Compound and method for decomposing and improving target protein

Abstract

To provide a bifunctional compound useful as ubiquitinated modulator subjected to targeting and useful as an inhibitor of various polypeptides decomposed by the bifunctional compound and / or obstructed in the other manners and the other proteins.SOLUTION: The bifunctional compound having the following formula includes a Von Hippel Lindau (VHL) E3 ubiquitin ligase bonding part (ULM) directly or connected through a chemicals linker (L) and a protein targeting part (PTM). The ULM is the group of the following chemical structure or salt pharmacologically allowed, a stereoisomer, a solvate or a polymorph.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 135,125, filed March 18, 2015, entitled "Compounds and Methods for the Enhanced Degradation of Targeted Proteins and Other Polypeptides by an E3 Ubquitin Ligase," which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. AI084140 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] 1. Field of Discovery The present invention relates to bifunctional compounds useful as modulators of targeted ubiquitination. In particular, the present invention relates to compounds comprising a VHL ligand at one end that binds to the VHL E3 ubiquitin ligase and a moiety that binds to a target protein at the other end, such that degradation of the target protein / polypeptide is effected. The present invention demonstrates a wide range of pharmacological activities associated with the compounds of the present invention, consistent with the degradation / inhibition of the target polypeptide. [Background technology]

[0004] 2. Background information E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination, making them more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Development of ligands for E3 ligases has proven challenging, in part due to the fact that they necessarily disrupt protein-protein interactions; however, recent developments have provided specific ligands that bind to these ligases. Protein-protein interactions are notoriously difficult to target using small molecules due to the large surface areas involved and the shallow grooves or flat interfaces involved. Conversely, most small molecule drugs bind to enzymes or receptors in tight, well-defined pockets. Following the discovery of the first small molecule E3 ligase inhibitor, nutlin, additional compounds targeting inhibitors of apoptosis proteins (IAPs), SCFMet30 and SCFCdc4, were reported, but the field remains evolving.

[0005] One E3 ligase with exciting therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor, which is the substrate-recognition subunit of the E3 ligase complex VCB and is also composed of elongins B and C, Cul2, and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the proangiogenic growth factor VEGF and the erythropoiesis-inducing cytokine erythropoietin in response to low oxygen levels. Although HIF-1α is constitutively expressed, its intracellular levels are maintained very low under normoxic conditions by its hydroxylation by prolyl hydroxylase domain (PHD) proteins and subsequent VHL-mediated ubiquitination (Figure 1).

[0006] The crystal structure of VHL with a ligand was obtained, confirming that small molecule compounds can mimic the binding mode of the transcription factor HIF-1α, a major substrate of VHL. Using rational design, the first small molecule ligand of von Hippel-Lindau (VHL), the substrate recognition subunit of the E3 ligase VCB, an important target in cancer, chronic anemia, and ischemia, was generated.

[0007] However, there remains a continuing need in the art for small molecule therapeutics that are effective across disease indications. Provided herein are tools for recruiting proteins to E3 ligases for ubiquitination and degradation with the goal of providing therapies based on targeted protein degradation. Summary of the Invention

[0008] overview The present disclosure relates to the discovery that ubiquitin pathway proteins ubiquitinate target proteins when the ubiquitin pathway proteins and any target protein are brought into close proximity by chimeric constructs that bind to the ubiquitin pathway proteins and any target protein. Accordingly, the present invention provides compositions and related methods of use that result in the ubiquitination and subsequent degradation of a selected target protein. The present invention also provides libraries of compositions and uses thereof.

[0009] In one aspect, the present disclosure provides small molecules (i.e., non-peptide-based compounds) that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation.

[0010] In another aspect, the present disclosure provides proteolysis targeting chimeric compounds or PROTACs that can be used to regulate protein degradation in a patient or subject and treat a disease state or condition regulated by degraded proteins.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound described herein, particularly including an inhibitor, for therapeutic treatment of a patient or subject, preferably including a human patient or subject.

[0012] In another aspect, the present disclosure provides methods for identifying endogenous proteins in biological systems, including particularly human systems, that bind to protein-binding moieties in the compounds of the present invention.

[0013] In another aspect, the disclosure provides methods for identifying the effect of degradation of a protein of interest in a biological system using the compounds of the invention.

[0014] In another aspect, the present disclosure provides a method for treating a disease or disorder in a subject, e.g., a patient, such as a human, wherein targeted protein degradation produces an intended therapeutic effect.

[0015] In another aspect, the present disclosure provides compounds and compositions usable in first medical applications.

[0016] Where appropriate, or unless specifically disclaimed, it is contemplated that it is possible to combine any one aspect or embodiment described herein with any other embodiment or embodiments, even if those embodiments are described under different aspects of the invention.

[0017] The foregoing general areas of application are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure and the appended claims. Those skilled in the art will recognize additional objects and advantages associated with the compositions, methods, and processes of the present invention in light of the appended claims, this specification, and the examples. For example, the various aspects and embodiments of the present invention can be utilized in numerous combinations, all of which are expressly contemplated by this specification. These additional advantages, objects, and embodiments are expressly included within the scope of the present invention. Publications and other materials used herein are incorporated by reference to provide a background for the invention and, in certain cases, to provide further details regarding its implementation. [Brief explanation of the drawings]

[0018] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several aspects of the present invention and, together with the description, serve to explain the principles of the present invention. The drawings are only for the purpose of illustrating one aspect of the invention and are not to be construed as limiting the invention. Further objects, features, and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which illustrate exemplary aspects of the invention.

[0019] [Figure 1] (A) HIF-1α accumulation results in transcriptional upregulation of genes involved in hypoxic responses, such as erythropoietin and VEGF. (B) Under normoxic conditions, HIF-1α is hydroxylated, recognized by VHL, and ubiquitinated and degraded by the proteasome, preventing transcriptional upregulation. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description The following is a detailed description provided to assist those skilled in the art in practicing the present invention. Those skilled in the art can make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings, and other references mentioned herein, including WO 2013 / 106643 and US 2014-0356322, are expressly incorporated by reference in their entirety.

[0021] Described herein are compositions that bind to E3 ubiquitin ligase protein complexes. In particular, compositions that bind to von Hippel-Lindau (VHL), the substrate recognition subunit of the E3 ligase complex VCB, are described. Additionally, the present specification provides bifunctional compounds containing the same and related methods of use for ubiquitination and / or degradation of selected target proteins. The present specification also provides libraries of the compounds described herein.

[0022] The following terms are used to describe the present invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and one of ordinary skill in the art will apply the term in context to its use in describing the invention. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0024] When a range of values ​​is recited, it is understood that each intervening value between the upper and lower limit of that range and any other stated or intervening value within that stated range, to the tenth of the unit of the lower limit, is encompassed within the invention, unless the context clearly dictates otherwise (e.g., in the case of a group containing a number of carbon atoms, each number of carbon atoms within the range is recited). The upper and lower limits of these subranges may independently be included in the subranges and are also encompassed within the invention, provided that any limit with respect to the stated range is specifically excluded. When the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0025] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. For example, "an element" means one element or more than one element.

[0026] The term "and / or," as used in this specification and the appended claims, should be understood to mean "one or both" of the elements so coordinated, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so coordinated. Other elements, related or unrelated to the elements specifically identified by the "and / or" clause, may be present. Thus, as a non-limiting example, a reference to "A and / or B," when used in combination with open-ended terms such as "comprising," can mean, in one embodiment, A only (optionally including elements other than B), in another embodiment, B only (optionally including elements other than A), or in yet another embodiment, both A and B (optionally including other elements).

[0027] As used herein and in the appended 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 being inclusive, i.e., including not only at least one, but also two or more of the elements of a number or list and, optionally, additional unlisted items. Only terms clearly indicating the contrary, such as "only one" or "exactly one," or "consisting of" as used in the appended claims, shall imply the inclusion of exactly one element of a number or list. In general, the term "or" as used herein, when preceded by terms indicating exclusivity such as "either," "one," "only one," or "exactly one," shall be interpreted as indicating only exclusive alternatives (i.e., "one or the other, but not both").

[0028] In the appended claims and the above specification, all transitional phrases such as "comprising," "including," "holding," "having," "containing," "comprising," and the like, are to be understood to mean open-ended, i.e., "including, but not limited to." Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0029] As used herein and in the appended claims, the phrase "at least one," in reference 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 not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also contemplates that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements, may be present. 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 mean, in one embodiment, at least one A that optionally includes two or more As, and no Bs (optionally including elements other than B); in another embodiment, at least one B that optionally includes two or more Bs, and no As (optionally including elements other than A); in yet another embodiment, at least one A that optionally includes two or more As, and at least one B that optionally includes two or more Bs (optionally including other elements);

[0030] It should also be understood that, in particular methods described herein that include more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are described, unless the context dictates otherwise.

[0031] The terms "co-administration" and "co-administering," or "combination therapy," refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a time different from the time of administration of one or more additional therapeutic agents), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred aspects, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly including anti-cancer agents. In particularly preferred aspects, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0032] As used herein, the term "compound," unless otherwise indicated, refers to any specific compound disclosed herein and includes, within the context, tautomers, positional isomers, geometric isomers, and, where appropriate, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), thereof, as well as, where appropriate, pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof. Within the context of use, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. Within the context, the term also refers to prodrug forms of compounds modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the present compounds, numerous substituents and variables associated therewith are specifically described. Those skilled in the art will understand that the molecules described herein are stable compounds, as generally described below. Bonding When TIFF2025128169000002.tif6128 is depicted, both double and single bonds are represented within the context of the depicted compound.

[0033] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with the compositions of the present invention is administered. With respect to the treatment of an infection, condition, or disease state specific to a particular animal, such as a human patient, the term patient refers to the particular animal, including domestic animals such as dogs or cats, or livestock such as horses, cows, sheep, etc. Generally, in the present invention, the term patient refers to a human patient, unless otherwise stated or implied from the context of the use of the term.

[0034] The term "effective" is used to describe an amount of a compound, composition, or ingredient that produces a desired result when used in the context of its intended use. The term effective encompasses all other terms relating to effective amount or effective concentration alternatively described or used in this application.

[0035] The terms "VCB E3 ubiquitin ligase," "von Hippel-Lindau (or VHL) E3 ubiquitin ligase," "VHL," or "ubiquitin ligase" are generally used interchangeably unless the context indicates otherwise, e.g., to describe the target enzyme binding site of the ubiquitin ligase moiety described herein in the bifunctional (chimeric) compounds described herein. VCB E3s are proteins that, in combination with an E2 ubiquitin-conjugating enzyme, cause the attachment of ubiquitin to lysines on target proteins, and the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome. Thus, the E3 ubiquitin ligase, alone or in complex with an E2 ubiquitin-conjugating enzyme, is responsible for the transfer of ubiquitin to the targeted protein. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to the first, a third ubiquitin binds to the second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which the ubiquitin ligase attaches only one ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead can alter their cellular location or function, for example, by binding to other proteins with ubiquitin-binding domains. To further complicate matters, different lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to create polyubiquitin, which is recognized by the proteasome.

[0036] As used herein, a moiety that binds to an E3 ubiquitin ligase or a component thereof, such as VHL, is referred to as a ubiquitin ligase binding moiety or "ULM."

[0037] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein or polypeptide of interest or other proteins or polypeptides and positions / places the protein or polypeptide in proximity to ubiquitin ligase so that degradation of the protein or polypeptide by ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding molecules include, among others, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHR). The compositions described below exemplify some members of these and other types of small molecule target proteins. By binding a ULM to a protein target binding moiety ("PTM"), the target protein is ubiquitinated and / or degraded by the proteasome (see Figure 1).

[0038] As noted above, the present specification relates to the surprising and unexpected discovery that an E3 ubiquitin ligase protein will ubiquitinate a target protein when the E3 ubiquitin ligase protein and the target protein are brought into close proximity by a bifunctional PROTAC compound that binds to the E3 ubiquitin ligase protein or a component thereof and the target protein. Accordingly, the present specification provides compounds that bind to E3 ubiquitin ligase proteins, and bifunctional PROTAC compounds comprising the same.

[0039] Compounds and Compositions Compounds useful for regulating protein activity are described herein. The compounds include a ubiquitin pathway protein binding moiety described herein (preferably for an E3 ubiquitin ligase, either alone or in complex with an E2 ubiquitin-conjugating enzyme that is responsible for the transfer of ubiquitin to the targeted protein). Preferably, the E3 ubiquitin ligase binding moiety is a small molecule (i.e., not peptide-based). In certain aspects and embodiments, the ubiquitin pathway protein binding moiety is chemically linked to the protein targeting moiety by bond or through a chemical linker, wherein the ubiquitin ligase binding moiety recognizes the ubiquitin ligase, the targeting moiety recognizes the target protein, and the ubiquitin ligase protein binding moiety is bound to the targeting moiety.

[0040] In one aspect, the description provides ubiquitin ligase-binding compounds (ULMs) capable of binding to an E3 ubiquitin ligase, e.g., VHL, as further described below. In certain embodiments, the ULMs bind to VHL.

[0041] In a further aspect, the invention relates to compounds of the structure L-ULM, where L is a linker group and ULM is a ubiquitin ligase binding moiety. In certain embodiments, ULM is attached to a PTM directly or by a chemical linker.

[0042] In another aspect, the description provides compounds of the general structure ULM-L-PTM comprising a PTM group, where ULM is an E3 ubiquitin ligase-binding moiety, e.g., a VHL-binding moiety, and the PTM is a chemical moiety (protein targeting moiety) that binds to a target protein or polypeptide, which is ubiquitinated by a ubiquitin ligase and is chemically linked to the ULM group directly or through a linker moiety, L, which can be a bond or a chemical linker. Alternatively, in certain embodiments, the PTM is a ULM' group, which is also an E3 ubiquitin ligase-binding moiety, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, and the ULM' group can be the same as or different from the ULM group and is linked to the ULM group directly or through a linker moiety. In certain embodiments, at least one of the ULM and ULM' (if present) is linked to the PTM, PTM', or a combination thereof, directly (a bond) or by a chemical linker.

[0043] In certain aspects of the invention where the PTM is a ULM' group, the compound is like a dimeric compound where both ends of the compound contain a ubiquitin ligase binding moiety as described elsewhere herein.

[0044] The ULM and PTM groups can be covalently linked to the linker group through any group that is suitable and stable to the linker chemistry, although in certain embodiments, as described in further detail below, the linkers can be independently covalently linked to the ULM and PTM groups through an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, any of which groups can be inserted anywhere on the ULM and PTM groups to achieve maximal coupling between the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain aspects where the PTM group is a ULM group, the target protein to be degraded can be the ubiquitin ligase itself.) In certain aspects, the linker can be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, an aryl group, or a heterocyclic group on the ULM and / or PTM group.

[0045] In a further aspect, the description provides a library of compounds, the library including two or more compounds, each of which is a ULM as described herein.

[0046] In a further aspect, the description provides a library of compounds of formula AB, where A is a ubiquitin pathway protein binding moiety or ULM (preferably an E3 ubiquitin ligase moiety as disclosed elsewhere herein); B is a protein-binding moiety or PTM of a molecular library; A is linked to B (preferably through a linker moiety); and the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein, particularly an E3 ubiquitin ligase. In certain embodiments, the library comprises a ubiquitination recognition moiety (a ubiquitin pathway protein binding moiety as disclosed elsewhere herein) specific for VHL as an E3 ubiquitin ligase, along with a random target protein binding element (e.g., a compound library). Thus, the target protein is not determined in advance, and the method can be used to determine the activity of a putative protein-binding element as a target for degradation by a ubiquitin ligase, and its pharmacological value.

[0047] In any aspect or embodiment described herein, ULM, and, if present, ULM′, is each independently a group of the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000003.tif36128In formula, R 1' is an optionally substituted C1-C6 alkyl group, an optionally substituted -(CH2) n OH, optionally substituted -(CH2) n SH, optionally substituted (CH2) n an optionally substituted —O—(C1-C6) alkyl group, including an epoxide moiety WCOCW, where each W is independently H or a C1-C3 alkyl group (CH2); n -WCOCW-(C0-C6) alkyl group, optionally substituted -(CH2) n COOH, optionally substituted -(CH2) n C(O)—(C1-C6 alkyl), optionally substituted —(CH2) n NHC(O)-R1, optionally substituted -(CH2) n C(O)-NR1R2, optionally substituted -(CH2) n OC(O)-NR1R2, -(CHO) n H, optionally substituted -(CH2) n OC(O)—(C1-C6 alkyl), optionally substituted —(CH2) n C(O)—O—(C1-C6 alkyl), optionally substituted —(CHO) n COOH, optionally substituted -(OCH2) n O-(C1-C6 alkyl), optionally substituted -(CHO) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2) n NHC(O)-R1, optionally substituted -(CHO) n C(O)-NR1R2, -(CH2CH2O) n H, optionally substituted -(CH2CH2O) n COOH, optionally substituted -(OCH2CH2)n O-(C1-C6 alkyl), optionally substituted -(CH2CH2O) n C(O)—(C1-C6 alkyl), optionally substituted —(OCH2CH2) n NHC(O)-R1, optionally substituted -(CH2CH2O) n C(O)-NR1R2, optionally substituted -SO2R S , optionally substituted S(O)R S , NO2, CN, or halogen (F, Cl, Br, I, preferably F or Cl); R1 and R2 are each independently H or a C1-C6 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups (preferably fluorine); R S is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl, or heterocyclic group, or -(CH2) m is an NR1R2 group, X and X' are each independently C=O, C=S, -S(O), or S(O)2 (preferably, X and X' are both C=O); R 2' is optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w Alkyl groups, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w NR 1N R 2N group, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -(C=O)v NR1(SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -aryl, optionally substituted -NR 1 -(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, or optionally substituted -NR 1 -(CH2) n -(C=O) v NR1(SO2) w -heterocycle, optionally substituted -X R2' -Alkyl group; optionally substituted -X R2' -aryl group; optionally substituted -X R2' -heteroaryl group; optionally substituted -X R2' - a heterocyclic group; R 3' is optionally substituted alkyl, optionally substituted -(CH2) n -(O) u (NR1) v (SO2) w -Alkyl, optionally substituted -(CH2) n-C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -C(O)NR1R2, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -aryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -alkyl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2)w -aryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heteroaryl, optionally substituted -NR 1 -(CH2) n -C(O) u (NR1) v (SO2) w -heterocycle, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -Alkyl, optionally substituted -O-(CH2)n-(C=O) u (NR1) v (SO2) w -NR 1N R 2N , optionally substituted —O—(CH2)n—(C═O) u (NR1) v (SO2) w -NR1C(O)R 1N , optionally substituted —O—(CH2)n—(C═O) u (NR1) v (SO2) w -aryl, optionally substituted -O-(CH2) n -(C=O) u (NR1) v (SO2) w -heteroaryl, or optionally substituted -O-(CH) n -(C=O) u (NR1) v (SO2) w -heterocycle; -(CH2) n -(V) n' -(CH2) n -(V) n' -Alkyl group, optionally substituted -(CH2) n -(V) n' -(CH2) n -(V) n' -aryl group, optionally substituted -(CH2) n -(V) n' -(CH2)n -(V) n' -heteroaryl group, optionally substituted -(CH2) n -(V) n' -(CH2) n -(V) n' -heterocyclic group, optionally substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -Alkyl group, optionally substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -aryl group, optionally substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -heteroaryl group, optionally substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -heterocyclic group, optionally substituted -X R3' -Alkyl group; optionally substituted -X R3' -aryl group; optionally substituted -X R3' -heteroaryl group; optionally substituted -X R3' - a heterocyclic group; R 1N and R 2N are each independently H, C1-C6 alkyl optionally substituted with one or two hydroxyl groups and up to three halogen groups, or optionally substituted -(CH2) n -aryl, -(CH2) n -heteroaryl, or -(CH2) n - a heterocyclic group; V is O, S, or NR1; R1 is the same as above; R 1 and R 1' are each independently H or a C1-C3 alkyl group; X R2' and X R3'each independently represents an optionally substituted —CH2) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group, and X v is H, halo, or an optionally substituted C1-C3 alkyl group; m is independently 0, 1, 2, 3, 4, 5, or 6; each m' is independently 0 or 1; n is independently 0, 1, 2, 3, 4, 5, or 6; each n' is independently 0 or 1; each u is independently 0 or 1; each v is independently 0 or 1; each w is independently 0 or 1; If PTM is not ULM', R of ULM 1' , R 2' , R 3' Any one or more of X, X, and X' may be modified to be covalently attached to a PTM group through a linker group, or, if the PTM is a ULM', each R of the ULM and ULM'. 1' , R 2' , R 3' Any one or more of X, X, and X' may be modified to be covalently linked to each other directly or through a linker group.

[0048] In any aspect or embodiment described herein, ULM, and, if present, ULM′, is each independently a group of the following chemical structure or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: TIFF2025128169000004.tif45128 formula, R 1' , R 2' , and R 3'are the same as above, and X is C=O, C=S, a -S(O) group, or a S(O) group, more preferably a C=O group; If the PTM is not ULM', R 1' , R 2' , and R 3' any one or more of may be modified to be attached to a linker group, which may be further covalently attached to a PTM group, or, when the PTM is a ULM′, each R of the ULM and ULM′ 1' , R 2' , R 3' Any one or more of may be modified to be covalently linked to each other directly or through a linker group.

[0049] In any aspect or embodiment described herein, ULM, and, if present, ULM′, each independently has the following chemical structure or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof: TIFF2025128169000005.tif45128 formula, If the PTM is not ULM', R 1' , R 2' , and R 3' any one or more of may be modified to be attached to a linker group, which may be further covalently attached to a PTM group, or, when the PTM is a ULM′, each R of the ULM and ULM′ 1' , R 2' , R 3' Any one or more of may be modified to be covalently linked to each other directly or through a linker group.

[0050] In a further preferred aspect of the invention, R 1' is preferably a hydroxyl group or a group that can be metabolized to a hydroxyl group or a carboxyl group. Exemplary preferred R 1' Examples of groups include -(CH2) n OH, (CH2) n-O-(C1-C6) alkyl group, -(CH2) n COOH, -(CHO) n H, optionally substituted -(CH2) n OC(O)-(C1-C6 alkyl) or optionally substituted -(CH2) n C(O)—O—(C1-C6 alkyl), where n is 0 or 1. 1' is or contains a carboxylic acid group, a hydroxyl group, or an amine group, the hydroxyl group, carboxylic acid group, or amine (any of which may be substituted) can be further chemically modified to provide covalent attachment to a linker group having attached PTM groups (including ULM′ groups); X and X', when present, are preferably C=O, C=S, -S(O), or S(O) groups, more preferably C=O groups; R 2' is optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl group or optionally substituted -NR 1 -T-heterocycle is preferred, and R 1 is H or CH3, preferably H, and T is optionally substituted -(CH2) n - group, each methylene group being optionally substituted with one or two substituents preferably selected from halogen, an amino acid side chain as described elsewhere herein, or a C1-C3 alkyl group, preferably one or two optionally substituted methyl groups; n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -group, and either group may be substituted.

[0051] R 2'Preferred aryl groups include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, which are optionally substituted with a linker group to which a PTM group (including a ULM′ group) is attached, a halogen (preferably F or Cl), an amine, a mono- or di-alkylamine (preferably dimethylamine), F, Cl, OH, COOH, a C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or a CN group (all of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably para). and optionally substituted at ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position), an optionally substituted phenyl group (which itself may be substituted with a linker group attached to a PTM group, including a ULM′ group, and / or at least one of F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN group (at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably at the para-position)), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole. oxazole, optionally substituted oxazoles including methyl substituted oxazoles, optionally substituted thiazoles including methyl substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) substituted or methyl substituted pyridine groups or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines,An optionally substituted group having the following chemical structure: TIFF2025128169000006.tif72128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C1-C6 alkyl), each of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted phenyl group, an optionally substituted heteroaryl, or an optionally substituted heterocycle, preferably, for example, piperidine, morpholine, pyrrolidine, tetrahydrofuran; R PROis H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl) group, heteroaryl group, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, and azaindolizine; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). ,or, an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine, or morpholine (each of which, if substituted, is preferably substituted with methyl or halo (F, Br, Cl), and each of which may be substituted with a linker group to which is attached a PTM group (including a ULM' group)); Examples include:

[0052] In certain preferred aspects, TIFF2025128169000007.tif23128 TIFF2025128169000008.tif21128 group, wherein R PRO and n is the same as above.

[0053] R 2'Preferred heteroaryl groups include optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole, optionally substituted indolizine, optionally substituted azaindolizine, optionally substituted benzofuran including optionally substituted benzofuran, optionally substituted isoxazole, optionally substituted thiazole, optionally substituted isothiazole, optionally substituted thiophene, optionally substituted pyridine (2-, 3, or 4-pyridine), optionally substituted imidazole, optionally substituted pyrrole, optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted oximidazole, or a group of the following chemical structure: TIFF2025128169000009.tif68128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C1-C6 alkyl), each of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, each of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a Either group may be substituted with a linker group to which a PTM group (including a ULM' group) is attached.

[0054] R 2' Preferred heterocyclic groups include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, oxane, or thiane, any of which may be substituted, or groups of the following chemical structure: TIFF2025128169000010.tif24128, preferably TIFF2025128169000011.tif21128 groups, During the ceremony, R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; Each n is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1). Any group may be substituted with a linker group to which a PTM group (including a ULM' group) is attached.

[0055] Preferred R for use in the present invention 2' The substituents are R groups found in the identified compounds disclosed herein, including the specific compounds disclosed in this specification and the accompanying drawings. 2' The substituents are also specifically included (and not limited to the particular compounds disclosed). 2' The substituents may also be any number of R 3' It can be used in combination with a substituent.

[0056] R 3' is preferably an optionally substituted -T-aryl, an optionally substituted -T-heteroaryl, an optionally substituted -T-heterocycle, an optionally substituted -NR 1 -T-aryl, optionally substituted -NR 1 -T-heteroaryl or optionally substituted -NR 1 -T-heterocycle, and R 1 is H or a C1-C3 alkyl group, preferably H or CH3, and T is an optionally substituted -(CH2) n- group, where each methylene group is optionally substituted with one or two substituents preferably selected from halogen, a C1-C3 alkyl group, or an amino acid side chain as described elsewhere herein, preferably an optionally substituted methyl; n is 0-6, often 0, 1, 2, or 3, preferably 0 or 1. Alternatively, T is -(CHO) n -group, -(OCH2) n - group, -(CH2CH2O) n - group, -(OCH2CH2) n -group, and either group may be substituted.

[0057] R 3' Preferred aryl groups include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, which are linker groups having attached PTM groups (including ULM′ groups), and / or halogens (preferably F or Cl), amines, mono- or dialkylamines (preferably dimethylamine), amide groups (preferably —(CH) m -NR1C(O)R2 group, where m, R1, and R2 are the same as above), halo (often F or Cl), OH, CH3, CF3, OMe, OCF3, NO2, CN, or S(O)2R S Group(R S is a C1-C6 alkyl group, an optionally substituted aryl group, a heteroaryl group, or a heterocyclic group, or -(CH2) mand optionally substituted with an NRR group), a phenyl or naphthyl group (each of which may be substituted at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position), or an aryl (preferably phenyl), heteroaryl, or heterocycle. Preferably, the phenyl group of the substituent is an optionally substituted phenyl group (i.e., the phenyl group of the substituent is itself preferably substituted with at least one of F, Cl, OH, SH, COOH, CH, CF, OMe, OCF, NO, CN, or a linker group to which a PTM group (including a ULM' group) is attached, the substitution occurring at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position), such as a naphthyl group optionally substituted as described above, an optionally substituted heteroaryl (preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole, an optionally substituted oxazole, including a methyl-substituted oxazole, an optionally substituted thiazole, including a methyl-substituted thiazole, ... optionally substituted pyrroles including ethyl-substituted pyrroles, optionally substituted imidazoles including methylimidazole, benzylimidazole or methoxybenzylimidazole, oximidazole or methyloximidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, pyridine groups including halo (preferably F)- or methyl-substituted pyridine groups, or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), or optionally substituted heterocycles (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane, or thiane). Each aryl, heteroaryl, or heterocyclic group may be substituted with a linker group to which is attached a PTM group (including a ULM' group).

[0058] R 3'Preferred heteroaryl groups include optionally substituted quinoline (which may be attached to the pharmacophore and may be 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, benzoxofuran, 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 -(CH m -O-C1 to C6 alkyl group 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 of the following chemical structure: TIFF2025128169000012.tif55128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C1-C6 alkyl), each of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, each of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a Each of said heteroaryl groups is optionally substituted with a linker group to which is attached a PTM group (including a ULM' group).

[0059] R 3'Preferred heterocyclic groups include tetrahydroquinoline, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxane, and thiane, any of which may be substituted, or groups of the following chemical structure: TIFF2025128169000013.tif23128, preferably TIFF2025128169000014.tif21128 groups, During the ceremony, R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl) group, heteroaryl group, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, and azaindolizine; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), and each of said heterocyclic groups is optionally substituted with a linker group to which is attached a PTM group (including a ULM' group).

[0060] Preferred R for use in the present invention 3' The substituents are R groups found in the identified compounds disclosed herein, including the specific compounds disclosed in this specification and the accompanying drawings. 3' The substituents are also specifically included (and not limited to the particular compounds disclosed). 3' The substituents may also be any number of R 2'It can be used in combination with a substituent.

[0061] In certain alternative preferred embodiments, R 2' is optionally substituted -NR1-X R2' -Alkyl group, -NR1-X R2' -aryl group; optionally substituted -NR1-X R2' -HET, optionally substituted -NR1-X R2' -aryl-HET or optionally substituted -NR1-X R2' -HET-aryl; where: R1 is H or a C1-C3 alkyl group (preferably H); X R2' (optionally substituted -CH2) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, -(CHCHO) n - or a C3-C6 cycloalkyl group; X v is H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; Alkyl is optionally substituted C1-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often Cl or Br); Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, or quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl). or a group of the following chemical structure: TIFF2025128169000015.tif75128 formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C1-C6 alkyl), any of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, any of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl) group, heteroaryl group, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, and azaindolizine; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; Each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1). Each of the foregoing groups may be substituted with a linker group to which is attached a PTM group (including a ULM' group).

[0062] In certain alternative preferred embodiments of the present invention, R 3' is optionally substituted -(CH2) n -(V) n' -(CH2) n -(V) n' -R S3' group, optionally substituted -(CH2) n -N(R 1' )(C=O) m' -(V) n' -R S3' an optionally substituted -X group; R3' -Alkyl group, optionally substituted -X R3' -aryl group; optionally substituted -X R3' -HET group, optionally substituted -X R3' -aryl-HET group or optionally substituted -X R3' -HET-aryl group; where: R S3' is an optionally substituted alkyl group (C1-C 10 , preferably C1-C6 alkyl), an optionally substituted aryl group, or a HET group; R 1' is H or a C1-C3 alkyl group (preferably H); V is O, S, or NR 1' and; X R3' Ha-(CH2) n -, -(CH2CH2O) n -, -CH2) n -CH(X v )=CH(X v )-(cis or trans), -CH2) n -CH≡CH-, or a C3-C6 cycloalkyl group, either of which may be substituted; X vis H, halo, or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or up to three halogen groups; Alkyl is optionally substituted C1-C 10 an alkyl (preferably C1-C6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often Cl or Br); Aryl is an optionally substituted phenyl or naphthyl group (preferably a phenyl group); HET is optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, or quinoline (when substituted, each is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl). or a group of the following chemical structure: TIFF2025128169000016.tif75128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C0-C6 alkyl), any of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, any of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R PROis H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl) group, heteroaryl group, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, and azaindolizine; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; each n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); m' is 0 or 1; n' is 0 or 1; Each of the foregoing compounds may be optionally substituted, preferably on an alkyl, aryl, or Het group, with a linker group to which a PTM group (including a ULM' group) is attached.

[0063] In an alternative embodiment, R 3 ' is -(CH2) n -aryl, -(CH2CH2O) n -aryl, -(CH2) n -HET, or -(CH2CH2O) n -HET; where: Aryl is phenyl optionally substituted with one or two substituents, the substituents being -(CH2) n OH, CN itself, halo (up to 3 halo groups), C1-C6 alkyl optionally further substituted with OH, -(CH2) nPreferably, O(C1-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, or The aryl group is —(CH2) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine in which the alkyl group on the amine may be substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, CN, NO2, optionally substituted -(CH2) n -(V) m' -CH2) n -(V) m' -(C1-C6) alkyl group, -(V) m' -(CH2CH2O) n -R PEG group, and V is O, S, or NR 1' and R 1' is H or a C1-C3 alkyl group (preferably H), and R PEGis H or an optionally substituted C1-C6 alkyl group (including optionally substituted with a carboxyl group), or the aryl group may be substituted with a heterocycle including heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, and azaindolizine (each of which, when substituted, is preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl). or a group of the following chemical structure: TIFF2025128169000017.tif74128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SSis H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C0-C6 alkyl), any of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, any of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R PROis H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl (phenyl or naphthyl) group, heteroaryl group, or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, and azaindolizine; R PRO1 and R PRO2 are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; HET is preferably oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thien, dihydrothien, tetrahydrothien, pyridine, piperidine, piperazine, morpholine, quinoline (each preferably substituted with a C1-C3 alkyl group, preferably methyl, or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine. or a group of the following chemical structure: TIFF2025128169000018.tif75128In formula, S c is CHR SS , N.R. URE , or O; R HET is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R ais an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or optionally substituted —C(O)(C1-C6 alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or —C(O)(C0-C6 alkyl), any of which may be substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, or piperazine, any of which may be substituted; Y C is N or CR YC and R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), or R a is an optionally substituted acetylene group, —C≡CR, where —C≡CR is H or a C1-C6 alkyl group (preferably a C1-C3 alkyl group). a and; R PRO is H, an optionally substituted C1-C6 alkyl, or an optionally substituted aryl, heteroaryl, or heterocyclic group; R PRO1 and R PRO2are each independently H, an optionally substituted C1-C3 alkyl group, or together form a keto group; each m' is independently 0 or 1; n is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); Each of the foregoing compounds may be substituted, preferably on the aryl or HET group, with a linker group to which a PTM group (including a ULM' group) is attached.

[0064] In still further aspects, preferred compounds include compounds of the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000019.tif45128 formula, R 1' is OH or a group that is metabolized to OH in the patient or subject; R 2' is -NH-CH-aryl-HET (preferably phenyl directly linked to a methyl substituted thiazole); R 3' Ha-CHR CR3' -NH-C(O)-R 3P1 group or -CHR CR3' -R 3P2 It is a base; R CR3' is a C1-C4 alkyl group, preferably methyl, isopropyl, or tert-butyl; R 3P1 is a C1-C3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl-substituted), and n is 1 or 2 (preferably 2), -(CH2) n OCH3 group, or TIFF2025128169000020.tif14128 group (the ethyl ether group is preferably meta-substituted on the phenyl moiety), a morpholino group (linked to the carbonyl at the 2- or 3-position); R 3P2 teeth TIFF2025128169000021.tif17128 group; Aryl is phenyl; HET is an optionally substituted thiazole or isothiazole; R HET is H or a halo group (preferably H); Each of the above compounds may be substituted with a linker group to which is attached a PTM group (including a ULM' group).

[0065] In certain aspects, the bifunctional compound comprises a ubiquitin E3 ligase binding moiety (ULM), wherein the ULM is a group having the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000022.tif30128 formula, R5 and R6 are each independently OH, SH, or optionally substituted alkyl, or R5, R6 and the carbon atom to which they are attached form a carbonyl; R7 is H or optionally substituted alkyl; E is a bond, C=O, or C=S; G is a bond, optionally substituted alkyl, —COOH, or C═J; J is O or N-R8; R8 is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, or TIFF2025128169000023.tif13128; R9 and R 10 are each independently H; an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxyalkyl, an optionally substituted thioalkyl, a disulfide-linked ULM, an optionally substituted heteroaryl, or a haloalkyl; or R, R 10and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R 11 is an optionally substituted heterocycle, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, or TIFF2025128169000024.tif13128; R 12 is H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, R 14 are each independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl; R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; R 16 are each independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; R 25 are each independently H or optionally substituted alkyl; or both R 25 the groups can be taken together to form an oxo group or an optionally substituted cycloalkyl group; R 23 is H or OH; Z1, Z2, Z3, and Z4 are independently C or N; and o is 0, 1, 2, 3, or 4.

[0066] In certain embodiments, ULM is linked to a protein targeting moiety (PTM) either directly by a bond or through a chemical linker (L).

[0067] In certain embodiments, G is C=J, J is O, R7 is H, and R 14 are H and o is 0.

[0068] In certain embodiments, G is C=J, J is O, R7 is H, and R 14 are H and R 15 is optionally substituted heteroaryl and o is 0. In other cases, E is C=O and M is TIFF2025128169000025.tif13128.

[0069] In certain embodiments, E is C=O and R 11 is an optionally substituted heterocycle or TIFF2025128169000026.tif13128, and M is TIFF2025128169000027.tif13128.

[0070] In certain embodiments, E is C=O and M is TIFF2025128169000028.tif13128, R 11 teeth TIFF2025128169000029.tif18128, R 18 are each independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.

[0071] In certain embodiments, ULM, and, if present, ULM′, are each independently a group of the following chemical structure: TIFF2025128169000030.tif30128In the formula, G is C=J, J is O, R7 is H, and R14 are H, o is 0, and R 15 teeth TIFF2025128169000031.tif17128, R 17 is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl. 17 is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl). In certain embodiments, the ULM is attached to the PTM directly by a bond or by a chemical linker.

[0072] In other embodiments, ULM, and, if present, ULM′, are each independently a group of the following chemical structure: TIFF2025128169000032.tif30128In the formula, G is C=J, J is O, R7 is H, and R 14 are H, o is 0, and R 15 is selected from the group consisting of: TIFF2025128169000033.tif103143In formula, R 30 is H or optionally substituted alkyl. In certain embodiments, the ULM is attached to the PTM directly by a bond or by a chemical linker.

[0073] In other embodiments, ULM, and, if present, ULM′, are each independently a group of the following chemical structure: TIFF2025128169000034.tif30128In the formula, E is C=O and M is TIFF2025128169000035.tif13128, R 11 is selected from the group consisting of: TIFF2025128169000036.tif127129In certain embodiments, the ULM is linked to the PTM either directly by a bond or by a chemical linker.

[0074] In yet another embodiment, a compound having the following chemical structure: TIFF2025128169000037.tif30128 formula, E is C=O and R 11 teeth TIFF2025128169000038.tif13128; M is TIFF2025128169000039.tif13128; q is 1 or 2; R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or TIFF2025128169000040.tif17128; R 21 is H or optionally substituted alkyl; R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl. In certain embodiments, the ULM is attached to the PTM directly by a bond or by a chemical linker.

[0075] In any of the above aspects, R 11 is selected from the group consisting of: TIFF2025128169000041.tif62133TIFF2025128169000042.tif211146TIFF2025128169000043.tif109141

[0076] In certain embodiments, R 11 is selected from the group consisting of: TIFF2025128169000044.tif72137TIFF2025128169000045.tif138132TIFF2025128169000046.tif85139

[0077] In certain embodiments, ULM (or ULM′, if present) is a group of the following chemical structure: TIFF2025128169000047.tif45128 formula, X is O or S; Y is H, methyl, or ethyl; R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M is optionally substituted heteroaryl, optionally substituted aryl, and R9 is H; R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl; R11 is an optionally substituted heteroaromatic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl, or TIFF2025128169000048.tif13128, R 12 is H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

[0078] In some embodiments, ULM, and, if present, ULM′, are each independently a group of the following chemical structure: TIFF2025128169000049.tif51128 formula, Y is H, methyl, or ethyl; R9 is H; R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; R11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle.

[0079] In other preferred embodiments of the present invention, ULM, and, if present, ULM′, are each independently a group of the following chemical structure: TIFF2025128169000050.tif51128 in formula, R 17 is methyl, ethyl, or cyclopropyl; R9, R 10 , and R 11 is as defined above. In other cases, R9 is H; R 10 is H, alkyl, or cycloalkyl (preferably isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl).

[0080] In any aspect or embodiment described herein, the ULM described herein (or ULM', if present) may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, or polymorph thereof. Further, in any aspect or embodiment described herein, the ULM described herein (or ULM', if present) may be attached to a PTM directly by a bond or by a chemical linker.

[0081] In certain aspects of the invention, the ULM moiety is selected from the group consisting of: TIFF2025128169000051.tif198145TIFF2025128169000052.tif171145TIFF2025128169000053.t if196145TIFF2025128169000054.tif168145TIFF2025128169000055.tif173145TIFF20251281690 00056.tif179145TIFF2025128169000057.tif183145TIFF2025128169000058.tif192145TIFF202 5128169000059.tif188144TIFF2025128169000060.tif186145TIFF2025128169000061.tif189145 TIFF2025128169000062.tif183144TIFF2025128169000063.tif183144TIFF2025128169000064.t if183144TIFF2025128169000065.tif219134TIFF2025128169000066.tif194155TIFF20251281690 00067.tif186128TIFF2025128169000068.tif220126TIFF2025128169000069.tif227166TIFF202 5128169000070.tif215125TIFF2025128169000071.tif187147TIFF2025128169000072.tif142137

[0082] The term "independently" is used herein to indicate that independently applied variables vary independently from application to application.

[0083] The term "alkyl" refers, in context, to an optionally substituted straight-chain, branched-chain, or cyclic fully saturated hydrocarbon or alkyl group, preferably C1-C 10, more preferably C1-C6 or C1-C3 alkyl groups. Examples of alkyl groups include 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, among others. In certain embodiments, the alkyl groups are end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds of the invention can be used to covalently attach to dehalogenase enzymes. Generally, these compounds contain a side chain (often linked through a polyethylene glycol group) distal to an alkyl group bearing a halogen substituent (often chlorine or bromine) that allows the compound containing the moiety to be covalently attached to a protein.

[0084] The term "alkenyl" refers to a straight, branched, or cyclic C-C alkyl group containing at least one C=C bond. 10 It means a (preferably C2 to C6) hydrocarbon group.

[0085] The term "alkynyl" refers to a straight, branched, or cyclic C-C alkyl group containing at least one C≡C bond. 10 It means a (preferably C2 to C6) hydrocarbon group.

[0086] When the term "alkylene" is used, it refers to an optionally substituted -(CH) n- group (n is generally an integer from 0 to 6). When substituted, the alkylene group is preferably substituted on one or more methylene groups with a C1-C6 alkyl group (including a cyclopropyl or t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or with one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (of 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), which in turn is substituted with an alkyl chain substituted with one halogen, preferably a chlorine, group (preferably, but not limited to, at the distal end of the polyethylene glycol chain). In still other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as the side chain group of a natural or unnatural amino acid, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0087] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with H. Thus, a range of carbon atoms that is C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with C0 being replaced with H.

[0088] The terms "substituted" or "optionally substituted" are intended to refer independently to one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, and often 1 or 2 substituents on a moiety in a compound of the invention, which may themselves include substituents which may be further substituted) at any carbon (or nitrogen) position on the molecule within the context (i.e., when more than one substituent occurs, each substituent is independent of the other substituents), including hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably 1, 2, or 3 halogens, especially on an alkyl, especially a methyl group, e.g., trifluoromethyl), alkyl groups (preferably C1-C 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl, or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl), including alkylene esters (in alkylene esters, the bond is on the alkylene group rather than the ester functionality, which is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including 5- or 6-membered cyclic alkylene amines). and C1-C6 alkylamine or C1-C6 dialkylamine, wherein the alkyl group is optionally substituted with one or two hydroxyl groups; an optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (which may be substituted with a polyethylene glycol chain to which is further attached an alkyl group containing one halogen, preferably chlorine, substituent); hydrazine; an amide preferably substituted with one or two C1-C6 alkyl groups (including a carboxamide optionally substituted with one or two C1-C6 alkyl groups); an alkanol (preferably C1-C6 alkyl or aryl); or an alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents of the present invention include, for example, a -SiR1R2R3 group, where R1 and R2 are as defined elsewhere herein, and R3 is H or a C1-C6 alkyl group; preferably, R1, R2, and R3 in this context are a C1-C3 alkyl group (including an isopropyl or t-butyl group). Each of the above groups may be directly linked to the substituted moiety, or the substituent may be substituted with any one or more of the above substituents -(CH) m -(OCH2) optionally substituted with a - group or any one or more of the above substituents. m -, -(OCH2CH2) m - or -(CH2CH2O) mIt may be linked to the substituted moiety through a - group (preferably in the case of an aryl or heteroaryl moiety). m -or-(CH2) n Alkylene groups such as - groups or other chains such as ethylene glycol chains may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogens, C1-C6 (preferably C1-C3) alkyl groups, optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or an amino acid side chain as described elsewhere herein, and optionally substituted amide groups (preferably carboxamido substituted as described above) or optionally substituted urethane groups (often optionally substituted with one or two C0-C6 alkyl substituents, which may be further substituted). In certain embodiments, the alkylene group (often a 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 groups, or an amino acid side chain as described elsewhere herein. In the present invention, moieties in a molecule may be substituted with up to five substituents, preferably up to three substituents. Most often, in the present invention, a substituted moiety is substituted with one or two substituents.

[0089] Additionally, the term "substituted" (each substituent being independent of any other substituent) is intended to mean, within the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane -OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly including C1-C6 alkylene -NR1R2 optionally substituted with one or two hydroxyl groups, mono- or di-C1-C6 alkyl-substituted amines). Each of these groups contains 1 to 6 carbon atoms, unless otherwise indicated within the context. In certain embodiments, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2), depending on the context of the use of the substituent. m - (where m and n are 1, 2, 3, 4, 5, or 6, as appropriate in context), -S-, -S(O)-, SO2-, -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R Sis C1-C6 alkyl or -(CH2) m Examples of alkylene groups include an —NR1R2 group), NO2, CN, or a halogen (F, Cl, Br, I, preferably F or Cl). R1 ​​and R2 are each, within context, H or a C1-C6 alkyl group (optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" is also intended to mean an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group, as described elsewhere herein, within the chemical context of the specified compound and the substituents used. The alkylene group may be substituted, as otherwise disclosed herein, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, which provide a chiral center), the side chain of an amino acid group, as described elsewhere herein, an amide group as previously described, or an O-C(O)—NR1R2 group, where R1 and R2 are urethane groups, as described elsewhere herein, although numerous other groups may be used as substituents. The various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer, and preferably one or two substituents. It should be noted that unless the context of the substitution indicates otherwise, where a substitution is required in a compound at a particular position in a molecule (primarily for valence reasons), but no substitution is indicated, the substituent is to be interpreted or understood to be H.

[0090] The terms "aryl" or "aromatic" refer, in context, to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), which may be attached to a compound of the invention at any available stable position on the ring or as otherwise indicated in the chemical structure provided. Other examples of aryl groups, in context, include heterocyclic aromatic ring systems "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be substituted as described above.Heteroaryl groups that may be mentioned include nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; Particular mention is made of oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridooxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be substituted.

[0091] The term "substituted aryl" refers to an aromatic carbocyclic group composed of at least one aromatic ring or multiple fused rings, at least one of which is aromatic, and the rings are substituted with one or more substituents. For example, an aryl group can be -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n-C(O)O(C0-C6) alkyl, -(CH2) n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine in which the alkyl group on the amine may be substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted at the ortho-, meta-, and / or para-positions of the phenyl ring, preferably the para-position), optionally substituted phenyl group (the phenyl group itself may be substituted with ULM and / or a linker group attached to the PTM group, which is preferably substituted with at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, an optionally substituted oxazole, including methyl-substituted oxazole, a methyl The aryl group may comprise a substituent selected from an optionally substituted thiazole, including a substituted thiazole; an optionally substituted isothiazole, including a methyl-substituted isothiazole; an optionally substituted pyrrole, including a methyl-substituted pyrrole; an optionally substituted imidazole, including a methylimidazole; an optionally substituted benzimidazole or methoxybenzylimidazole; an optionally substituted oximidazole or methyloximidazole; an optionally substituted diazole, including a methyldiazole, group; an optionally substituted triazole, including a methyl-substituted triazole; an optionally substituted pyridine, including a halo (preferably F)- or methyl-substituted pyridine, or an oxapyridine group (wherein the pyridine group is linked to the phenyl group by an oxygen); an optionally substituted furan; an optionally substituted benzofuran; an optionally substituted dihydrobenzofuran; an optionally substituted indole, indolizine, or azaindolizine (2-, 3-, or 4-azaindolizine); an optionally substituted quinoline; and combinations thereof.

[0092] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and these generic substituents have the same meaning as in the definitions of the corresponding groups defined herein.

[0093] The term "heteroaryl" or "hetaryl" refers to an optionally substituted quinoline (which may be attached to the pharmacophore and may be substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3, or 4-azaindolizine), an optionally substituted benzimidazole, a benzodiazole, a benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and / or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably methyl and / or thiol substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably methyl, triisopropylsilyl, or optionally substituted -(CH)). m -O-C1 to C6 alkyl group or optionally substituted -(CH2) m It can mean, but is in no way limited to, 1,2,3-triazole substituted with —C(O)—O—C1-C6 alkyl group), optionally substituted pyridine (2-, 3, or 4-pyridine).

[0094] The terms "aralkyl" and "heteroarylalkyl" refer to groups that include both aryl or heteroaryl, respectively, as defined above, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems, as defined above.

[0095] The term "arylalkyl," as used herein, refers to an aryl group, as defined above, appended to an alkyl group, as defined above. The arylalkyl group is attached to the parent moiety through an alkyl group of 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as defined above.

[0096] The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, such as N, O, or S, and can be aromatic (heteroaryl) or non-aromatic. Heteroaryl moieties are therefore included within the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described above.

[0097] 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, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, and benzothiazolyl. Examples include thiazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, and oxathiolanylthiane.

[0098] Heterocyclic groups may be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, and N-alkoxy-nitrogen-containing heterocycles. The term "heterocycle" also includes bicyclic groups in which either heterocycle is fused to a benzene or cyclohexane ring or to another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0099] The term "cycloalkyl" can 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, for example, a monocyclic saturated hydrocarbon group having 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can refer to, but is in no way limited to, a monocyclic or polycyclic alkyl group substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, and these generic substituents have the same meaning as the definition of the corresponding group defined in this Description.

[0100] The term "hydrocarbyl" is intended to mean a compound that contains carbon and hydrogen and may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0101] Exemplary Linkers In -A1-...-Aq-, A1 is a group that links a moiety selected from the group consisting of a ULM, a PTM, and combinations thereof to the linker Aq or directly to a moiety selected from the group consisting of a ULM, a PTM, and combinations thereof.

[0102] In certain embodiments, compounds described herein include one or more PTMs chemically linked or attached to one or more ULMs or ULM's by a chemical linker (L). In certain embodiments, the linker group L is linked to one or more covalently connected structural units A (e.g., -A...A q -), wherein A1 is bonded to at least one of a ULM, a PTM, or a combination thereof. 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.

[0103] In certain embodiments, e.g., embodiments where q is greater than 2, Aq is a group connected to the ULM or ULM' moiety, and A and A q are connected by structural units A (the number of structural units A: q-2).

[0104] In certain embodiments, e.g., embodiments where q is 2, A q is a group connecting A1 and the ULM or ULM′ moiety.

[0105] In certain embodiments, e.g., embodiments where q is 1, the structure of the linker group, L, is -A1-, where A1 is a group connecting the ULM or ULM' moiety and the PTM moiety.

[0106] In further embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

[0107] In certain embodiments, A1 to A q are independently bonded, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3~11 Cycloalkyl, 0 to 6 R L1 and / or R L2C optionally substituted with a group 3~11 Heterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl optionally substituted with a group, R L1 or R L 2 independently connects to other A groups to form 0 to 4 R L5 groups can form cycloalkyl and / or heterocyclyl moieties which can be further substituted; R L1 , R L2 , R L3 , R L4 , and R L5 are independently H, halo, and C 1~8 Alkyl, OC 1~8 Alkyl, SC 1~8 Alkyl, NHC 1~8 Alkyl, N(C 1~8 Alkyl)2, C 3~11 Cycloalkyl, aryl, heteroaryl, C 3~11 Heterocyclyl, OC 1~8 Cycloalkyl, SC 1~8 Cycloalkyl, NHC 1~8 Cycloalkyl, N(C 1~8 cycloalkyl)2, N(C 1~8 Cycloalkyl)(C 1~8 alkyl), OH, NH2, SH, SO2C 1~8 Alkyl, P(O)(OC 1~8 Alkyl)(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 1~8Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1~8 Alkyl, SO2N(C 1~8 Alkyl)2, SONHC 1~8 Alkyl, SON(C 1~8 alkyl)2, CONHC 1~8 Alkyl, CON(C 1~8 alkyl)2, N(C 1~8 alkyl)CONH(C 1~8 alkyl), N(C 1~8 alkyl)CON(C 1~8 alkyl)2, NHCONH(C 1~8 alkyl), NHCON(C 1~8 alkyl)2, NHCONH2, N(C 1~8 alkyl)SO2NH(C 1~8 alkyl), N(C 1~8 alkyl)SO2N(C 1~8 alkyl)2, NHSO2NH(C 1~8 alkyl), NHSO2N(C 1~8 alkyl)2, NHSO2NH2.

[0108] In certain embodiments, A is independently a bond (i.e., absent), —(CH) i -O, -(CHR) i -O, (CR2) i -O, -(CH2) i -S, -(CH2) i -NR, -S, -S(O), -S(O)2, -OP(O)OR, -SiR2, TIFF2025128169000073.tif8128 groups, and X1Y1 is an amide group, a urethane group, an ester group, or a thioester group, or TIFF2025128169000074.tif10128 group formed; R are each independently H, or a C1-C3 alkyl, alkanol, or heterocycle (including a water-soluble heterocycle that promotes water solubility of the linker group, preferably a morpholino, piperidine, or piperazine group); each Y is independently a bond, O, S, or NR; Each i is independently 0 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6; 1, 2, 3, 4, or 5.

[0109] In a preferred aspect, A is TIFF2025128169000075.tif15128 group, D is independently a bond (absent), TIFF2025128169000076.tif42128; j is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; k is 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4, or 5; preferably, k is 1, 2, 3, 4, or 5; m' is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; n is 1-100, 1-75, 1-60, 1-55, 1-50, 1-45, 1-40, 2-35, 3-30, 1-15, 1-10, 1-8, 1-6, 1, 2, 3, 4, or 5; X 1 is O, S, or NR, preferably O; Y is as defined above; CON, when present in the linker group, converts A1 to A q is a connecting group (which can be a bond) that connects

[0110] In a preferred aspect, CON is a bond (absent), a heterocycle, including a water-soluble heterocycle such as piperazinyl or other group, or TIFF2025128169000077.tif42128 group, During the ceremony, X 2are independently O, S, NR4, OP(O)OR, SiR2, -CC, cycloalkyl, heterocyclyl, S(O), S(O)2, -S(O)2O, -OS(O)2, or OS(O)2O; X 3 is O, S, CHR4, NR4; R 4 is H or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof.

[0111] In an alternative preferred aspect, CON is a group as described above or an amide group.

[0112] In another aspect, the linker can be asymmetric or symmetric.

[0113] In an alternative preferred aspect, CON is TIFF2025128169000078.tif15128 group or amide group.

[0114] In alternative preferred aspects, the linker group is an optionally substituted (poly)ethylene glycol having 1 to about 100 ethylene glycol units, about 1 to about 50 ethylene glycol units, 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, 1 to 6 ethylene glycol units, or 2 to 4 ethylene glycol units. In certain embodiments, the linker may be substituted, i.e., comprises chemical groups interspersed within or on the PEG linker. In certain further embodiments, the PEG linker is substituted with alkyl, alkylene, aromatic, or aryl groups, such as phenyl, benzyl, or heterocyclyl groups, or amino acid side chains, and may be interspersed with optionally substituted O, N, S, P, or Si atoms.

[0115] In certain embodiments, the linker (L) is selected from the group consisting of: TIFF2025128169000079.tif49128TIFF2025128169000080.tif197147

[0116] While the ULM and PTM groups (including ULM' groups) can be covalently linked to the linker group through any group that is suitable and stable to the linker chemistry, in preferred aspects of the invention, the linkers are independently covalently linked to the ULM and PTM groups (including ULM' groups), preferably through an amide, ester, thioester, keto group, carbamate (urethane), or ether, any of which can be inserted anywhere on the ULM and PTM groups (including ULM' groups) to achieve maximal coupling between the ULM group on the ubiquitin ligase and the PTM group on the target protein to be degraded. (Note that in certain aspects where the PTM group is a ULM' group, the target protein to be degraded 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, an aryl group, or a heterocyclic group on the ULM and / or PTM group.

[0117] Exemplary Structures with Sites for Linkers In a further aspect, particularly preferred compounds of the present invention can be identified according to any one or more of the chemical structures set forth in Figure 19 herein, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000081.tif35128 formula, R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC Any one or more of the TIFF2025128169000082.tif10128 group, L is a linker group; TIFF2025128169000083.tif8128 is the protein targeting portion.

[0118] In a preferred embodiment, R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC Two or fewer of TIFF2025128169000084.tif10128 group, other R 1PC , R 2PC , R 3PC , R 4PC , R 5PC , R 6PC , R 7PC , R 8PC , R 9PC , R 10PC , R 11PC , R 12PC , R 13PC , and R 14PC The groups are independently H or CH3 groups, often H.

[0119] Certain preferred embodiments relate to ULM compounds of the following chemical structure, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000085.tif34128 formula, R 7PC and R 10PC are each independently a -[L-PTM] group or H. Preferably, R 7PC or R 10PC one of the R 7PC or R 10PC is H.

[0120] In yet another preferred embodiment, the compound has the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000086.tif51128 formula, R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC are each independently a -[L-PTM] group or H. Preferably, R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC wherein one of the groups is a -[L-PTM] group and the other group is H; or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0121] In yet another preferred embodiment, the compound has the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000087.tif49128 formula, R 4PC , R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC are each independently a -[L-PTM] group or H. Preferably, R 4PC , R 7PC Either of these or R 11PC , R 12PC , R 13PC , and R 14PC wherein one of the groups is a -[L-PTM] group and the other group is H; or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0122] In still other embodiments, the ULM compound has the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000088.tif48128 formula, R 3PC , R 7PC , R 11PC , R12PC , R 13PC , and R 14PC are each independently a -[L-PTM] group or H. Preferably, R 3PC , R 7PC , R 11PC , R 12PC , R 13PC , and R 14PC wherein one of the groups is a -[L-PTM] group and the other group is H; or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0123] In yet another preferred embodiment, the compound has the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: TIFF2025128169000089.tif31128 formula, R 7PC and R 9PC are each independently a -[L-PTM] group or H. Preferably, R 7PC and R 9PC wherein one of the groups is a -[L-PTM] group and the other group is H. or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

[0124] In the above embodiments, the linker group can be any of the linker groups described above, but is preferably a polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to about 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0125] Exemplary PTMs In other aspects of the invention, the PTM group is a group that binds to a target protein. Targets for the PTM group are numerous and selected from proteins expressed in cells such that at least a portion of the sequence is found in the cell and capable of binding to a PTM. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length to be capable of binding to the PTM groups of the invention. Any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi, as described elsewhere herein, is a target for ubiquitination mediated by the compounds of the invention. Preferably, the target protein is a eukaryotic protein. In certain aspects, the protein-binding moiety is a haloalkane (preferably a C1-C10 alkyl group substituted with at least one halo group, preferably at the distal end of the alkyl group (i.e., away from the linker or ULM group)), which can be covalently attached to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.

[0126] PTM groups of the present invention include, for example, any moiety that specifically binds to a protein (binds to a target protein), including, among others, the following non-limiting examples of small molecule target protein moieties: 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). The compositions described below exemplify several members of these nine classes 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 a 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 targeting moiety is bound) is in close proximity to the ubiquitin ligase for ubiquitination and degradation.

[0127] Any protein that can be attached to a protein targeting moiety or PTM group and acted upon or degraded by a ubiquitin ligase is a target protein of the present invention. In general, target proteins include, for example, proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell-to-cell communication, regulation of biological processes, development, cell differentiation, stimulation, and the like. These proteins may include structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integrated function of cells, including proteins involved in response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity), etc. Proteins of interest may include proteins from eukaryotes and prokaryotes, including humans, other animals, including domestic animals, as targets for drug therapy, microorganisms for the identification of targets for antibiotics and other antimicrobial agents, and plants, as well as viruses, among others.

[0128] In yet other embodiments, the PTM groups are haloalkyl groups, which generally range in size from about 1 or 2 carbons to about 12 carbons in length, often from about 2 to 10 carbons in length, often from about 3 to about 8 carbons in length, and more often from about 4 to about 6 carbons in length. Haloalkyl groups are generally straight-chain alkyl groups (although branched-chain alkyl groups may also be used) and are end-capped with at least one halogen group, preferably one halogen group, often one chlorine group. Haloalkyl PTM groups for use in the present invention have the chemical structure -(CH2)v Preferably, it is represented by -halo, where v is any integer from 2 to about 12, often from about 3 to about 8, and more often from about 4 to about 6. Halo can be any halogen, but is preferably Cl or Br, and more often Cl.

[0129] In still other embodiments, the PTM group is: TIFF2025128169000090.tif29128 groups wherein w is 0 to 3, preferably 1 or 2. This group selectively binds to the estrogen receptor and is useful for treating diseases modulated by the estrogen receptor, particularly cancer, such as breast cancer, endometrial cancer, ovarian cancer, and uterine cancer in particular.

[0130] The present invention can be used to treat a number of disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and in which the patient would benefit from protein degradation.

[0131] In another aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of the compound described above in combination with a pharmaceutically acceptable carrier, additive, or vehicle, and optionally, an additional biologically active agent.

[0132] In an alternative aspect, the present invention relates to a method for treating a disease state by degrading a protein or polypeptide by which the disease state or condition is regulated, comprising administering to said patient or subject an effective amount of at least one of the compounds described above, optionally in combination with an additional bioactive agent. The method of the present invention, by administering an effective amount of at least one compound described herein, can be used to treat numerous disease states or conditions, including cancer.

[0133] Protein targeting moieties of the present invention include, for example, 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). The compositions described below exemplify some members of these classes 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 proteins of interest. The references cited below are incorporated herein by reference in their entirety.

[0134] Heat shock protein 90 (HSP90) inhibitors HSP90 inhibitors as used herein include, but are not limited to: 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," include: YKB N-[4-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide TIFF2025128169000091.tif49128 derivatization, where the linker group L or TIFF2025128169000092.tif15128 groups are linked by a terminal amide group; 2. HSP90 inhibitor p54 (modified): p54 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine TIFF2025128169000093.tif39128wherein the linker group L or TIFF2025128169000094.tif15128 groups are linked by a terminal acetylene group; 3. HSP90 inhibitors identified in Broough, et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J.MED.CHEM. vol: 51, pag:196 (2008), including 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 (modification): TIFF2025128169000095.tif51128 derivatization, where the linker group L or TIFF2025128169000096.tif15128 group is attached by an amide group (at the amine or at an alkyl group on the amine); 4. HSP90 inhibitors (modifications) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the following structure: TIFF2025128169000097.tif36128wherein the linker group L or TIFF2025128169000098.tif15128 is linked by a butyl group; and 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-desmethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")) (derivatized, wherein the linker group L or TIFF2025128169000099.tif15128 groups are linked by amide groups).

[0135] II. Kinase and phosphatase inhibitors Kinase inhibitors as used herein include, but are not limited to: Erlotinib derivative tyrosine kinase inhibitor TIFF2025128169000100.tif30128wherein R is a linker group L attached by an ether group or TIFF2025128169000101.tif15128 group; 2. Kinase inhibitor sunitinib (derivatized): TIFF2025128169000102.tif30128 (derivatized. where R is a linker group L or TIFF2025128169000103.tif15128 group); 3. Kinase inhibitor sorafenib (derivatized) TIFF2025128169000104.tif23128 (derivatized. where R is a linker group L attached to the phenyl moiety or TIFF2025128169000105.tif15128 group); 4. Kinase inhibitor dasatinib (derivatized) TIFF2025128169000106.tif40128 (derivatized. Wherein R is a linker group L or TIFF2025128169000107.tif15128); Kinase inhibitor lapatinib (derivatized) TIFF2025128169000108.tif45128 derivatization, where the linker group L or TIFF2025128169000109.tif15128 group is attached by the terminal methyl of the sulfonylmethyl group; Kinase inhibitor U09-CX-5279 (derivatized) TIFF2025128169000110.tif43128 derivatization, where the linker group L or TIFF2025128169000111.tif15128 group is attached by an amine (aniline), carboxylic acid, or amine, or cyclopropyl group, which is alpha to the cyclopropyl group; 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, pag:7797 (2011), including kinase inhibitors Y1W and Y1X (derivatized) having the following structures: TIFF2025128169000112.tif481281-Ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea Derivatization, wherein the linker group L or TIFF2025128169000113.tif15128 groups are preferably attached by propyl groups; TIFF2025128169000114.tif521281-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea Derivatization, wherein the linker group L or TIFF2025128169000115.tif15128 groups are preferably attached by propyl or butyl groups; 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 0TP (derivatized) having the following structures: TIFF2025128169000116.tif391284-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide Thienopyridine 19 Derivatization, wherein the linker group L or TIFF2025128169000117.tif15128 groups are preferably attached via a terminal methyl group attached to the amide moiety; TIFF2025128169000118.tif391284-Amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide Thienopyridine 8 Derivatization, wherein the linker group L or TIFF2025128169000119.tif15128 groups are preferably attached via a terminal methyl group attached to the amide moiety; 9. Kinase inhibitors identified in Van Eis, et al., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes," Biorg. Med. Chem. Lett. 2011 Dec 15;21(24):7367-72, including kinase inhibitor 07U having the following structure: TIFF2025128169000120.tif461282-Methyl-N~1~-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine Derivatization, wherein the linker group L or TIFF2025128169000121.tif15128 groups are preferably attached via a secondary amine or terminal amino group; 10. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011), including the kinase inhibitor YCF having the following structure: TIFF2025128169000122.tif22128 derivatization, where the linker group L or TIFF2025128169000123.tif15128 groups are preferably attached via either terminal hydroxyl group; 11. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy," J.STRUCT.BIOL. vol:176, pag:292 (2011), including the kinase inhibitors XK9 and NXP (derivatized) having the following structures: TIFF2025128169000124.tif32128N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide TIFF2025128169000125.tif68128N-{4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide Derivatization, wherein the linker group L or TIFF2025128169000126.tif15128 groups are preferably attached via a terminal hydroxyl group (XK9) or a hydrazone group (NXP); 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, where the linker group L or TIFF2025128169000127.tif15128 groups are preferably attached by aliphatic amine groups); 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, where the linker group L or TIFF2025128169000128.tif15128 groups are preferably attached by methoxy groups); 14. The kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine) (derivatized, where the linker group L or TIFF2025128169000129.tif15128 groups are preferably attached by methoxy or ether groups); TIFF2025128169000130.tif3112815. Kinase inhibitor lenvatinib (derivatized) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivatized, where the linker group L or TIFF2025128169000131.tif15128 groups are preferably attached by a cyclopropyl group); 16. The kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized, where a linker group L or TIFF2025128169000132.tif15128 groups are preferably attached by methoxy or hydroxyl groups; and 17. 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, where the linker group L or TIFF2025128169000133.tif15128 groups are preferably attached by sulfonylpropyl groups); 18. Kinase inhibitor Gleevec (derivatized): TIFF2025128169000134.tif38128 (derivatized. Wherein the linker group L or TIFF2025128169000135.tif15128 group R is preferably attached via an amide or aniline amine group); Kinase inhibitor pazopanib (derivatized) (VEGFR3 inhibitor): TIFF2025128169000136.tif35128 (derivatized. where R is preferably a linker group L or TIFF2025128169000137.tif15128 group); Kinase inhibitor AT-9283 (derivatized) Aurora kinase inhibitor TIFF2025128169000138.tif31128, where R is preferably a linker group L attached to the phenyl moiety or TIFF2025128169000139.tif15128 group); Kinase inhibitor TAE684 (derivatized) ALK inhibitor TIFF2025128169000140.tif36128, where R is preferably a linker group L attached to the phenyl moiety or TIFF2025128169000141.tif15128 (base 1) Kinase inhibitor Nilotinib (derivatized) Abl inhibitor: TIFF2025128169000142.tif41128 (derivatized. wherein R is preferably a linker group L or TIFF2025128169000143.tif15128 group); 27. Kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor TIFF2025128169000144.tif46128 (derivatized. where R is a linker group L or TIFF2025128169000145.tif15128); 28. Kinase inhibitor Crizotinib-derivatized Alk inhibitor TIFF2025128169000146.tif51128 (derivatized. where R is a linker group L or TIFF2025128169000147.tif16128 group); 29. Kinase Inhibitor JNJ FMS (derivatized) Inhibitor TIFF2025128169000148.tif38128 (derivatized. where R is preferably a linker group L attached to the phenyl moiety or TIFF2025128169000149.tif15128 base); Kinase inhibitor foretinib (derivatized) Met inhibitor TIFF2025128169000150.tif35128 (derivatized. where R is a linker group L attached to the phenyl moiety or to a hydroxyl or ether group on the quinoline moiety TIFF2025128169000151.tif15128 group); 31. Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivatized): TIFF2025128169000152.tif57128 derivatization, where the linker group L or TIFF2025128169000153.tif15128 groups are preferably attached at the R shown. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatized): TIFF2025128169000154.tif43128 derivatization, where the linker group L or Preferably, the TIFF2025128169000155.tif15128 group is attached at R. BRAF(BRAF V600E ) / MEK inhibitor (derivatized): TIFF2025128169000156.tif40128 derivatization, where the linker group L or Preferably, the TIFF2025128169000157.tif15128 group is attached at R. 34. Tyrosine kinase ABL inhibitor (derivatized) TIFF2025128169000158.tif38128 (derivatized. where "R" represents a linker group L on the piperazine moiety or TIFF2025128169000159.tif15128 (showing the site for binding of the nucleotide).

[0136] III. MDM2 inhibitors MDM2 inhibitors as used herein include, but are not limited to: 1. MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol:303, pag:844-848 (2004) and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908, including (or in addition to) the compounds Nutlin-3, Nutlin-2, and Nutlin-1 (derivatized), and all derivatives and analogs thereof, as set forth below: TIFF2025128169000160.tif50128 (derivatized. Wherein the linker group L or TIFF2025128169000161.tif15128 groups are preferably attached at the methoxy or hydroxyl groups) TIFF2025128169000162.tif44128 (derivatized. Wherein the linker group L or TIFF2025128169000163.tif15128 groups are preferably attached at the methoxy or hydroxyl groups); TIFF2025128169000164.tif50128 (derivatized. Wherein the linker group L or TIFF2025128169000165.tif15128 groups are attached by methoxy or hydroxyl groups); and trans-4-Iodo-4'-boranyl-chalcone TIFF2025128169000166.tif25128 (derivatized. Wherein the linker group L or TIFF2025128169000167.tif15128 group is a linker group L or TIFF2025128169000168.tif15128 groups are attached by hydroxy groups);

[0137] IV. Compounds targeting human BET bromodomain-containing proteins Compounds that target human BET bromodomain-containing proteins include, but are not limited to, compounds related to the targets described below, where "R" can be, for example, a linker group L or TIFF2025128169000169.tif15128 shows the site for binding of the group: 1. TIFF2025128169000170.tif31128JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010) 2. TIFF2025128169000171.tif35128I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains. J. Med Chem. (2011). 3. TIFF2025128169000172.tif32128Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761. 4. TIFF2025128169000173.tif51128I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia. Nature (2011). (wherein "R" in each case indicates a site for attachment of, for example, a linker group L or a -(L-ULM) group).

[0138] V. HDAC inhibitors HDAC inhibitors (derivatized) include, but are not limited to: 1. TIFF2025128169000174.tif34128Finnin, MS et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188-193 (1999). (derivatized, where "R" is a linker group L or TIFF2025128169000175.tif15128 indicates the site for attachment of the group; and 2. Compounds defined by formula (I) of PCT WO0222577 (“DEACETYLASE INHIBITORS”) (derivatized, wherein the linker group L or TIFF2025128169000176.tif15128 groups are attached by hydroxyl groups);

[0139] VI. Human Lysine Methyltransferase Inhibitors Human lysine methyltransferase inhibitors include, but are not limited to: 1. TIFF2025128169000177.tif39128Chang et al. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat Struct Mol Biol (2009) vol. 16 (3) pp. 312-7 (derivatized, where "R" is a linker group L or TIFF2025128169000178.tif15128 (showing the site for binding of the group); 2. TIFF2025128169000179.tif39144Liu F, Chen X, Allali-Hassani A, et al. Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 2009;52(24):7950-3 (derivatized, where "R" is a linker group L or TIFF2025128169000180.tif15128 showing potential sites for attachment of groups); 3. Azacitidine (derivatized) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (derivatized, where the linker group L or TIFF2025128169000181.tif15128 groups are attached by hydroxyl or amino groups); and 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (derivatized, where a linker group L or TIFF2025128169000182.tif15128 groups are attached by either the hydroxy group or at the amino group).

[0140] VII. Angiogenesis inhibitors Angiogenesis inhibitors include, but are not limited to: 1. GA-1 (derivatized) and its derivatives and analogs, showing the structure and linkage to the linker 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; 2. A linker group L or 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. TIFF2025128169000183.tif15128 group-conjugable estradiol (derivatized); 3. Structures and linker groups L 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, or estradiol, testosterone (derivatized), and related derivatives, including but not limited to DHT and its derivatives and analogs, exhibiting binding to the TIFF2025128169000184.tif15128 group; and 4. Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and U.S. Pat. No. 7,208,157. The structures and linker groups L or TIFF2025128169000185.tif15128 Ovalicin, fumagillin (derivatized), and their derivatives and analogs showing binding to the .tif group.

[0141] VIII. immunosuppressive compounds Immunosuppressant compounds include, but are not limited to: 1. Structures and linker groups L 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, or TIFF2025128169000186.tif15128 showing binding to the AP21998 group (derivatized); 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (derivatized, where a linker group L or TIFF2025128169000187.tif15128 groups attached to either hydroxyl, for example) and beclomethasone dipropionate (derivatized. Wherein the linker group or TIFF2025128169000188.tif15128 is bound to, for example, propionate); 3. Methotrexate (derivatized, where a linker group or TIFF2025128169000189.tif15128 groups may be attached, for example, to either terminal hydroxyl); 4. Cyclosporin (derivatized, where a linker group or TIFF2025128169000190.tif15128 groups may be attached to, for example, any of the butyl groups); 5. Tacrolimus (FK-506) and rapamycin (derivatized, where the linker group L or TIFF2025128169000191.tif15128 groups can be attached, for example, to one methoxy group; and 6. Actinomycin (derivatized, where the linker group L or TIFF2025128169000192.tif15128 groups can be attached to, for example, one isopropyl group).

[0142] IX. Compounds that target the aryl hydrocarbon receptor (AHR) Compounds that target the aryl hydrocarbon receptor (AHR) include, but are not limited to: 1. Apigenin (Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007) is prepared by using a linker group L or TIFF2025128169000193.tif15128 derivatized to bind to the group; and 2. SR1 and LGC006 (linker group L or TIFF2025128169000194.tif15128 derivatized to allow binding).

[0143] X. Compounds that target RAF receptors (kinases) TIFF2025128169000195.tif41128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000196.tif15128 (showing the site for binding of the nucleotide).

[0144] XI. Compounds targeting FKBP TIFF2025128169000197.tif61128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000198.tif15128 (showing the site for binding of the nucleotide).

[0145] XII. Compounds that target the androgen receptor (AR) 1. RU59063 Ligand (Derivatization) of the Androgen Receptor TIFF2025128169000199.tif28128 (derivatized. where "R" is a linker group L or TIFF2025128169000200.tif15128 indicates the site for binding of the group. 2. Androgen Receptor SARM Ligands (Derivatization) TIFF2025128169000201.tif27128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000202.tif15128 (showing the site for binding of the nucleotide). 3. Androgen receptor ligand DHT (derivatized) TIFF2025128169000203.tif33128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000204.tif16128 (showing the site for binding of the group). MDV3100-like ligand (derivatized) TIFF2025128169000205.tif25128wherein R is a linker group L or TIFF2025128169000206.tif shows 5128 groups; ARN-509-like ligand (derivatized) TIFF2025128169000207.tif26128wherein R is a linker group L or TIFF2025128169000208.tif shows 5128 groups; Hexahydrobenzisoxazole TIFF2025128169000209.tif21128wherein R is a linker group L or TIFF2025128169000210.tif shows 5128 groups; Tetramethylcyclobutane TIFF2025128169000211.tif27128wherein R is a linker group L or TIFF2025128169000212.tif shows 5128 groups;

[0146] XIII. Estrogen Receptor (ER) Targeting Compound ICI-182780 1. Estrogen receptor ligands TIFF2025128169000213.tif27128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000214.tif15128 (showing the site for binding of the nucleotide). Compounds that target the thyroid hormone receptor (TR) Thyroid hormone receptor ligands (derivatized) TIFF2025128169000215.tif60128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000216.tif15128 indicates the site for attachment of the methyl group, and MOMO indicates a methoxymethoxy group).

[0147] XV. Compounds that target the HIV protease HIV protease inhibitors (derivatized) TIFF2025128169000217.tif23128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000218.tif15128 (showing the site for attachment of the methyl group). See J. Med. Chem. 2010, 53, 521-538. HIV protease inhibitors TIFF2025128169000219.tif33128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000220.tif15128 (showing potential sites for attachment of groups). See J. Med. Chem. 2010, 53, 521-538.

[0148] XVI. Compounds that target HIV integrase HIV integrase inhibitors (derivatized) TIFF2025128169000221.tif47128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000222.tif15128 (showing the site for attachment of the methyl group). See J. Med. Chem. 2010, 53, 6466. 2. HIV integrase inhibitors (derivatized) TIFF2025128169000223.tif45128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000224.tif15128 (showing the site for attachment of the methyl group). See J. Med. Chem. 2010, 53, 6466.

[0149] XVII. Compounds targeting HCV protease HCV protease inhibitor (derivatized) TIFF2025128169000225.tif67128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000226.tif15128 (showing the site for binding of the nucleotide).

[0150] XVIII. Compounds Targeting Acyl-Protein Thioesterases 1 and 2 (APT1 and APT2) APT1 and APT2 inhibitors (derivatized) TIFF2025128169000227.tif50128 (derivatized. Wherein "R" is a linker group L or TIFF2025128169000228.tif15128) showing the site for attachment of the hydroxyl group. See Angew. Chem. Int. Ed. 2011, 50, 9838-9842, where: L is a linker group as described elsewhere herein and the ULM groups are as described elsewhere herein, thus: TIFF2025128169000229.tif15128 attaches a ULM group to a PTM group described elsewhere herein.

[0151] Hereinafter, the term "target protein" is used to describe proteins or polypeptides that are targeted for conjugation to the compounds of the invention and degradation by 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 may target the protein of interest. These binding moieties are linked to the ULM group through a linker group, L.

[0152] Pharmaceutical Compositions In a further aspect, the present disclosure provides therapeutic or pharmaceutical compositions comprising at least one compound described herein, including, for example, an effective amount of at least one ULM, at least one PROTAC, and combinations thereof. A pharmaceutical composition comprising an effective amount of at least one bifunctional compound of the present invention and optionally, each in effective amounts of one or more compounds otherwise described herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient represents a further aspect of the present disclosure.

[0153] In certain embodiments, the compositions comprise pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. Acids used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned base compounds include acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, hydrogen tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), among others.

[0154] In addition, pharmaceutically acceptable base addition salts can be used to produce pharmaceutically acceptable salt forms of the present compounds or derivatives.The chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic are those that form non-toxic base salts with the compounds.Such non-toxic base salts include, but are not limited to, base salts derived from pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and lower alkanolammonium salts and other base salts of pharmaceutically acceptable organic amines.

[0155] In certain embodiments, the compounds described herein can be administered orally, parenterally, or topically in single or divided unit doses. Administration of the active compound can range from continuous administration (e.g., intravenous infusion) to multiple oral doses per day (e.g., four times daily), and routes of administration can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, sublingual, and suppository administration. Enteric-coated oral tablets may be used to improve the bioavailability of the compounds via oral administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the disease in the patient. Administration of the compounds of the present invention as sprays, mists, or aerosols for nasal, intratracheal, or pulmonary administration may also be used. Accordingly, the present invention also contemplates pharmaceutical compositions comprising an effective amount of a compound of the present invention, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle. The compounds of the present invention can be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Sustained- or controlled-release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injections in the form of liposomes may also be used to control or sustain the release of the compound at the injection site.

[0156] The compositions of the present invention can be conventionally formulated using one or more pharmaceutically acceptable carriers, and can be administered as controlled-release preparations.The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include but are not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, buffer substances such as glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block copolymer, polyethylene glycol, and wool fat.

[0157] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0158] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in preparing injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Swiss Pharmacopoeia or similar alcohols.

[0159] 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 aqueous solutions.For oral tablets, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also usually added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavors, or coloring agents can be added.

[0160] 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 materials include cocoa butter, beeswax, and polyethylene glycol.

[0161] The pharmaceutical compositions described herein may be administered topically. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically acceptable transdermal patches may also be used.

[0162] For topical application, pharmaceutical compositions can be formulated as a suitable ointment, which comprises the active ingredient suspended or dissolved in one or more carriers.The carrier for topical administration of the compound of the present invention includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.In a particular preferred aspect of the present invention, the compound can be coated on the stent that is to be surgically implanted in patients, so as to prevent or reduce the possibility of stent blockage in patients.

[0163] Alternatively, the pharmaceutical compositions can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers, including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0164] 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, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0165] The pharmaceutical compositions of the invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0166] The amount of compound in the pharmaceutical compositions of the present invention that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease being treated, and the particular mode of administration. Preferably, the compositions will be formulated to contain from about 0.05 milligrams to about 750 milligrams or more of the active ingredient, more preferably from about 1 milligram to about 600 milligrams, and even more preferably from about 10 milligrams to about 500 milligrams, alone or in combination with at least one other compound of the present invention.

[0167] It should also be understood that the specific dosage and treatment regimen in any particular patient will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease or condition being treated.

[0168] Patients or subjects in need of treatment using the compounds of the present invention can be treated by administering to the patient (subject) an effective amount of a compound of the present invention, e.g., a pharmaceutically acceptable salt, solvate, or polymorph thereof, optionally present in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known erythropoiesis stimulating agents as otherwise identified herein.

[0169] These compounds can be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, including transdermally, in liquid, cream, gel, or solid form, or by aerosol form.

[0170] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the target indication without causing significant toxic effects in the treated patient. Preferred doses of the active compound for all conditions referred to herein range from about 10 ng / kg to 300 mg / kg per day, preferably 0.1 to 100 mg / kg, and more typically 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical dosages range from 0.01 to 5% wt / wt in a suitable carrier.

[0171] The compounds are conveniently 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. In many cases, an oral dosage of about 25 to 250 mg is convenient.

[0172] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, whether in saline or aqueous medium, or by administration of the active ingredient as a bolus. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0173] The concentration of the active compound in the drug composition depends on the absorption rate, distribution rate, inactivation rate and excretion rate of the drug, and other factors known to those skilled in the art.It should also be noted that the dosage value varies depending on the severity of the condition to be alleviated.It should be further understood that for any specific subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person who administers or supervises the administration of the composition, and that the concentration ranges described herein are only illustrative and are not intended to limit the scope or implementation of the claimed compositions.The active ingredient may be administered at once or divided into several small doses that are administered at varying time intervals.

[0174] Oral compositions generally contain an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition.

[0175] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or cornstarch; lubricants such as magnesium stearate or Sterotes; 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, in addition to the above-mentioned types of materials, it may contain a liquid carrier such as fatty oil. Furthermore, the unit dosage form may contain various other materials that modify the physical form of the unit dosage form, such as sugar coating, shellac, or enteric coating.

[0176] The active compound or its pharmaceutically acceptable salts can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0177] The active compounds or pharmaceutically acceptable salts thereof may also be mixed with other active substances that do not impair the desired action, or substances that supplement the desired action, such as erythropoietin stimulating agents, including EPO and darbepoetin alfa, among others. In certain preferred aspects of the invention, one or more compounds of the invention are co-administered with another bioactive agent, such as an erythropoietin stimulating agent, including an antibiotic, or a wound healing agent, as described elsewhere herein.

[0178] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate buffers, and agents for adjusting tonicity such as sodium chloride or glucose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple dose vials.

[0179] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0180] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art.

[0181] Liposomal suspensions can also be pharmaceutically acceptable carriers.They can be prepared according to the methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (its entirety is incorporated herein by reference).For example, liposomal preparations can be prepared by dissolving suitable lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, and then evaporating the inorganic solvent, leaving a thin film of dry lipid on the surface of the container.Then, an aqueous solution of active compound is introduced into the container.Then, the container is stirred by hand to release lipid material from the side of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0182] The term "pharmaceutically acceptable salt" is used throughout this specification to describe, where appropriate, the salt form of one or more compounds described herein, which is provided to increase the solubility of the compound in the gastric juice of the patient's gastrointestinal tract in order to promote dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, salts derived from pharmaceutically acceptable inorganic or organic bases and acids. Among the many acid and base salts well known in the pharmaceutical field, suitable salts include salts derived from alkali metals such as potassium and sodium, and alkaline earth metals such as calcium, magnesium, and ammonium. Sodium salts and potassium salts are particularly preferred as neutralized salts of the phosphate salts of the present invention.

[0183] Throughout this specification, the term "pharmaceutically acceptable derivative" is used to describe any pharmaceutically acceptable prodrug form (such as an ester, amide, or other prodrug group) that, upon administration to a patient, directly or indirectly yields the compound or an active metabolite of the compound.

[0184] Treatment method As used herein, the terms "treat," "treating," and "treatment" refer to any effect that benefits a patient to whom the compound can be administered, including treatment of any disease state or condition that is modulated by the protein to which the compound binds. Disease states or conditions that can be treated using the compounds of the present invention, including cancer, are as described above.

[0185] In yet another aspect, the present disclosure provides a method for identifying a target protein associated with a predetermined cellular function, comprising the steps of incubating cells with a composition from a library of the present invention; monitoring the predetermined cellular function; identifying a composition that alters the predetermined cellular function; and identifying a target protein associated with the predetermined cellular function and that binds to the identified composition.

[0186] In yet another aspect, the present disclosure provides a method for identifying target proteins associated with a predetermined function of cells.The method includes the steps of incubating cells with a pool of entities from the library of the present invention; monitoring the predetermined function of cells; identifying the pool of entities that changes the predetermined function of cells; incubating cells with a composition from the identified pool of entities; monitoring the predetermined function of cells; identifying the composition that changes the predetermined function of cells; and identifying the target protein that is associated with the predetermined function of cells and binds to the identified composition.

[0187] In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. The method includes administering a bifunctional composition described elsewhere herein, comprising a ubiquitin pathway protein binding moiety and a targeting moiety, preferably linked via a linker moiety, wherein the ubiquitin pathway protein binding moiety is linked to the targeting moiety, the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the targeting moiety recognizes the target protein, such that degradation of the target protein occurs when the target protein is brought into proximity with 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 provided by the present disclosure provides for treatment of a disease state or condition regulated by the target protein by reducing the level of the target protein in the patient's cells.

[0188] In yet another aspect, the present disclosure provides a method for treating or preventing a disease state or condition in a patient in need thereof that is modulated by a protein, wherein degradation of the protein produces a therapeutic effect in the patient, comprising administering to the patient an effective amount of a compound of the present invention, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial agent or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that causes the disease state and / or condition.

[0189] Target proteins that can be bound to a protein targeting moiety and degraded by a ligase bound to a ubiquitin ligase binding moiety include those that have catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, protein degradation, proteins involved in biosynthesis, 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 (proteins, lipids, carbohydrates), receptor activity, cell motility, and membrane fusion. Proteins of interest include structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integrated function of cells, including proteins involved in cell-to-cell communication, control of biological processes, development, cell differentiation, response to stimuli, behavioral proteins, cell adhesion proteins, proteins involved in cell death, transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity). Proteins of interest can include proteins from eukaryotes and prokaryotes, including humans, microorganisms, viruses, fungi, and parasites, other animals, including domestic animals, microorganisms for the identification of targets for antibiotics and other antimicrobial agents, and plants, as well as viruses, among others.

[0190] More specifically, several drug targets for human therapeutics represent protein targets to which protein targeting moieties can be attached and incorporated into compounds of the present invention. These include proteins that can be used to restore function in numerous polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partners in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase, PDE IV phosphodiesterase 4, PDE I, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 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, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake These include receptors for endothelin, neuropeptide Y and receptors, estrogen receptors, androgen receptors, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA, the receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include ecdysone 20 monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Still further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0191] Haloalkane dehalogenase enzymes are another target for certain compounds of the present invention. Chloroalkane peptide-linked moieties (C1-C6) can be used to bind chloroalkane peptides, as described in PCT / US 2012 / 063401, filed December 6, 2011, and published June 14, 2012 as WO 2012 / 078559, the contents of which are incorporated herein by reference. 12 , often about C2 to C 10The compounds of the invention containing an alkylhalo group (such as alkane, alkane, or alkane-1, alkane-2, alkane-3, alkane-4, alkane-5, alkane-6, alkane-7, alkane-8, alkane-9, alkane-10, alkane-11, alkane-12, alkane-13, alkane-14, alkane-15, alkane-16, alkane-17, alkane-18, alkane-19 ...20, alkane-21, alkane-22, alkane-23, alkane-24, alkane-25, alkane-26, alkane-27, alkane-28, alkane-29, alkane-29, alkane-29, alkane

[0192] These various protein targets can be used in screens to identify compound moieties that bind to the protein, which, when incorporated into the compounds of the invention, can alter the activity level of the protein toward an ultimate therapeutic result.

[0193] The term "disease state or condition" is used to describe any disease state or condition in which dysregulation of a protein (i.e., an increase in the amount of protein expressed in a patient) occurs and in which degradation of one or more proteins in a patient can provide beneficial treatment or alleviation of symptoms to a patient in need thereof. In certain cases, the disease state or condition is curable.

[0194] Disease states or conditions that can be treated using the compounds of the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0195] Additional disease states or conditions treatable by the compounds of the 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's syndrome, and vasculitis.

[0196] Still further disease states or conditions treatable by the compounds of the present invention include aceruloplasminemia, achondroplasia type II, achondroplasia, acrocephaly, 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, alkaptonuric ochronosis, alpha 1 antitrypsin deficiency, alpha 1 proteinase inhibitors, emphysema, among others. , amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome , Familial Mediterranean fever, Benjamin syndrome, β-thalassemia, Bilateral acoustic neuromas (Neurofibromatosis type II), Factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (Incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevy-Ullrich syndrome (Turner syndrome), Bourneville disease (Tuberous sclerosis), Prion diseases, Birt-Hogg-Dubé syndrome, Brittle bone disease (Osteogenesis imperfecta), Broad hallux syndrome (Rubinstein-Taybi syndrome), Bronze diabetes / bronze cirrhosis (Hemochromatosis), Spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grüß syndrome Tu's syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disorder, chiropteran dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-a-cat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia), oto-spondylotic-giant 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, conotruncal dysfacial syndrome, Cooley anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Degenerative neurological disorders including Behle-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Grouch syndrome, and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythropoietic protoporphyria, red blood cell 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic disease, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Grenblatt-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cytic anemia, hemophilia, myelohepatic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, speckled dementia,Langer-Saldino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Peiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome Zucker's syndrome, Prader-Lovehart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's) (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal tonic muscular dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS Type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Levi syndrome, Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, Sarcoma-Breast-Leukemia-Adrenal Carcinoma (SBLA) syndrome, Tuberous sclerosis (sclerosis tuberose, tuberous sclerosis), SDAT, Spondyloepiphyseal dysplasia congenita (SED), SED Strudwick type (SEDc), Spondyloepiphyseal dysplasia congenita (SEMD) Strudwick syndrome (spondyloepiphyseal dysplasia Strudwick type), Shprintzen syndrome, dyschromia, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease,These include sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik's disease, Waardenburg syndrome, Warburg-Schöff-Fredelius syndrome, Weissenbacher-Zweymuller syndrome, Wolff-Hirschorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum.

[0197] Throughout this specification, the term "cancer" is used to mean a pathological process that results in the formation and proliferation of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation, often more rapidly than normal tissues, and that continue to grow even after the stimuli that initiated the new growth have ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues, most of which infiltrate surrounding tissues, metastasize to several sites, are likely to recur after attempted removal, and are likely to cause the death of the patient if not treated appropriately. Exemplary cancers treatable by the present compounds, alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, 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, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; Cancers that can be treated with the compound of the present invention include intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma.Other cancers that can be treated with the compound of the present invention include, for example, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell 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.

[0198] The term "co-administration" or "combination therapy" is intended to mean that at least two compounds or compositions are administered to a patient simultaneously such that effective amounts or concentrations of each of the two or more compounds can be found in the patient at a given time. While the compounds of the present invention can be co-administered to a patient, the term encompasses both simultaneous and different administration of two or more agents, provided that effective concentrations of all co-administered compounds or compositions are found in the patient at a given time.

[0199] In a further aspect, the present disclosure provides a combination therapy comprising an effective amount of a compound described herein in combination with an additional bioactive agent. The term "bioactive agent" is used to describe an agent other than the compound described herein that is used in combination with the compound as an agent having a biological activity that helps to achieve the intended treatment, inhibition, and / or prevention / prophylaxis of the compound. Preferred bioactive agents for use herein include agents having pharmacological activity similar to that for which the compound is used or administered, such as anti-cancer agents, antiviral agents, particularly anti-HIV and anti-HCV agents, antibacterial agents, antifungal agents, etc. In certain embodiments, the compound described herein, the additional bioactive agent, or both, are present in an effective amount, or in certain embodiments, a synergistically effective amount.

[0200] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be combined with a compound of 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, 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, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, dimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, Lucanton, LY317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliciclib;PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol Radiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] 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, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, Suplatin, 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 acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, PEGylated interferon α-2a, interferon α-2a, PEGylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalid Mido, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam,These include haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0201] The term "anti-HIV agent" or "additional anti-HIV agent" specifically includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., inhibitors not representative of the present invention), protease inhibitors, and fusion inhibitors, exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverse Transcriptase), Mention may be made of fusion inhibitors such as D4T (stavudine), Rasivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesylate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), and especially T20, fusions and mixtures thereof, which include anti-HIV compounds currently in clinical trials or development.

[0202] Other anti-HIV agents that can be used in co-administration with the compounds of the invention include, for example, nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, baicalin (TJN-151), ADAM-II (methylaminidase), among others. 3',3'-dichloro-4',4''-dimethoxy-5',5''-bis(methoxycarbonyl)-6,6-Diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), 5Cl3PhS-2Indo1CONH2 (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), capravirine (AG-1549, S-1153), atevirdine (U-87201E), aurintricarboxylic acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine-1 pyridine) 4 indolyl derivatives), 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine 1 pyridine 5 indolyl derivatives), 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC), 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine (piperazine 1 pyridine 5 indolyl derivatives), 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbon ... 633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, foscarnet (foscavir), HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine), HEPT-M (1-[(2-hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine), HEPT-S (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine), Inophyllum P, L-737,126, Mikellamine A (NSC650898), Mikellamine B (NSC649324), Mikellamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(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 derivatives), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)]thiourea {PETT pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea, N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497), L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl)ethyl}-5-ethyl-6-methyl(pyridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy-5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione (2-pyridinone 3-pyridyl 3MeNH derivative), R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, tivirapine (R86183), UC-38, and UC-84.

[0203] General synthetic approach A general scheme for the synthesis of ULM derivatives is now described. Briefly, compounds of the present invention are synthesized according to a general solution-phase synthesis scheme (shown below) and / or general scheme I for the solution-phase synthesis of compounds of the present invention. First, a hydroxyl-protected carboxy-substituted (and protected) pyrrolidine compound is reacted with a carboxylic acid-containing reagent, thereby introducing a carbonyl group at the amine of the pyrrolidine ring to form an amide group. Alternatively, the pyrrolidine amine can be protected, and an amide can be obtained on the right-hand side of the pyrrolidine moiety by condensing the carboxylic acid moiety with a nucleophilic group on the right-hand side. It is preferred that the left-hand and right-hand side fragments to be condensed onto the amine and carboxylic acid groups, respectively, of the pyrrolidine moiety are prepared prior to condensation onto the pyrrolidine group, although other approaches for introducing groups onto the pyrrolidine group may be employed. The individual components that are combined to produce the ULM group can be prepared by using a blocking group at a preferred functional group on the ULM group, which can be removed to react and covalently bond with a PTM moiety already attached to the protein binding moiety, or with a linker group prepared to accommodate the PTM group, or which can be further reacted to form a covalent bond with a PTM group, which may include a ULM' group as described elsewhere herein. Thus, condensation of a carboxylic acid-containing left-hand side fragment onto the amine group of the pyrroline yields R, as shown below: 1 An amide group can be formed with the left-hand fragment. Any number of nucleophilic (preferably amine-containing) right-hand fragments (pre-synthesized) can be condensed onto the carboxyl group to form the R 2 An amide group with the right fragment can be obtained. Formation of presynthesized groups to be condensed onto the amine and / or carboxyl moieties of the pyrrolidine proceeds readily. Solid-phase synthesis may also be used, which employs methods similar to those used in solution-phase synthesis, with the major difference being that the hydroxyl group can be attached to a solid support while other steps of the synthesis are carried out. The general synthetic method is applicable to virtually all compounds of the present invention, and easy modifications are made in accordance with the state of the art of chemical synthesis, either directly using or adapted from the specific teachings of the following examples.

[0204] Scheme 1. Solution-phase synthesis of UML derivatives of the present invention. TIFF2025128169000230.tif66137

[0205] liquid phase method Solution-phase synthesis, the technique traditionally used by most synthetic organic chemists, is favored by many for library construction due to the relatively wide range of organic reactions available, and products in solution can be relatively easily identified and characterized in standard drug targeting assays. The problem with solution-phase synthesis one molecule at a time is that final purification can be expensive and slow. Chromatography is typically the first resort, as it usually works well. Furthermore, the problems associated with solution-phase chemistry become complicated when attempting to generate libraries or "books" for libraries by making tens of thousands of compounds.

[0206] Numerous methods have been devised for generating compound libraries, which has led to the widespread use of large libraries of chemicals that facilitate the discovery of potential drug candidates. The generation of solution-free chemical libraries is typically the goal of most in the pharmaceutical industry. This goal is due to the nature of many drug targets and related assays. Furthermore, the construction and utility of chemical libraries is typically facilitated by the generation of master plates of compounds in solution that form the basis of the chemical library. Therefore, the general advantages of solid-phase synthesis methods are typically not fully realized in current drug discovery efforts. This is primarily because the focus is not on the binding of the compound to the drug target, but rather on demonstrating that the activity of the drug target is altered, which typically requires the compound to be solution-free. Additional challenges with solid-phase compound libraries arise from the potential impact of linkers and steric effects on solid-phase-bound compounds.

[0207] Thus, methods for the discovery of compounds that bind to target molecules are known in the art, and the optimization of initially discovered compounds, where affinity is improved by generating pools of related compounds through more selective combinatorial chemistry approaches, is also well known in the art.

[0208] The present invention provides a mechanism for overcoming these problems in drug and small molecule discovery.

[0209] Addition of ubiquitin ligase binding moiety (ULM) At this point in the compound discovery pathway for the present invention, the target protein binding elements of the compounds of the present invention have been identified. These optimal binding molecules are then subjected to further chemical reactions to add ubiquitin ligase binding moieties (ULMs) in accordance with the disclosure of this application.

[0210] Regulation of protein levels The present invention also relates to a method for the control of protein levels in cells, which is based on the use of compounds of the present invention that are known to interact with specific target proteins, such that the amount of the protein in a biological system is controlled, preferably to a specific therapeutic effect, by degradation of the target protein in vivo.

[0211] The following examples are used to help illustrate the present invention, but should not be construed as limiting the invention in any way. [Example]

[0212] General Methods for Chemical Synthesis The following general chemical synthetic methods are provided for synthesizing a number of compounds of the present invention as set forth in the Affinity Table of Table 2 above. Each method is provided for a specific compound, the synthetic details of which are set forth above. All numbered compounds can be synthesized with relative ease using the straightforward methods described below. In certain cases, synthetic details are further provided for certain preferred embodiments to provide information that may serve as a template for synthesizing several other compounds otherwise disclosed herein.

[0213] Unless otherwise noted, all reactions were carried out in oven-dried or flame-dried glassware fitted with rubber septa under positive nitrogen pressure. Air- and moisture-sensitive liquids were transferred via syringe or cannula. THF was distilled from sodium / benzophenone. Dichloromethane was distilled from calcium hydride. Analytical thin-layer chromatography (TLC) was performed using glass plates (0.25 mm) pre-coated with silica gel. TLC plates were visualized by exposure to ultraviolet light (UV) or KMnO4. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck) with the indicated solvents.

[0214] TIFF2025128169000231.tif33134 As an example, see the following synthesis of compound VL133.

[0215] Synthesis of VL133 (2S,4R)-4-Hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid TIFF2025128169000232.tif32128 (2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (124.9 mg, 0.4 mmol, 1 equiv.) was dissolved in DCM (18 mL) at room temperature. TFA (2 mL, 10%) was added, and the solution was stirred for 12 h. It was then concentrated under reduced pressure and purified by column chromatography (4→20% MeOH / DCM) to give a yellow oil (99.7 mg, 0.39 mmol, 98%). TIFF2025128169000233.tif32150

[0216] (2S,4R)-N-(4-(1H-pyrrol-3-yl)benzyl)-4-hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxamide (VL133) (2S,4R)-4-Hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (52.6 mg, 0.207 mmol, 1.3 equiv.), (4-(1H-pyrrol-3-yl)phenyl)methanamine (27.3 mg, 0.159 mmol, 1 equiv.), EDC (39.7 mg, 0.207 mmol, 1.3 equiv.), and HOBt (28 mg, 0.207 mmol, 1.3 equiv.) were dissolved in DMF (4.1 mL) and cooled to 4 °C. DIPEA (0.083 mL, 0.477 mmol, 3 equiv.) was added, and the solution was allowed to warm slowly to room temperature. After 16 h, the mixture was poured into half-saturated sodium chloride (aq) and extracted three times with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (1→10% 0.5 N NH(MeOH) / DCM) afforded an off-white solid (41.5 mg, 0.102 mmol, 64%). TIFF2025128169000235.tif45146

[0217] For further details, please refer to the following paper and the references cited therein: Buckley DL et al. J. Am. Chem. Soc 2012, 134, 4465-4468. Van Molle I et al. A Chemistry & Biology 2012, 19, 1300-1312 Buckley, D Angew. Chem. Int. Ed., 2012, 51, 11463-11467 Buckley, D. Let al. Angew. Chem. 2012, 124, 11630-11634.

[0218] TIFF2025128169000236.tif27128As an example, see the following synthesis of compound VL116.

[0219] Synthesis of VL116 (2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (53.7 mg, 0.173 mmol, 1.3 equiv.), (4-(4-methylthiazol-5-yl)phenyl)methanamine (27.2 mg, 0.133 mmol, 1 equiv.), EDC (33.2 mg, 0.173 mmol, 1.3 equiv.), and HOBt (23.4 mg, 0.173 mmol, 1.3 equiv.) were dissolved in DMF (3.5 mL) at 4 °C. DIPEA (0.07 mL, 0.4 mmol, 3 equiv.) was added, and the solution was allowed to warm slowly to room temperature. After 19 h, the mixture was poured into brine and extracted four times with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (1->5% MeOH / DCM) afforded a colorless oil (58.1 mg, 0.117 mmol, 88%). TIFF2025128169000238.tif38146

[0220] (2S,4R)-4-Hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VL116) TIFF2025128169000239.tif32128 (2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (58.1 mg, 0.117 mmol) was dissolved in DCM (8 mL). TFA (2 mL, 20% vol / vol) was added, and the solution was stirred at room temperature for 12 h, after which it was concentrated under reduced pressure. Purification by column chromatography (1→10% 0.5 N NH(MeOH) / DCM) afforded a colorless oil (28.4 mg, 0.065 mmol, 56%). TIFF2025128169000240.tif38147

[0221] TIFF2025128169000241.tif24128As an example, see the following synthesis of compound VL 156:

[0222] Synthesis of VL156 In a 1-dram vial, 1H-imidazol-1-ylacetic acid (20.6 mg, 0.163 mmol, 1.3 equiv.), EDC (31.2 mg, 0.163 mmol, 1.3 equiv.), and HOBt (22 mg, 0.163 mmol, 1.3 equiv.) were dissolved in DCM (2.5 mL) and DMF (0.4 mL) at room temperature. After stirring for 15 min, DIPEA (0.055 mL, 0.313 mmol, 2.5 equiv.) was added, followed by (2S,4R)-4-(tert-butoxy)-N-(4-chlorobenzyl)pyrrolidine-2-carboxamide (38.9 mg, 0.125 mmol, 1 equiv.) 30 min later. The mixture was stirred for 14 hours, then diluted with EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (1->10% MeOH / DCM) gave a white solid, which was used directly in the next step. TIFF2025128169000243.tif25146

[0223] The white solid was dissolved in DCM (9 mL) at room temperature. TFA (1 mL) was added, and the mixture was stirred for 12 h and concentrated. Purification by column chromatography (1→20% 0.5 N methanolic ammonia / DCM) gave a white solid (39.8 mg, 0.11 mmol, 88% over two steps). TIFF2025128169000244.tif38149

[0224] TIFF2025128169000245.tif24128As an example, see the following synthesis of compound VL 217.

[0225] Synthesis of VL217 TIFF2025128169000246.tif18128

[0226] (2S,4R)-4-(tert-butoxy)-1-(3-ethoxybenzoyl)-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide 3-Ethoxybenzoic acid (13.3 mg, 0.08 mmol, 1 equiv.), EDC (16.9 mg, 0.088 mmol, 1.1 equiv.), and HOBt (11.9 mg, 0.88 mmol, 1.1 equiv.) were dissolved in DCM (0.8 mL) at room temperature. DIPEA (0.0279 mL, 0.16 mmol, 2 equiv.) was added, followed by (2S,4R)-4-(tert-butoxy)-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (33.0 mg, 0.096 mmol, 1.2 equiv.). The solution was stirred for 21 h, then diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (1→5% MeOH / DCM) afforded a colorless oil (36.1 mg, 0.073 mmol, 92%). TIFF2025128169000248.tif32148

[0227] VL217 TIFF2025128169000249.tif23128 (2S,4R)-4-(tert-butoxy)-1-(3-ethoxybenzoyl)-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (36.1 mg, 0.073 mmol, 1 equiv.) was dissolved in DCM (9 mL) at room temperature. TFA (1 mL) was added, and the solution was stirred for 13 h and then concentrated. Purification by column chromatography (1→10% MeOH / DCM) afforded a colorless oil (22.9 mg, 0.053 mmol, 72%). TIFF2025128169000250.tif45148

[0228] TIFF2025128169000251.tif32128As an example, see the following synthesis of compound VL 219.

[0229] Synthesis of VL219 TIFF2025128169000252.tif35128VL219 TIFF2025128169000253.tif231283-Ethoxybenzoic acid (17 mg, 0.1 mmol, 1 equiv.) was dissolved in 1 mL of 10:1 DCM:DMF, and EDC (25 mg, 0.13 mmol, 1.3 equiv.) and HOBt (21 mg, 0.13 mmol, 1.3 equiv.) were added. After stirring for 5 min, (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (31 mg, 0.095 mmol, 1 equiv.) was added. After stirring for 18 h, the reaction was diluted with 15 mL of EtOAc and washed with 25 mL of 10% aqueous citric acid and 25 mL of saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (DCM to 9% MeOH (0.5N NH3) in DCM) to give 25 mg (56% yield) of the product as a white solid. TIFF2025128169000254.tif45149

[0230] TIFF2025128169000255.tif22128 Method F encompasses Methods C, D, and E and is a general method that proceeds through commercially available amines.

[0231] The following procedures were used to synthesize and / or characterize compounds of the present invention.

[0232] Compound characterization and purification 1 HNMR (300 or 400 MHz) and 13 C NMR (100.6 MHz) spectra were recorded on a Bruker spectrometer at room temperature using TMS or the residual solvent peak as an internal standard. Line positions or multiplicities are indicated (δ), and coupling constants (J) are given as absolute values ​​in Hertz (Hz). 1 Multiplicities in H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad (broadened).

[0233] Analytical LC-MS data were collected on a Shimadzu LCMS-2020 with mobile phases 0.05% TFA in acetonitrile (A) and 0.05% TFA in HPLC-grade water (B); 0.1% FA in acetonitrile (A) and 0.1% FA in HPLC-grade water (B); acetonitrile (A) and 5 mM ammonium bicarbonate in HPLC-grade water (B). The Shimadzu LCMS-2020 is equipped with an LC-20AD or 30AD pump, an SPD-M20A PDA, and an Alltech 3300 ELSD. The system uses the following conditions with run times of 2.0, 2.6, 3, 3.6, 5, or 5.6 minutes: Run time 2.0 min: Kinetex XB-C 18 100A column, 2.6 μm, 3.0 x 50 mm. Flow rate 1.5 mL / min, run time 2.0 min, gradient profile 10% A 0.01 min, 100% A 1.10 min, 100% A 1.60 min, 10% A 1.70 min, 10% A 2.00 min. Run time 2.6 min: Shim-pack VP-ODS column, 2.2 μm, 3.0 x 50 mm. Flow rate was 1.5 mL / min, run time was 2.6 min, gradient profile was 5% A 0.01 min, 100% A 1.20 min, 100% A 2.20 min, 5% A 2.30 min, 5% A 2.60 min. Run time 3.0 min: ACE UltraCore Super C18 column, 2.5 μm, 3.0 x 50 mm. Flow rate was 1.5 mL / min, run time was 3.0 min, gradient profile was 10% A 0.01 min, 95% A 2.00 min, 95% A 2.60 min, 10% A 2.70 min, 10% A 3.00 min. Run time 3.6 min: Shim-pack VP-ODS column, 2.2 μm, 3.0 x 50 mm. Flow rate was 1.5 mL / min, run time was 3.6 min, gradient profile was 5% A 0.01 min, 100% A 2.20 min, 100% A 3.20 min, 5% A 3.30 min, 5% A 3.60 min. Run time 5.0 min: ACE UltraCore Super C18 column, 2.5 μm, 3.0 x 50 mm. Flow rate was 1.5 mL / min, run time was 5.0 min, and gradient profile was 10% A 0.01 min, 60% A 4.00 min, 60% A 4.70 min, 10% A 4.80 min, 10% A 5.00 min. Run time 5.6 min: Shim-pack VP-ODS column, 2.2 μm, 3.0 x 50 mm. Flow rate was 1.5 mL / min, run time was 5.6 min, gradient profile was 5% A 0.01 min, 50% A 3.00 min, 50% A 5.00 min, 5% A 5.20 min, 5% A 5.60 min.

[0234] LCMS data were also collected on an Agilent infinity 1260 LC; Agilent 6230 TOF mass spectrometer. Analyses were performed on a Poroshell 120 EC C18 column (50 mm x 3.0 mm internal diameter, 2.7 μm packing diameter) at 45 °C.

[0235] The eluents used were as follows: A = 0.1% v / v formic acid in water. B = 0.1% v / v formic acid in acetonitrile.

[0236] The gradient used was as follows: TIFF2025128169000256.tif57128

[0237] Ultraviolet detection was performed with an average signal between 210 nm and 350 nm wavelength, and mass spectra were recorded on a mass spectrometer using positive mode electrospray ionization.

[0238] Unless otherwise stated, all LC-MS data reported was based on the instrumentation and methods described above. All compounds were prepared with LC-MS purity >95% unless otherwise stated.

[0239] Below are the mobile phases and gradients used when the compounds underwent purification by mass-directed automated preparative HPLC.

[0240] Mass-directed automated preparative HPLC (formic acid modifier) HPLC analysis was carried out on a Sunfire C18 column (150 mm×30 mm id, 5 μm packing diameter) at ambient temperature.

[0241] The solvents used were as follows: A = 0.1% v / v formic acid in water. B = 0.1% v / v formic acid in acetonitrile.

[0242] Mass-directed automated preparative HPLC (trifluoroacetic acid modifier) HPLC analysis was carried out on a Sunfire C18 column (150 mm×30 mm id, 5 μm packing diameter) at ambient temperature.

[0243] The solvents used were as follows: A = 0.1% v / v aqueous trifluoroacetic acid solution. B = 0.1% v / v trifluoroacetic acid in acetonitrile.

[0244] Mass-Directed Automated Preparative HPLC (Ammonium Bicarbonate Modifier) HPLC analysis was carried out on an XBridge C18 column (150 mm×30 mm id, 5 μm packing diameter) at ambient temperature.

[0245] The solvents used were as follows: A = 10 mM ammonium bicarbonate solution adjusted to pH 10 with ammonia solution. B = acetonitrile.

[0246] For each mass-directed automated preparative purification, regardless of the modifier used, the gradient used depended on the retention time recorded in the analytical LCMS of the particular compound undergoing purification and was as follows: For compounds with analytical LCMS retention times below 0.6 minutes, the following gradient was used: TIFF2025128169000257.tif50128For compounds with analytical LCMS retention times between 0.6 and 0.9 minutes, the following gradient was used: TIFF2025128169000258.tif50128For compounds with analytical LCMS retention times between 0.9 and 1.2 minutes, the following gradient was used: TIFF2025128169000259.tif50128For compounds with analytical LCMS retention times between 1.2 and 1.4 minutes, the following gradient was used: TIFF2025128169000260.tif50128

[0247] Ultraviolet detection was by averaging the signal between 210 nm and 350 nm wavelength, and mass spectra were recorded on a mass spectrometer using alternating scan positive-negative mode electrospray ionization.

[0248] Preparative HPLC purification was also performed on a Waters® UV-Directed Purification System equipped with a 2545 Binary Gradient Module, a 2767 Sample Manager, and a 2489 UV / Visible Detector, controlled by MassLynx V4.1 software. All purification work was completed using the following columns: Atlantis Prep T3 OBD Column, SunFire Prep C18 OBD Column, and XBridge Prep Phenyl OBD Column. The mobile phase consisted of water (containing 0.1% TFA or 0.01% NH4HCO3) and acetonitrile, and all reagents used were HPLC grade. The flow rate was 30 ml / min. After the column, a 1:1000 LC packing flow splitter diverted a small portion of the eluent into the UV detector. The electrospray source was set at a capillary voltage of 3.0 kV, a cone voltage of 30 V, a source temperature of 110° C., a desolvation temperature of 350° C., a desolvation gas flow of 600 L / hr, and a cone gas flow of 60 L / hr. In the analyzer, the frequency multiplier was set at 550 for the preparative tune method.

[0249] Following the general synthetic methods described above and as previously described, the following compounds were similarly synthesized:

[0250] Example 1 TIFF2025128169000261.tif39128(2S,4R)-N-(4-(4-bromothiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0251] Example 2 TIFF2025128169000262.tif39128(2S,4R)-N-(4-(4-cyclopropylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0252] Example 3 TIFF2025128169000263.tif35128(2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0253] Example 4 TIFF2025128169000264.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-vinylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0254] Example 5 TIFF2025128169000265.tif39128(2S,4R)-N-(4-(4-ethylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0255] Example 6 TIFF2025128169000266.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0256] Example 7 TIFF2025128169000267.tif39128(2S,4R)-1-((S)-2-(7-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0257] Example 8 TIFF2025128169000268.tif39128(2S,4R)-1-((S)-2-(7-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0258] Example 9 TIFF2025128169000269.tif45128((2S,4R)-1-((S)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0259] Example 10 TIFF2025128169000270.tif45128(2S,4R)-1-((R)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0260] Example 11 TIFF2025128169000271.tif45128(2S,4R)-1-((S)-2-(6-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0261] Example 12 TIFF2025128169000272.tif34128(2S,4R)-1-((S)-3,3-dimethyl-2-propionamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0262] Example 13 TIFF2025128169000273.tif34128(2S,4R)-1-((S)-2-butylamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0263] Example 14 TIFF2025128169000274.tif36128(2S,4R)-1-((S)-3,3-dimethyl-2-pivalamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0264] Example 15 TIFF2025128169000275.tif40128(2S,4R)-4-Hydroxy-1-((S)-2-(7-methoxy-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0265] Example 16 TIFF2025128169000276.tif44128(2S,4R)-1-((S)-2-(5-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0266] Example 17 TIFF2025128169000277.tif45128(2S,4R)-1-((S)-2-(6-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0267] Example 18 TIFF2025128169000278.tif38128(2S,4R)-1-((S)-3,3-dimethyl-2-(3-methylbutanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0268] Example 19 TIFF2025128169000279.tif40128(2S,4R)-1-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0269] Example 20 TIFF2025128169000280.tif47128(2S,4R)-1-((S)-2-(3-cyclohexylpropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0270] Example 21 TIFF2025128169000281.tif40128(2S,4R)-1-((S)-3,3-dimethyl-2-(2-phenylacetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0271] Example 22 TIFF2025128169000282.tif41128(2S,4R)-4-Hydroxy-1-((R)-2-(4-methylpentanamido)-3-(methylthio)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0272] Example 23 TIFF2025128169000283.tif39128(2S,4R)-N-(4-Bromobenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0273] Example 24 TIFF2025128169000284.tif39128(2S,4R)-N-((S)-1-(4-bromophenyl)ethyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0274] Example 25 TIFF2025128169000285.tif44128(2S,4R)-1-((S)-2-(5-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0275] Example 26 TIFF2025128169000286.tif39128(2S,4R)-1-((S)-2-(4-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0276] Example 27 TIFF2025128169000287.tif34128(2S,4R)-4-Hydroxy-1-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0277] Example 28 TIFF2025128169000288.tif41128(2S,4R)-1-((S)-3,3-dimethyl-2-(4-methylpentanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0278] Example 29 TIFF2025128169000289.tif41128(2S,4R)-1-((S)-2-benzamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0279] Example 30 TIFF2025128169000290.tif39128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-methyl-2-(1-oxoisoindolin-2-yl)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0280] Example 31 TIFF2025128169000291.tif40128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-methyl-2-(4-methylpentanamido)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0281] Example 32 TIFF2025128169000292.tif37128(2S,4R)-1-((S)-2-cyclopentyl-2-(isopentylamino)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0282] Example 33 TIFF2025128169000293.tif39128(2S,4R)-1-((S)-2-(4-fluoro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0283] Example 34 TIFF2025128169000294.tif44128(2S,4R)-1-((S)-2-(5-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0284] Example 35 TIFF2025128169000295.tif43128(2S,4R)-1-((S)-2-(4-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0285] Example 36 TIFF2025128169000296.tif41128(2S,4R)-1-((S)-2-(cyclohexanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0286] Example 37 TIFF2025128169000297.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((R)-3-(methylthio)-2-(1-oxoisoindolin-2-yl)propanoyl)pyrrolidine-2-carboxamide;

[0287] Example 38 TIFF2025128169000298.tif39128(2S,4R)-1-((S)-2-cyclopentyl-2-(1-oxoisoindolin-2-yl)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0288] Example 39 TIFF2025128169000299.tif39128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2-carboxamide;

[0289] Example 40 TIFF2025128169000300.tif39128(2S,4R)-N-(biphenyl-4-ylmethyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0290] Example 41 TIFF2025128169000301.tif39128(2S,4R)-N-(4-(1H-pyrazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0291] Example 42 TIFF2025128169000302.tif39128(2S,4R)-1-((S)-2-(7-bromo-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0292] Example 43 TIFF2025128169000303.tif47128(2S,4R)-1-((S)-2-(4-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0293] Example 44 TIFF2025128169000304.tif48128(2S,4R)-1-((S)-3,3-dimethyl-2-(3-phenylpropanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0294] Example 45 TIFF2025128169000305.tif39128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-hydroxy-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0295] Example 46 TIFF2025128169000306.tif39128(2S,4R)-4-Hydroxy-1-(2-methyl-2-(1-oxoisoindolin-2-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0296] Example 47 TIFF2025128169000307.tif39128(2S,4R)-1-((S)-2-(7-cyano-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0297] Example 48 TIFF2025128169000308.tif39128(2S,4R)-4-Hydroxy-1-((R)-3-mercapto-2-(1-oxoisoindolin-2-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0298] Example 49 TIFF2025128169000309.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide;

[0299] Example 50 TIFF2025128169000310.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclopentanecarbonyl)pyrrolidine-2-carboxamide;

[0300] Example 51 TIFF2025128169000311.tif43128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-hydroxy-2-(4-methylpentanamido)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0301] Example 52 TIFF2025128169000312.tif43128(2S,4R)-4-Hydroxy-1-((R)-2-(4-methylpentanamido)-2-(thiophen-2-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0302] Example 53 TIFF2025128169000313.tif52128(2S,4R)-4-Hydroxy-1-((S)-2-(5-(3-methoxyprop-1-ynyl)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0303] Example 54 TIFF2025128169000314.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclohexanecarbonyl)pyrrolidine-2-carboxamide;

[0304] Example 55 TIFF2025128169000315.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(1-(1-oxoisoindolin-2-yl)cyclobutanecarbonyl)pyrrolidine-2-carboxamide;

[0305] Example 56 TIFF2025128169000316.tif43128(2S,4R)-1-((S)-2-cyclohexyl-2-(4-methylpentanamido)acetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0306] Example 57 TIFF2025128169000317.tif56128(2S,4R)-4-Hydroxy-1-((S)-2-(5-(3-methoxypropyl)-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0307] Example 58 TIFF2025128169000318.tif39128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((R)-2-(1-oxoisoindolin-2-yl)-2-(thiophen-2-yl)acetyl)pyrrolidine-2-carboxamide;

[0308] Example 59 TIFF2025128169000319.tif41128(2S,4R)-4-Hydroxy-1-((R)-3-mercapto-2-(4-methylpentanamido)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0309] Example 60 TIFF2025128169000320.tif41128(2S,4R)-4-Hydroxy-1-((R)-3-(((S)-3-((2R,4S)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-2-(4-methylpentanamido)-3-oxopropyl)disulfanyl)-2-(4-methylpentanamido)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0310] Example 61 TIFF2025128169000321.tif40128(S)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)-4-oxopyrrolidine-2-carboxamide;

[0311] Example 62 TIFF2025128169000322.tif40128(2S,4S)-4-Hydroxy-4-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0312] Example 63 TIFF2025128169000323.tif34128(2S,4R)-4-Hydroxy-1-(3-methoxybenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0313] Example 64 TIFF2025128169000324.tif34128(2S,4R)-1-Benzoyl-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0314] Example 65 TIFF2025128169000325.tif39128(2S,4R)-1-((S)-3,3-dimethyl-2-(1-oxoisoindolin-2-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0315] Example 66 TIFF2025128169000326.tif34128(4R)-4-Hydroxy-1-(3-methoxybenzoyl)-2-methyl-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0316] Example 67 TIFF2025128169000327.tif34128(4R)-2-Ethyl-4-hydroxy-1-(3-methoxybenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0317] Example 68 TIFF2025128169000328.tif40128((2S,4R)-1-((S)-2-(4-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0318] Example 69 TIFF2025128169000329.tif34128(2S,4R)-1-((S)-2-acetamido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0319] Example 70 TIFF2025128169000330.tif41128(2S,4R)-1-((S)-2-(2-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0320] Example 71 TIFF2025128169000331.tif42128(2S,4R)-1-((S)-2-(3-cyanobenzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0321] Example 72 TIFF2025128169000332.tif44128(2S,4R)-4-Hydroxy-1-((S)-2-(5-methoxy-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0322] Example 73 TIFF2025128169000333.tif44128(2S,4R)-1-((S)-2-(5-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0323] Example 74 TIFF2025128169000334.tif45128(2S,4R)-1-((S)-2-(6-chloro-1-oxoisoindolin-2-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0324] Example 75 TIFF2025128169000335.tif45128N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1-methylpiperidine-4-carboxamide;

[0325] Example 76 TIFF2025128169000336.tif54128(2S,4R)-4-Hydroxy-1-((S)-2-(3-(4-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0326] Example 77 TIFF2025128169000337.tif50128(2S,4R)-4-Hydroxy-1-((S)-2-(3-(3-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0327] Example 78 TIFF2025128169000338.tif41128N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)picolinamide;

[0328] Example 79 TIFF2025128169000339.tif38128(2S,4R)-4-Hydroxy-4-methyl-1-[(2S)-3-methyl-2-(1-oxo-2,3-dihydro-1H-isoindol-2-yl)butanoyl]pyrrolidine-2-carboxylic acid;

[0329] Example 80 TIFF2025128169000340.tif40128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(3-methylpyridin-4-yl)benzyl)pyrrolidine-2-carboxamide;

[0330] Example 81 TIFF2025128169000341.tif39128(2S,4R)-4-Hydroxy-N-(4-methoxybenzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0331] Example 82 TIFF2025128169000342.tif39128(2S,4R)-N-(2-fluoro-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0332] Example 83 TIFF2025128169000343.tif48128(2S,4R)-4-Hydroxy-1-((S)-2-(3-(2-methoxyphenyl)propanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0333] Example 84 TIFF2025128169000344.tif41128N-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)nicotinamide;

[0334] Example 85 TIFF2025128169000345.tif34128(2S,4R)-1-((S)-2-acetamidopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0335] Example 86 TIFF2025128169000346.tif34128(2S,4R)-1-(2-acetamidoacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0336] Example 87 TIFF2025128169000347.tif34128(S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl acetate;

[0337] Example 88 TIFF2025128169000348.tif34128(2S,4R)-4-Hydroxy-1-(4-methoxy-2-methylbenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0338] Example 89 TIFF2025128169000349.tif34128(2S,4R)-1-(2-amino-3,3,3-trifluoropropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0339] Example 90 TIFF2025128169000350.tif34128(2S,4R)-1-(2-acetamido-3,3,3-trifluoropropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0340] Example 91 TIFF2025128169000351.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-morpholinobenzyl)pyrrolidine-2-carboxamide;

[0341] Example 92 TIFF2025128169000352.tif39128(2S,4R)-4-Hydroxy-N-(4-(1-methyl-1H-pyrazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0342] Example 93 TIFF2025128169000353.tif39128(2S,4R)-N-(3-fluoro-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0343] Example 94 TIFF2025128169000354.tif45128(2S,4R)-1-((2S,3S)-2-(6-fluoro-1-oxoisoindolin-2-yl)-3-methylpentanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0344] Example 95 TIFF2025128169000355.tif34128(2S,4R)-4-Hydroxy-1-(5-methoxy-2-methylbenzoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0345] Example 96 TIFF2025128169000356.tif39128(2S,4R)-4-Hydroxy-N-(4-(1-methyl-1H-imidazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0346] Example 97 TIFF2025128169000357.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0347] Example 98 TIFF2025128169000358.tif34128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(2-oxopyrrolidin-1-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0348] Example 99 TIFF2025128169000359.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0349] Example 100 TIFF2025128169000360.tif39128(2S,4R)-N-(4-(1H-1,2,3-triazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0350] Example 101 TIFF2025128169000361.tif39128(2S,4R)-N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0351] Example 102 TIFF2025128169000362.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-(trifluoromethyl)thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0352] Example 103 TIFF2025128169000363.tif39128(2S,4R)-N-(4-(1,4-dimethyl-1H-imidazol-5-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0353] Example 104 TIFF2025128169000364.tif39128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-methyl-2-(phenethylamino)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0354] Example 105 TIFF2025128169000365.tif40128(2S,4R)-4-Hydroxy-1-((2S,3S)-3-methyl-2-(1-phenylethylamino)pentanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0355] Example 106 TIFF2025128169000366.tif39128(2S,4R)-N-(4-(1,5-dimethyl-1H-imidazol-4-yl)benzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0356] Example 107 TIFF2025128169000367.tif34128(2S,4R)-1-((S)-2-acetamidobutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0357] Example 108 TIFF2025128169000368.tif34128(2S,4R)-1-((S)-3,3-dimethyl-2-(N-methylacetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0358] Example 109 TIFF2025128169000369.tif34128(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-(3-phenoxyphenyl)pyrrolidine-2-carboxamide;

[0359] Example 110 TIFF2025128169000370.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carbothioamide;

[0360] Example 111 TIFF2025128169000371.tif36128(2S,4R)-4-Hydroxy-1-((S)-2-(4-methoxy-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-methylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0361] Example 112 TIFF2025128169000372.tif40128(2S,4R,E)-N'-cyano-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide;

[0362] Example 113 TIFF2025128169000373.tif39128(2S,4R)-N-(4-cyclopropylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0363] Example 114 TIFF2025128169000374.tif39128(2S,4R)-N-(4-cyclobutylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0364] Example 115 TIFF2025128169000375.tif39128(2S,4R)-N-(4-cyclopentylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0365] Example 116 TIFF2025128169000376.tif39128(2S,4R)-N-(4-cyclopentenylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0366] Example 117 TIFF2025128169000377.tif39128(2S,4R)-N-(4-cyclohexylbenzyl)-4-hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0367] Example 118 TIFF2025128169000378.tif39128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(tetrahydro-2H-pyran-4-yl)benzyl)pyrrolidine-2-carboxamide;

[0368] Example 119 TIFF2025128169000379.tif40128(2S,4R)-4-Mercapto-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0369] Example 120 TIFF2025128169000380.tif40128(2S,4R,E)-4-Hydroxy-N'-methoxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide;

[0370] Example 121 TIFF2025128169000381.tif401282-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzylamino)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoindolin-1-one;

[0371] Example 122 TIFF2025128169000382.tif42128tert-Butyl (S)-1-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-ylcarbamate;

[0372] Example 123 TIFF2025128169000383.tif36128(2S,4R)-1-((S)-2-((S)-2-aminopropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0373] Example 124 TIFF2025128169000384.tif42128tert-Butyl 2-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-2-oxoethylcarbamate;

[0374] Example 125 TIFF2025128169000385.tif36128(2S,4R)-1-((S)-2-(2-aminoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0375] Example 126 TIFF2025128169000386.tif40128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboximidamide;

[0376] Example 127 TIFF2025128169000387.tif39128(2S,4R)-4-Hydroxy-N-(4-(3-hydroxyoxetan-3-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0377] Example 128 TIFF2025128169000388.tif39128((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide isomer A;

[0378] Example 129 TIFF2025128169000389.tif39128((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide isomer B;

[0379] Example 130 TIFF2025128169000390.tif34128(2S,4R)-1-((S)-2-acetamido-3-methylbutanethioyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0380] Example 131 TIFF2025128169000391.tif39128((4R)-4-Hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide isomer C;

[0381] Example 132 TIFF2025128169000392.tif39128((4R)-4-hydroxy-2-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide isomer D;

[0382] Example 133 TIFF2025128169000393.tif40128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0383] Example 134 TIFF2025128169000394.tif34128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(N-methylacetamido)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0384] Example 135 TIFF2025128169000395.tif35128(2S,4R)-4-Hydroxy-1-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0385] Example 136 TIFF2025128169000396.tif39128(2S,4R)-4-Hydroxy-N-(4-(isoxazol-5-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0386] Example 137 TIFF2025128169000397.tif40128(2S,4R)-4-Hydroxy-N-(4-(isoxazol-4-yl)benzyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)pyrrolidine-2-carboxamide;

[0387] Example 138 TIFF2025128169000398.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0388] Example 139 TIFF2025128169000399.tif35128(2S,4R)-4-Hydroxy-1-((S)-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0389] Example 140 TIFF2025128169000400.tif35128(2S,4R)-4-Hydroxy-1-(2-methyl-2-(3-methylisoxazol-5-yl)propanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0390] Example 141 TIFF2025128169000401.tif35128(2S,4R)-4-Hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0391] Example 142 TIFF2025128169000402.tif39128(2S,4R)-4-Hydroxy-4-methyl-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0392] Example 143 TIFF2025128169000403.tif35128(2S,4R)-4-Hydroxy-1-(2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0393] Example 144 TIFF2025128169000404.tif43128(2S,4S)-4-Hydroxy-4-(hydroxymethyl)-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0394] Example 145 TIFF2025128169000405.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0395] Example 146 TIFF2025128169000406.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0396] Example 147 TIFF2025128169000407.tif40128(2S,3R,4S)-3,4-Dihydroxy-1-((S)-3-methyl-2-(1-oxoisoindolin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0397] Example 148 TIFF2025128169000408.tif34128(2S,4R)-1-((S)-2-acetamidopentanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0398] Example 149 TIFF2025128169000409.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0399] Example 150 TIFF2025128169000410.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0400] Example 151 TIFF2025128169000411.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0401] Example 152 TIFF2025128169000412.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0402] Example 153 TIFF2025128169000413.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(4-methyloxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0403] Example 154 TIFF2025128169000414.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0404] Example 155 TIFF2025128169000415.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0405] Example 156 TIFF2025128169000416.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0406] Example 157 TIFF2025128169000417.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-(4-(thiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0407] Example 158 TIFF2025128169000418.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0408] Example 159 TIFF2025128169000419.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0409] Example 160 TIFF2025128169000420.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(thiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0410] Example 161 TIFF2025128169000421.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0411] Example 162 TIFF2025128169000422.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0412] Example 163 TIFF2025128169000423.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0413] Example 164 TIFF2025128169000424.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0414] Example 165 TIFF2025128169000425.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0415] Example 166 TIFF2025128169000426.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(4-methyloxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0416] Example 167 TIFF2025128169000427.tif35128(2S,4R)-4-Hydroxy-1-((R)-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(oxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0417] Example 168 TIFF2025128169000428.tif35128(2S,4R)-1-((R)-3,3-dimethyl-2-(3-methylisoxazol-5-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(oxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0418] Example 169 TIFF2025128169000429.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)-N-((S)-1-(4-(oxazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide;

[0419] Example 170 TIFF2025128169000430.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(3-methylisothiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0420] Example 171 TIFF2025128169000431.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(3-methyl-1,2,4-thiadiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0421] Example 172 TIFF2025128169000432.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0422] Example 173 TIFF2025128169000433.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-4H-1,2,4-triazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0423] Example 174 TIFF2025128169000434.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0424] Example 175 TIFF2025128169000435.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0425] Example 176 TIFF2025128169000436.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methylisoxazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0426] Example 177 TIFF2025128169000437.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methylisothiazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0427] Example 178 TIFF2025128169000438.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-1,2,4-thiadiazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0428] Example 179 TIFF2025128169000439.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0429] Example 180 TIFF2025128169000440.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-1H-pyrazol-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0430] Example 181 TIFF2025128169000441.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyl-1H-imidazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0431] Example 182 TIFF2025128169000442.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(5-methyloxazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0432] Example 183 TIFF2025128169000443.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(5-methylthiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0433] Example 184 TIFF2025128169000444.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(4-methyloxazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0434] Example 185 TIFF2025128169000445.tif35128(2S,4R)-4-Hydroxy-1-((S)-3-methyl-2-(4-methylthiazol-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0435] Example 186 TIFF2025128169000446.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(2-methyloxazol-4-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0436] Example 187 TIFF2025128169000447.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(2-methylthiazol-4-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0437] Example 188 TIFF2025128169000448.tif35128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(2-methyl-1H-imidazol-5-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0438] Example 189 TIFF2025128169000449.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-phenylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0439] Example 190 TIFF2025128169000450.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(pyridin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0440] Example 191 TIFF2025128169000451.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(pyridazin-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0441] Example 192 TIFF2025128169000452.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(pyridin-3-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0442] Example 193 TIFF2025128169000453.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(pyrazin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0443] Example 194 TIFF2025128169000454.tif34128(2S,4R)-4-Hydroxy-1-((R)-3-methyl-2-(pyrazin-2-yl)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;

[0444] Example 195 TIFF2025128169000455.tif35128(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0445] Example 196 TIFF2025128169000456.tif35128(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-({4-[4-(hydroxymethyl)-1,3-thiazol-5-yl]phenyl}methyl)pyrrolidine-2-carboxamide

[0446] Example 197 TIFF2025128169000457.tif36128(2S,4R)-1-[(2S)-2-Acetamido-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,2,3-thiadiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0447] Example 198 TIFF2025128169000458.tif361282S,4R)-4-Hydroxy-N-[(1S)-1-{4-[4-(hydroxymethyl)-1,2,3-thiadiazol-5-yl]phenyl}ethyl]-1-[(2S)-3-methyl-2-(4-methyl-1H-imidazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

[0448] Example 199 TIFF2025128169000459.tif36128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-(4-methyl-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

[0449] Example 200 TIFF2025128169000460.tif43128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-(4-phenyl-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

[0450] Example 201 TIFF2025128169000461.tif44128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

[0451] Example 202 TIFF2025128169000462.tif44128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[4-(pyridin-3-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

[0452] Example 203 TIFF2025128169000463.tif36128(2S,4R)-4-Hydroxy-1-[(2S)-2-(4-methoxy-1H-pyrazol-1-yl)-3-methylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0453] Example 204 TIFF2025128169000464.tif43128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-[4-(pyridin-2-yl)-1H-pyrazol-1-yl]butanoyl]pyrrolidine-2-carboxamide

[0454] Example 205 TIFF2025128169000465.tif45128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide

[0455] Example 206 TIFF2025128169000466.tif38128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]-1-[(2S)-3-methyl-2-(4-phenoxy-1H-pyrazol-1-yl)butanoyl]pyrrolidine-2-carboxamide

[0456] Example 207 TIFF2025128169000467.tif45128(2S,4R)-4-Hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]propyl]-1-[(2R)-3-methyl-2-(3-methyl-1,2-oxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide

[0457] Example 208 TIFF2025128169000468.tif45128(2S,4R)-4-Hydroxy-1-[(2R)-2-(3-methoxy-1,2-oxazol-5-yl)-3-methylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide

[0458] Exemplary Methods for PROTAC Synthesis Amide Coupling Route: An Exemplary PROTAC Synthesis Approach with ULM Bearing Free Amine Groups TIFF2025128169000469.tif72128

[0459] Mitsunobu Route: An Exemplary PROTAC Synthesis Route with ULM Having a Free Hydroxyl Group TIFF2025128169000470.tif88128

[0460] Suzuki Pathway: An Exemplary PROTAC Synthesis Route with Halogen-Containing ULM TIFF2025128169000471.tif73128

[0461] Using the approaches mentioned above and various other approaches well documented in the literature, the following exemplary PROTAC compounds were prepared (Tables 3 and 4). The exemplary compounds in Tables 3 and 4 were also assayed for their ability to effect degradation of BRD4 and AR. Accordingly, in certain aspects, the present disclosure provides compounds, including compositions comprising an effective amount of a compound or a derivative, analog, or prodrug thereof in combination with at least one of a pharmaceutically acceptable carrier, another active agent, including a second PROTAC molecule described herein, or a combination thereof. In further aspects, the present disclosure provides methods of treating a disease or condition in a subject in need thereof, comprising administering a composition comprising an effective amount of a compound listed below, wherein the composition is effective to treat or ameliorate the symptoms of the disease or condition.

[0462] Cell-based assays 1. Fluorescence Polarization Assay The ability of VHL ligands to compete for the HIF 1a binding site on VCB was determined via a fluorescence polarization competition assay as described in Buckley et al. JACS, 2012, 134, 4465-4468, WO 2013 / 106643, and US 2014-0356322, which are incorporated by reference in their entireties for all purposes.

[0463] 2. Androgen Receptor ELISA Assay In this assay, compounds were evaluated in LNCaP and / or VCaP cells using a similar protocol. The protocol used in VCaP cells is described below. The androgen receptor ELISA assay was performed using PathScan AR ELISA (Cell Signaling Cat. No. 12850) according to the following assay steps:

[0464] VCaP cells are seeded at 30,000 cells / well in 200 μL / well of Corning 3904 plates in VCaP assay medium [phenol red-free RPMI (Gibco catalog number 11835-030); 5% charcoal-stripped (dextran-treated) FBS (Omega Scientific, catalog number FB-04); Pen / Strep Life Technologies (Gibco catalog number: 10378-016); 0.1 nM R1881 (Sigma, catalog number R0908) is added at the beginning of the assay, not during the initial plating of cells]. Cells are allowed to grow for a minimum of 3 days.

[0465] Cells are initially dosed with compounds diluted in 0.1% DMSO - using polypropylene plates according to the following protocol: (1)(i) Make a 1000x stock plate in DMSO; (ii) Dilute the 20mM stock 1 / 6.7 with DMSO (5µL + 28.3µL DMSO) to 3mM and place in row H; (iii) Serially dilute from row H to row B at 1 / 2 log doses (10µL PROTAC + 20µL DMSO). Reserve row A for DMSO; (iv) Seven doses total (final concentrations in this 1000x plate will be 3mM, 1mM, 333µM, 111µM, etc.). (2)(i) Make a 10x stock plate in media; (ii) Transfer 2.5µL of the 1000x stock to a new 10x stock plate (using a 12-channel pipette, starting with A (DMSO control) and working down to H). When 247.5 μL of medium is added to this plate, it serves as the 10× stock; (iii) make medium + 1 nM R1881 to make the 10× stock plate; (iv) add 247.5 μL of medium with 1 nM R1881 to each well of the 10× stock plate and mix.

[0466] Next, add 22 μL of the 10x stock to the cells and incubate for 24 hours. Make 1x Cell Signaling Cell Lysis Buffer (Cat. No. 9803; provided with the kit) - prepare 50 μL / well. Keep on ice. Aspirate the media and add 50 μL / well of 1x Cell Lysis Buffer. Place the cells on ice for 10 minutes. Mix the solution, transfer to a PCR plate, and centrifuge at 4000 rpm for 10 minutes at 4°C.

[0467] Transfer 5 μL to a new plate (use immediately or freeze at -80°C) and add 115 μL ELISA diluent (0.15 μg / ml to 0.075 μg / ml; provided with PathScan ELISA).

[0468] Add 100 μL / well AR Elisa; Cover and shake for 2 hours at 37°C; Open, tap, and wash with 200 μL 4x ELISA wash buffer; Add 100 μL / well mouse AR detection Ab; Cover and shake for 1 hour at 37°C; Open, tap, and wash with 200 μL 4x ELISA wash buffer; Add 100 μL / well anti-mouse HRP-conjugated Ab (provided in the kit); Cover and shake for 30 minutes at 37°C; Allow TMB reagent to reach room temperature; Open, tap, and wash with 200 μL 4x Elisa wash buffer; Tap; Add 100 μL TMB and shake for 5 minutes - observe color. Add stop reagent when a light blue color develops. Add 100 μL stop solution; Shake and read at 450 nM.

[0469] Prostate cancer progression in patients treated with antiandrogen therapy typically involves one of several mechanisms of enhanced androgen receptor (AR) signaling, including increased intratumoral androgen synthesis, increased AR expression, and AR mutations. PROTACs (proteolysis targeting chimeras) use bifunctional molecules that simultaneously bind to a selected target and an E3 ligase, resulting in induced access, ubiquitination, and degradation of the targeted pathogenic protein. In contrast to traditional target inhibition, which is a competitive process, degradation is a gradual process. Therefore, degradation is less likely to result in increased endogenous ligands, target expression, or mutations in the target. Therefore, this technology appears ideal for addressing mechanisms of AR resistance in prostate cancer patients.

[0470] AR PROTACs degrade AR in LNCaP and VCaP cells with nM-pM potency, resulting in a greater than 85% reduction in AR concentrations (D max ) degradation was rapid, with 50% of AR lost within 15 minutes, and maximum degradation was observed at 4 hours. The duration of AR knockdown was prolonged, with no recovery of AR observed over several days. The degradation process in cells was specific, as PROTACs with an inactive epimer for E3 ligase binding did not degrade AR. AR PROTACs induced rapid apoptosis and cell death in VCaP cells. In LNCap and VCaP cell lines, AR PROTACs were activated under conditions in which enzalutamide was inactive, such as increasing concentrations of the AR agonist R1881, and when cells were AR-inactive. F876L Under conditions containing the mutation, AR PROTACs were antiproliferative. Typically, AR PROTACs are antiproliferative for several hours after intraperitoneal or subcutaneous injection. 1 / 2 In mice, the AR PROTAC demonstrated in vivo activity, including seminal vesicle atrophy, reduced AR protein levels in the prostate, and regression of VCaP tumors.

[0471] The androgen receptor ELISA assay described above was used to generate the results shown in Table 3, where compound potency was determined by the maximum observed percent androgen receptor degradation (D max ) was characterized.

[0472] BDR4 receptor ELISA assay (Table 4) 22RV-1 cells were seeded at 30,000 cells / well in 75 μL / well of RPMI + 10% FBS medium in 96-well plates and grown overnight at 37°C. Cells were dosed with 4x concentrations of compounds diluted in 0.4% DMSO, and compounds were serially diluted 1:3 in an 8-point dose curve. 25 μL of compound was added to the cells at final concentrations starting from 300 nM-0.3 nM in 0.1% DMSO and incubated for 18 hours. The medium was aspirated, and the cells were washed once with PBS and aspirated. Cells were lysed in 50 μL of RIPA buffer (50 mM Tris pH 8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The plate was incubated on ice for 15 minutes and then centrifuged at 4000 rpm for 10 minutes at 4°C. 50 μl of the clarified lysate was added from the 96-well assay plate to a 96-well c-myc ELISA plate (Novex, Life Technologies catalog number KH02041). The c-myc standards were reconstituted in standard dilution buffer to produce a standard curve ranging from 333 pg / ml to 0 pg / ml and diluted 1:2 in an 8-point dose curve. The remainder of the assay was performed according to the c-myc ELISA kit protocol. Data were analyzed and plotted using GraphPad Prism software.

[0473] Surface plasmon resonance assay Surface plasmon resonance (SPR) experiments were performed on a Biacore 3000 (GE Healthcare). 2+His-tagged VHL protein was immobilized onto a carboxymethylated dextran surface using chelation with nitriloacetic acid (NTA). The prepared surface was equilibrated for 3 hours in running buffer (Ambion 1x PBS buffer, pH 7 / 4, 0.005% Tween, 2% DMSO).

[0474] All compounds were prepared in 100% DMSO stock plates and serially diluted 3-fold to a top concentration of 5 mM. Compounds were transferred from the stock plate to the assay plate and diluted in running buffer without DMSO. All compounds were run as a 6-concentration series, with a final assay top concentration of 100 μM. Data analysis was performed with Scrubber 2 (BioLogic software, Campbell, Australia). Blanks were subtracted and data were corrected for DMSO using a standard DMSO curve. All reported KD values ​​represent the average of at least N=2 and were obtained by fitting a minimum of five concentrations using a 1:1 fitting algorithm.

[0475] Below (Table 1) are the VHL inhibition data (i.e., IC ) for each example at various DMSO concentrations (i.e., 0.25% in DMSO, 1% in DMSO, and 10% in DMSO) in a fluorescence polarization (FP) assay. 50 , μM).

[0476] Table 1. VHL inhibition data (i.e., IC) in the fluorescence polarization (FP) assay. 50 , μM) TIFF2025128169000472.tif62151TIFF2025128169000473.tif211151TIFF2025128169000474.tif214151 TIFF2025128169000475.tif211151TIFF2025128169000476.tif215151TIFF2025128169000477.tif102151

[0477] Table 2 shows VHL inhibition data (ie, Kd, ​​μM) for the examples included herein in a surface plasmon resonance (SPR) assay.

[0478] Table 2. SPR-measured VHL affinity of exemplary ULM TIFF2025128169000478.tif29150

[0479] Degradation Data for Exemplary PROTAC Compounds of the Invention Table 3 shows the functional (degradation Dmax) data for AR PROTACs encompassing the VHL ligands and analogs described herein. Dmax: + (Dmax≦25%); ++ (26%≦Dmax≦50%); +++ (51%≦Dmax≦70%); ++++ (71%≦Dmax).

[0480] Table 3. Degradation data for exemplary AR PROTACs TIFF2025128169000479.tif214150

[0481] Table 4 shows functional (cMyc Imax) data for BRD4 PROTACs encompassing the VHL ligands and analogs described herein. cMyc Imax: + (Imax≦25%); ++ (26%≦Imax≦50%); +++ (51%≦Imax≦70%); ++++ (71%≦Imax).

[0482] Table 4. Degradation readout data for exemplary Brd4 PROTACs TIFF2025128169000480.tif189141

[0483] The present specification, including the examples and experimental data, demonstrates the effectiveness and broad applicability of the bifunctional PROTAC compounds described herein in targeting any protein of interest for degradation. As shown herein, PROTAC-mediated protein degradation provides a mechanism for targeting "undruggable" pathogenic proteins that may not have been amenable targets for traditional approaches.

[0484] The contents of all references, patents, pending patent applications, and patent publications cited throughout this application are hereby expressly incorporated by reference.

[0485] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the appended claims. It is understood that the detailed examples and embodiments described herein are presented by way of example only for illustrative purposes and are not intended to limit the invention in any way. Various modifications or variations in light of this specification will be suggested to those skilled in the art and are within the spirit and scope of this application and are considered to be within the scope of the appended claims. For example, to optimize the desired effect, the relative amounts of the components may be varied, additional components may be added, and / or one or more components described may be substituted with similar components. Additional advantageous features and functionality associated with the systems, methods, and processes of the invention will be apparent from the appended claims. Moreover, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the appended claims.

Claims

1. 1. A bifunctional compound comprising a von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety (ULM) and a protein targeting moiety (PTM) connected directly or through a chemical linker (L), wherein the ULM is a group of the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: During the ceremony, R 5 and R 6 are each independently —OH, —SH, or optionally substituted alkyl; or R 5 , R 6 , and the carbon atom to which they are attached form a carbonyl; R 7 is H or optionally substituted alkyl; E is a bond, C=O, or C=S; G is a bond, optionally substituted alkyl, —COOH, or C═J; J is O or NR 8 and; R 8 is H, CN, optionally substituted alkyl, or optionally substituted alkoxy; M is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, or and; R 9 and R 10 are each independently H; an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxyalkyl, an optionally substituted thioalkyl, a disulfide-linked ULM, an optionally substituted heteroaryl, or a haloalkyl; or R 9 , R 10 and the carbon atom to which they are attached form an optionally substituted cycloalkyl; R 11 is an optionally substituted heterocycle, an optionally substituted alkoxy, an optionally substituted heteroaryl, an optionally substituted aryl, or and; R 12 is H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, R 14 are each independently H, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkyl, or optionally substituted heterocycloalkyl; R 15 is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl; R 16 are each independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy; R 25 are each independently H or optionally substituted alkyl; or both R 25 the groups can be taken together to form an oxo group or an optionally substituted cycloalkyl group; R 23 is H or OH; Z 1 , Z 2 , Z 3 , and Z 4 are independently C or N; and o is 0, 1, 2, 3, or 4.

2. R 15 The compound of claim 1, wherein: During the ceremony, R 30 is H or optionally substituted alkyl.

3. E is C=O; M and; R 11 but and; R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4; 3. The compound of claim 1 or 2.

4. R 11 but, 4. The compound of any one of claims 1 to 3, selected from the group consisting of:

5. E is C=O; M and; R 11 is an optionally substituted heteroaryl or an optionally substituted heterocycle, or and; q is 1 or 2; R 20 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or and; R 21 is H or optionally substituted alkyl; R 22 is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl; 3. The compound of claim 1 or 2.

6. E is C=O; M and; R 11 is an optionally substituted heterocycle, an optionally substituted heteroaryl, an optionally substituted aryl, or and; R 12 is H or optionally substituted alkyl; R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate, 3. The compound of claim 1 or 2.

7. R 11 but, 7. The compound of claim 5 or 6, selected from the group consisting of:

8. 10. The compound of claim 1, wherein the ULM is a group of the following chemical structure or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof: During the ceremony, X is O or S; Y is H, methyl, or ethyl; R 17 is H, methyl, ethyl, hydroxymethyl, or cyclopropyl; M is an optionally substituted heteroaryl or an optionally substituted aryl; R 9 is H; R 10 is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl; R11 is an optionally substituted heteroaromatic ring, an optionally substituted heterocyclic ring, an optionally substituted aryl, or and; R 12 is H or optionally substituted alkyl; and R 13 is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate.

9. The compound of claim 1, which has the following chemical structure: During the ceremony, Y is H, methyl, or ethyl; R9 is H; R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl; R11 is an optionally substituted amide, an optionally substituted isoindolinone, an optionally substituted isoxazole, or an optionally substituted heterocycle.

10. The ULM part is 2. The compound of claim 1, selected from the group consisting of:

11. The compound of any one of claims 1 to 10, wherein the linker group L is: -A 1 -...-A q - During the ceremony, A 1 is a bond or a chemical group attached to at least one of a ULM, a PTM, or a combination thereof, and q is an integer greater than or equal to 0; q is an integer from 1 to 20; A is independently a bond, CR L1 R L2 ,O,S,SO,SO 2 , N.R. L3 , SO 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3～11 cycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3～11 Heterocyclyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with a group, 0 to 6 R L1 and / or R L2 heteroaryl optionally substituted with a group; R L1 or R L2 are each independently linked to other A groups to form 0 to 4 R L5 groups can form cycloalkyl and / or heterocyclyl moieties which can be further substituted; R L1 , R L2 , R L3 , R L4 , and R L5 are independently H, halo, and C 1～8 Alkyl, OC 1～8 Alkyl, SC 1～8 Alkyl, NHC 1～8 Alkyl, N(C1-8 alkyl) 2 , C 3～11 Cycloalkyl, aryl, heteroaryl, C 3～11 Heterocyclyl, OC 1～8 Cycloalkyl, SC 1～8 Cycloalkyl, NHC 1～8 Cycloalkyl, N(C 1～8 Cycloalkyl) 2 , N(C 1～8 Cycloalkyl)(C 1～8 alkyl), OH, NH 2 , SH, SO 2 C 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, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , SO 2 NHC 1～8 Alkyl, SO 2 N(C 1～8 alkyl) 2 ,SONHC 1～8 Alkyl, SON(C 1～8 alkyl) 2 , CONHC 1～8 Alkyl, CON(C 1～8 alkyl) 2 , N(C 1～8 alkyl)CONH(C 1～8 alkyl), N(C 1～8 alkyl)CON(C 1～8 alkyl) 2 , NHCONH(C 1～8 alkyl), NHCON(C 1～8 alkyl) 2 ,NHCONH 2 , N(C 1～8 alkyl)SO 2 NH(C 1～8 alkyl), N(C 1～8 alkyl)SO 2 N(C 1～8 alkyl)2, NHSO 2 NH(C 1～8 alkyl), NHSO 2 N(C 1～8 alkyl) 2 ,NHSO 2 NH 2 is.

12. 12. The compound of any one of claims 1 to 11, wherein the linker group is an optionally substituted polyethylene group comprising 2 to 20 ethylene glycol units.

13. 13. The compound of any one of claims 1 to 12, wherein the polyethylene glycol group comprises 2 to 10 ethylene glycol units.

14. The PTM group is a moiety that binds to a target protein, and the target protein has catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, proteins involved in biosynthesis, 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 (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, intercellular signaling, regulation of biological processes, development, cell differentiation, and response to stimuli.

14. The compound of any one of claims 1 to 13, selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integrated function of a cell, including proteins involved in response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, and translation regulator activity).

15. The PTM group is a moiety that binds to a target protein, and the target protein may be 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 inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein, i.e., Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosoma, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 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, 5α-reductase inhibitor, angiotensin 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptor, adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA receptor for NGF, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 The compound of any one of claims 1-13, wherein the compound is selected from the group consisting of neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20 monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, and chloride channel. Still further target proteins include acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

16. 14. The compound of any one of claims 1 to 13, wherein the PTM group is an Hsp90 inhibitor; a kinase inhibitor, a phosphatase inhibitor, an MDM2 inhibitor, a compound targeting a human BET bromodomain-containing protein, an HDAC inhibitor, a human lysine methyltransferase inhibitor, a compound targeting a RAF receptor, a compound targeting an FKBP, an angiogenesis inhibitor, an immunosuppressant compound, a compound targeting an aryl hydrocarbon receptor, a compound targeting an androgen receptor, a compound targeting an estrogen receptor, a compound targeting a thyroid hormone receptor, a compound targeting an HIV protease, a compound targeting an HIV integrase, a compound targeting an HCV protease, or a compound targeting acylprotein thioesterase 1 and / or 2.

17. 17. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 16 in combination with a pharmaceutically acceptable carrier, excipient, or vehicle.

18. 18. The pharmaceutical composition of claim 17, further comprising an additional bioactive agent.

19. 20. The pharmaceutical composition of claim 18, wherein the additional bioactive agent is at least one of an anti-cancer agent, an anti-viral agent, an anti-HIV agent, an anti-HCV agent, or a combination thereof.

20. The anticancer drug may be everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, Aurora kinase inhibitor, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (MEK) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, dimatecan, IL13-PE38QQR, INO 1001, IPdR 1 KRX-0402, Lucanton, LY 317615, Neurajiab, Vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol) , estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, [D-Ser(But)6,Azgly10] acetate (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH 2 Acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X , where x = 1 to 2.4]), goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, Suplatin, 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 acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine,Endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, PEGylated interferon α-2a, interferon α-2a, PEGylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalid Mido, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam,20. The pharmaceutical composition of claim 19, wherein the active ingredient is selected from the group consisting of haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and combinations thereof.

21. 17. A method for treating or preventing a disease or disorder in a subject, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-16, wherein the compound is effective in modulating the amount or activity of a target protein in the subject, thereby ameliorating the symptoms of the disease or disorder.

22. The target protein may be a protein involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, protein degradation, biosynthesis, 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, intercellular communication, regulation of biological processes, development, cell differentiation, or response to stimuli. The method of claim 21, wherein the protein is selected from the group consisting of structural proteins, receptors, enzymes, cell surface proteins, proteins involved in the integrated function of a cell, including proteins involved in proteins, behavioral proteins, cell adhesion proteins, proteins involved in cell death, transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, virulence, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, and translation regulator activity).

23. The target proteins include 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 inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein i.e. Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and similar, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus type 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, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake 22. The method of claim 21, wherein the receptor is selected from the group consisting of: receptors for endothelin, 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, which is a receptor for NGF, beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibition, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20 monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

24. 22. The method of claim 21, wherein the disease or disorder is at least one of asthma, multiple sclerosis, cancer, cilia-related disease, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome.

25. If your disease or disorder 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, or obstructive thromboembolism vasculitis, Tourette's syndrome, vasculitis, aceruloplasminemia, achondroplasia type II, achondroplasia, acrocephaly, 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, alkaptonuric ochronosis, alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, diffuse truncal angiokeratoma, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple arthrochalasia (Ehlers-Danlos syndrome, arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome, familial Mediterranean fever, Benjamin syndrome, beta-serotonin-dependent neuropathy Racemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency),CGD (Chronic Granulomatous Disorder), Ankle Dysplasia, Biotinidase Deficiency, Cardiomyopathy (Noonan Syndrome), Cri-a-Cat Syndrome, CAVD (Congenital Absence of the Vas Deferens), Caylor Cardio-Facial Syndrome (CBAVD), CEP (Congenital Erythropoietic Porphyria), Cystic Fibrosis, Congenital Hypothyroidism, Chondrodysplasia Syndrome (Achondroplasia), Oto-Spondylotic-Giant Epiphyseal Dysplasia, Lesch-Nyhan Syndrome, Galactosemia, Ehlers-Danlos Syndrome, Thanatophoric Dysplasia, Coffin-Lowry Syndrome, Cockayne Syndrome, (Familial Adenomatous Polyposis), Congenital Erythropoietic Porphyria Wilson's disease, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal dysfacial syndrome, Cooley's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes' disease), hereditary coproporphyria, Cowden's syndrome, craniofacial joint abnormalities (Crouzon's syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne's syndrome, Cowden's syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyrate scalp syndrome, primary Degenerative neurological disorders including spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Grouch syndrome, and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythropoietic protoporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic pancreatic disease, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Grenblad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, myeloid hepatic porphyria (HEP),Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), immune system disorders including hyperandrogenism, hypochondroplasia, hypochromic anemia, X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, patchy dementia, Langer-Saldino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweene syndrome y chondrodysplasia, Niemann-Pick disease, Noack syndrome (Peiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Lovehart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prio Chronic hereditary (Hutchinson-Gilford progeria syndrome), progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal tonic muscular dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS Type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Levi syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma-breast-leukemia-adrenal carcinoma (SBLA) syndrome, tuberous sclerosis (sclerosis tuberose, tuberous sclerosis), SDAT, congenital spondyloepiphyseal dysplasia (SED), SED Strudwick type (spondyloepiphyseal dysplasia Strudwick type),Spondyloepiphyseal dysplasia (SEDc) congenital, SEMD Strudwick type (Spondyloepiphyseal dysplasia Strudwick type), Shprintzen syndrome, dyschromia, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variant porphyria), infantile-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo-X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik disease, Waardenburg syndrome, Warburg-Schönig syndrome Fredelius syndrome, Weissenbacher-Zweymuller syndrome, Wolff-Hirschorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, as well as xeroderma pigmentosum, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemia; benign and malignant lymphoma, especially Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor or teratoma, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell 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,22. The method of claim 21, wherein the disease is at least one of B-cell ALL, Philadelphia chromosome-positive ALL and Philadelphia chromosome-positive CML, HIV infection, and HCV infection.

26. 17. A method for degrading a target protein in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound according to any one of claims 1 to 16, wherein the compound effects degradation of the target protein.

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