levels of protein degradation observed in various cell types.

[0802] 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.

[0803] 1.TBK1 Western protocol

[0804] Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco) supplemented with 15% FBS (ATCC) and 10 U / mL human recombinant insulin (Gibco). DMSO control and compound treatment (0.1 μM, 0.3 μM and 1 μM) were performed 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 (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Standard protocols were used for immunoblotting. 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.

[0805] 2. ERRα Western blot protocol

[0806] NAMALWA cells (ATCC) were cultured in RPMI-1640 (Life Technologies) supplemented with 15% FBS (Life Technologies). DMSO control and compound incubation (0.1 μM, 0.3 μM, and 1 μM) were performed in 24-well plates for 16 hours. Cells were collected and lysed with cell lysis buffer (Cell Signaling Technologies) containing protease inhibitors (Thermo Scientific). Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Standard protocols were used for immunoblotting. 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.

[0807] 3.BRD4 Western Protocol

[0808] 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 harvested and lysed in RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes and protein concentrations were 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), and the detection reagent was Clarity Western ECL substrate (Bio-rad No. 170-5060).

[0809] 4.AR ELISA 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 (0.0001 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 the 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-conjugated antibody) is then used to recognize the bound detection antibody. HRP substrate TMB is added for color development. The magnitude of the absorbance developed is proportional to the amount of total androgen receptor protein.

[0811] The antibodies in the kit are custom formulations specific to the kit.

[0812] 5. c-Myc ELISA Assay Protocol

[0813] 22RV-1 cells were purchased from ATCC and cultured in RPMI + 10% FBS medium. Cells were harvested using trypsin (Gibco No. 25200-114), counted, and seeded in 96-well plates at 30,000 cells / well in RPMI + 10% FBS medium at a volume of 75 μL / well. Cells were dosed with compounds diluted in 0.1% DMSO, incubated for 18 hours, then washed and lysed in 50 μL RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 4000 rpm at 4°C for 10 minutes, and then aliquots were added to 96-well ELISA plates using the Novex Human c-myc ELISA Kit (Cat. No. KHO2041) from Life Technologies. Add 50 μL of c-Myc detection antibody to each well, incubate the plate at room temperature for 3 hours, then wash with ELISA wash buffer. Add 100 μL of 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 100 μL of TMB to each well, and monitor the color change every 5 minutes. Add 100 μL of stop solution, and read the plate at 450 nm.

[0814] D.Results

[0815] 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 are identified by chemical structure, mass spectrometric characterization, and compound name.

[0816] 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) the IC values ​​of compounds 24 and 26-35 were 50 <50 nM, while (E) IC of compounds 23 and 25 50 >50nM.

[0817] The contents of all references, patents, pending patent applications, and published patents cited throughout this application are hereby expressly incorporated by reference.

[0818] 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 experimentation. 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 by way of example only for illustrative purposes and are in no way considered to limit the present invention. Various modifications or variations thereof will occur to those skilled in the art and are included within the spirit and scope of this application and are considered to fall within the scope of the appended claims. For example, the relative amounts of the ingredients can be changed to optimize the desired effect, additional ingredients can be added, and / or one or more of the described ingredients can 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 experimentation. Such equivalents are intended to be covered by the following claims.

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837] Sequence Listing <110> Arvinas, Inc. Crew, Andrew Crews, Craig Wang, Jing Dong, Hanqing Jin, Meizhong Qian, Yimin Chen, Xin Ferraro, Caterina Siu, Kam <120> Imide-based proteolysis modulators and related methods of use <130> 315558(94666) <150> US 61 / 979,351 <151> 2014-04-14 <160> 5 <170> PatentIn version 3.5 <210> 1 <211> 41 <212> DNA <213> Artificial sequence <220> <223> Primer sequences <400> 1 gtgccgcgtg gctccatggc cggcgaagga gatcagcagg a 41 <210> 2 <211> 41 <212> DNA <213> Artificial sequence <220> <223> Primer sequences <400> 2 gcttcctttc gggcttatta caagcaaagt attactttgt c 41 <210> 3 <211> 50 <212> DNA <213> Artificial sequence <220> <223> Primer sequences <400> 3 tcgggcgcgg ctctcggtcc gaaaaggatg tcgtacaact acgtggtaac 50 <210> 4 <211> 61 <212> DNA <213> Artificial sequence <220> <223> Primer sequences <400> 4 gcttcctttc gggcttattt ttcgaactgc gggtggctcc aatggatccg agttagctcc 60 t 61 <210> 5 <211> 61 <212> DNA <213> Artificial sequence <220> <223> Primer sequences <400> 5 gcttcctttc gggcttactt atcgtcatcg tccttgtagt ccaagcaaag tattactttg 60 t 61

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound 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 ] tridecan-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-azadodec-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 ] tridecan-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 ] tridecan-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; and 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. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, additive and / or excipient.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing degradation of a target protein in a cell.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 2, in the preparation of a medicament for treating a disease state or condition in a patient wherein dysregulated protein activity is responsible for the disease state or condition, said use comprising administering an effective amount of said compound or composition.

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