Cereblon ligands and bifunctional compounds comprising those ligands

Abstract

To provide cereblon ligands and bifunctional compounds comprising the ligands.SOLUTION: The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present disclosure. Specifically, the description provides compounds which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein, so that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activity consistent with the degradation / inhibition of targeted polypeptides of nearly any type.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure is an international application claiming priority to U.S. patent application Ser. No. 15 / 953,108, filed April 13, 2018, which is a continuation-in-part of U.S. patent application Ser. No. 14 / 686,640, filed April 14, 2015, which claims priority to U.S. provisional patent application Ser. No. 61 / 979,351, filed April 14, 2014, and to U.S. provisional patent application Ser. No. 14 / 792,414, filed July 6, 2015, which claims priority to U.S. provisional patent application Ser. No. 61 / 979,351, filed April 14, 2014, and U.S. provisional patent application Ser. No. 62 / 171,090, filed June 4, 2015, all of which are incorporated herein by reference in their entireties.

[0002] References U.S. Patent Application No. 15 / 230,354, filed August 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719; U.S. Patent Application No. 15 / 801,243, filed November 1, 2017; and U.S. Patent Application No. 15 / 206,497, filed July 11, 2016; and U.S. Patent Application No. 15 / 209,648, filed July 13, 2016; and U.S. Patent Application No. 15 / 730,728, filed October 11, 2017; U.S. Patent Application No. 15 / 829,541, filed December 1, 2017; U.S. Patent Application No. 15 / 881,318, filed January 26, 2018; and U.S. Patent Application No. U.S. Patent Application No. 14 / 686,640, published as Publication No. 2015 / 0291562; and U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as Publication No. 2016 / 0058872; and U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, published as Publication No. 2014 / 0356322; and U.S. Patent Application No. 15 / 074,820, filed March 18, 2016, published as Publication No. 2016 / 0272639; and U.S. Patent Application No. 15 / 885,671, filed January 31, 2018, are incorporated herein by reference in their entireties. Additionally, all references cited herein are incorporated herein by reference in their entireties.

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

[0004] Most small molecule drugs bind to enzymes or receptors within tight, well-characterized pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target with small molecules due to their large contact surfaces and the shallow grooves or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) impart substrate specificity to ubiquitination and are therefore more attractive therapeutic targets than general proteasome inhibitors, which are specific for a limited number of protein substrates. Developing ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitors, the nutlins, additional compounds targeting E3 ligases have been reported, but the field remains underdeveloped.

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

[0006] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates numerous developmental processes, including limb and otic vesicle formation. Ultimately, this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage-binding protein.

[0007] Thalidomide is approved for the treatment of numerous immune indications and certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogs are currently under investigation for use in the treatment of various other types of cancer. The exact mechanism of thalidomide's antitumor activity is still elucidated, and it is known to inhibit angiogenesis. Recent publications discussing the biology of this drug include Lu et al., Science 343, 305 (2014) and Kronke et al., Science 343, 301 (2014). In particular, thalidomide and its analogs, such as pomolaminoide and lenalinomide, are known to bind cereblon. These agents bind cereblon, altering the specificity of the complex and inducing the ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for the growth of multiple myeloma. In fact, elevated cereblon expression is associated with increased efficacy of imidate drugs in the treatment of multiple myeloma. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Lu et al Science 343, 305 (2014) [Non-patent document 2] Kronke et al Science 343, 301 (2014) Summary of the Invention [Means for solving the problem]

[0009] There is a continuing need in the art for effective treatments for diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, non-specific activity and the inability to fully target and regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anti-cancer drugs. Therefore, small molecule therapeutics that exploit or enhance the substrate specificity of cereblon while also being tunable to target a broad class of proteins and regulate specificity would be highly useful as therapeutics.

[0010] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. Specifically, the present disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that are useful as modulators of the targeted ubiquitination of various polypeptides or other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that a wide range of pharmaceutical activity is possible, consistent with degrading / inhibiting target polypeptides from almost any protein class or family. Furthermore, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease conditions such as cancer, e.g., multiple myeloma.

[0011] Thus, in one aspect, the present disclosure provides novel imide-based compounds as described herein.

[0012] In additional aspects, the present disclosure provides bifunctional or PROTAC compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase or "ULM" group) and a moiety that binds a target protein (i.e., a protein / polypeptide targeting ligand or "PTM" group), thereby bringing the target protein / polypeptide into proximity with the ubiquitin ligase, resulting in degradation (and inhibition) of the protein. In a preferred embodiment, the ULM is a cereblon E3 ubiquitin ligase binding moiety (i.e., "CLM"). For example, the structure of a bifunctional compound can be illustrated as follows: [ka]

[0013] The respective positions and numbers of PTM and CLM moieties as described herein are provided by way of example only and are not intended to limit the compounds in any way. As one of ordinary skill in the art will appreciate, bifunctional compounds as described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0014] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be illustrated as follows: [ka] where PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety.

[0015] In certain preferred embodiments, the E3 ubiquitin ligase is cereblon. Thus, in certain additional embodiments, the CLM of the bifunctional compound has a chemical nature such as an imide, amide, thioamide, or thioimide-derived moiety. In additional embodiments, the CLM comprises a phthalimide group, or an analog or derivative thereof. In yet additional embodiments, the CLM comprises a phthalimide-glutarimide group, or an analog or derivative thereof. In still other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0016] In certain embodiments, a compound as described herein comprises multiple CLMs, multiple PTMs, multiple chemical linkers, or a combination thereof.

[0017] In any aspect or embodiment described herein, the ULM (ubiquitination ligase modulator) can be a von Hippel-Lindau E3 ubiquitin ligase (VHL)-binding moiety (VLM), or a cereblon E3 ubiquitin ligase-binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase-binding moiety (MLM), or an IAP E3 ubiquitin ligase-binding moiety (i.e., "ILM"). In any aspect or embodiment described herein, the bifunctional compound comprises at least one additional E3 ligase-binding moiety selected from the group consisting of a VLM, a VLM', a CLM, a CLM', a MLM, a MLM', an ILM, an ILM', or a combination thereof. For example, there can be at least 1, 2, 3, 4, or 5 additional E3 ligase-binding moieties.

[0018] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or salt form thereof as described herein and a pharmaceutically acceptable carrier. The therapeutic composition can be used to regulate protein degradation in a patient or subject, such as an animal, such as a human, and treat or ameliorate a disease state or condition regulated through protein degradation. In certain embodiments, the therapeutic composition as described herein can be used to cause the degradation of a protein of interest for the treatment or amelioration of a disease, such as cancer. In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound as described herein comprising a CLM and a PTM, preferably linked via a linker moiety as otherwise described herein, where the CLM is linked to the PTM, the CLM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase such as cereblon), and the PTM recognizes a target protein such that, when the target protein is brought into proximity with the ubiquitin ligase, degradation of the target protein occurs, thereby resulting in degradation / inhibition of the target protein's action and suppression of protein levels. This suppression of protein levels provided by the present disclosure reduces the level of the target protein in the patient's cells, thereby providing treatment for a disease state or condition regulated via that protein.

[0019] In additional aspects, the present description provides methods for assessing (i.e., determining and / or measuring) the binding affinity of a CLM. In certain embodiments, the methods include providing a test agent or compound of interest, e.g., an agent or compound having an imide moiety, e.g., a phthalimide group, a phthalimide-glutarimide group, a derivatized thalidomide, a derivatized lenalidomide, or a derivatized pomalidomide, and comparing the cereblon-binding affinity and / or inhibitory activity of the test agent or compound to agents or compounds known to bind to and / or inhibit the activity of cereblon.

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

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

[0022] The foregoing general scope is provided by way of example only and is not intended to be limiting with respect to the scope of the present disclosure and the appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be recognized by those skilled in the art in light of the claims, description, and examples herein. For example, the various aspects and embodiments of the present invention may be utilized in numerous combinations, all of which are expressly contemplated by this description. These additional advantages, objects, and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to clarify the background of the invention, and in specific cases to provide additional details regarding its practice, are incorporated by reference.

[0023] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present invention. The drawings are for the purpose of illustrating embodiments of the invention only 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 show illustrative embodiments of the invention. [Brief explanation of the drawings]

[0024] [Figure 1A]

[0023] Figure 1 illustrates the general principle for PROTAC function. An exemplary PROTAC includes a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that links or tethers the PTM to the ULM. [Figure 1B]

[0023] Figure 1 illustrates the general principle for PROTAC function.

[0024] Figure 2 illustrates the functional use of PROTACs as described herein. Briefly, ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase forms a complex with an E2 ubiquitin-conjugating protein and catalyzes the attachment of ubiquitin (dark circle) to lysines of the target protein via an isopeptide bond, either alone or via the E2 protein. The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasome machinery. DETAILED DESCRIPTION OF THE INVENTION

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

[0026] Described herein are compositions and methods related to the surprising and unexpected discovery that when an E3 ubiquitin ligase protein, such as cereblon, and a target protein are brought into close proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein, the E3 ubiquitin ligase protein ubiquitinates the target protein. Accordingly, the present disclosure provides compounds and compositions that contain an E3 ubiquitin ligase binding moiety ("ULM") linked to a protein target binding moiety ("PTM"), resulting in ubiquitination of a selected target protein, thereby directing the target protein for degradation by the proteasome (see Figures 1A and 1B). The present disclosure also provides libraries of compositions and uses thereof.

[0027] In certain aspects, the present disclosure provides ligands, e.g., small molecule ligands (i.e., less than 2,000 daltons, less than 1,000 daltons, less than 500 daltons, or less than 200 daltons), that can bind to ubiquitin ligases, such as IAP, VHL, MDM2, or cereblon. The present invention provides compounds comprising a PTM, ULM, or PROTAC (having a molecular weight of less than 1000). The compounds also comprise a moiety capable of binding to a target protein such that the target protein is brought into proximity with a ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. Small molecule, in addition to the above, can mean that the molecule is non-peptidyl, i.e., not generally considered to be a peptide, and contains, for example, fewer than 4, 3, or 2 amino acids. In accordance with this description, a PTM, ULM, or PROTAC molecule can be a small molecule.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in this description is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0029] Where a range of values ​​is given, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated value or intervening value within that stated range, is encompassed within the invention, unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms where each number of carbon atoms is given in the range). The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also encompassed within the invention, subject to any specific excluded limit in the stated range. 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.

[0030] The following terms are used to describe the present invention. Unless specifically defined herein, the terms are given their art-recognized meaning by those of ordinary skill in the art who will apply the term to its use in context when writing this specification.

[0031] 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 indicates otherwise. By way of example, "an element ( "element" means one element or more than one element.

[0032] The phrase "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements connected thereby, i.e., elements that may be conjunctive or disjunctive. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements connected thereby. Other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended terms such as "comprising," can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0033] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating listed items, "or" or "and / or" shall be interpreted as being inclusive, i.e., including not only at least one but also more than one of any number or listed elements and optionally additional unlisted items. Only terms clearly marked to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," shall be interpreted as including any number or series of elements. It refers to the inclusion of exactly one of the listed elements. Generally, as used herein, the term "or" shall only be construed as marking exclusive alternatives (i.e., "one or the other, but not both") when preceded by language of exclusion, such as "either," "one of," "only one of," or "exactly one of."

[0034] In the claims, as in the specification above, words such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," etc. may be used. All transitional phrases in this section shall be open-ended, i.e., construed to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" are used in the United States Patent Office Manual of Patent Examining Procedures, Section Each of these is a closed or semi-closed transitional phrase as defined in § 2111.03. It is said that.

[0035] As used herein in the specification and 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 each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements referred to by the phrase "at least one," whether related or unrelated to the specifically identified elements. Thus, as non-limiting examples, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally including more than one A and no B (and optionally including elements other than B); in another embodiment to at least one, optionally including more than one B and no A (and optionally including elements other than A); in yet another embodiment to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); etc.

[0036] Additionally, for any particular method described herein that includes more than one step or act, the order of the method steps or acts should not be construed as necessarily limited to the recited order of the method steps or acts, unless the context dictates otherwise.

[0037] 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 different time than the administration of the additional therapeutic agent or 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 embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0038] The term "compound," as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein, and, depending on the context, includes tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), thereof, as well as pharmaceutically acceptable salts, and, where applicable, prodrugs and / or deuterated forms thereof. Deuterated small molecules contemplated are those in which one or more hydrogen atoms contained in the drug molecule have been replaced with deuterium.

[0039] As used in context, the term "compound" generally refers to a single compound, but can also include other compounds of the disclosed compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), as well as specific enantiomers or enantiomer-enriched mixtures. Depending on the context, the term also refers to prodrug forms of the compounds, which have been modified to facilitate administration and delivery of the compound to the site of activity. It should be noted that in describing the compounds of the present application, numerous substituents and variants, among others, are described. It will be understood by those skilled in the art that the molecules described herein are stable compounds, as generally described below. When bonds are depicted, both double and single bonds are depicted or understood within the context of the depicted compound and the well-known rules of valence interactions.

[0040] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation.For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the addition of ubiquitin to the lysine on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome.Therefore, E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is involved in the transfer of ubiquitin to target proteins.Usually, ubiquitin ligase is involved in polyubiquitination, so that a second ubiquitin is added to the first one; a third is added to the second one, and so on.Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that limit monoubiquitination, in which only a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may have their cellular location or function altered, for example, through conjugation with other proteins that contain domains capable of binding ubiquitin. To further complicate matters, different lysines on ubiquitin can be targeted by E3s to generate chains. The most common lysine is Lys48 on the ubiquitin chain, which is the lysine used to generate polyubiquitin that is recognized by the proteasome.

[0041] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or livestock animal, that is provided treatment, including prophylactic treatment, with a composition according to the present disclosure. For treatment of those infections, conditions, or pathologies that are specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including livestock animals such as dogs or cats, or farm animals such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient unless otherwise stated or implied by the context of the use of the term.

[0042] The term "effective" is used to describe an amount of a compound, composition, or component that produces an intended result when used within the context of its intended use. The term effective encompasses all other effective amount or effective concentration phrases otherwise described or used herein.

[0043] Compounds and Compositions In one aspect, the present description provides a compound comprising an E3 ubiquitin ligase binding moiety ("ULM") that is a cereblon E3 ubiquitin ligase binding moiety ("CLM"). In one embodiment, the CLM is linked to a chemical linker (L) according to the following structure: (I) L-CLM wherein L is a chemical linker group and CLM is a cereblon E3 ubiquitin ligase binding moiety. The number and / or relative positions of moieties in the compounds described herein are provided by way of example only. As will be appreciated by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative positions of respective functional moieties.

[0044] The terms ULM and CLM are used inclusively unless the context dictates otherwise. For example, the term ULM encompasses all ULMs, including those that bind cereblon (i.e., CLMs). Furthermore, the term CLM encompasses all possible cereblon E3 ubiquitin ligase binding moieties.

[0045] In another aspect, the present disclosure provides bifunctional or multifunctional PROTAC compounds useful for modulating protein activity by inducing target protein degradation. In certain embodiments, the compounds comprise a CLM that is directly or indirectly linked, e.g., covalently linked, to a moiety that binds the target protein (i.e., protein targeting moiety or "PTM"). In certain embodiments, the CLM and PTM are joined or linked via a chemical linker (L). The CLM recognizes cereblon E3 ubiquitin ligase, and the PTM recognizes the target protein, and the interaction of each moiety with their target promotes target protein degradation by placing the target protein in proximity to the ubiquitin ligase protein. Exemplary bifunctional compounds can be illustrated as follows: (II) PTM-CLM

[0046] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). For example, the bifunctional compound can be illustrated as follows: (III) PTM-L-CLM where PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ligase binding moiety.

[0047] In certain embodiments, the compounds described herein include multiple PTMs (targeting the same or different protein targets), multiple CLMs, one or more ULMs (i.e., moieties that specifically bind to different E3 ubiquitin ligases, such as VHL), or combinations thereof. In any aspect of the embodiments described herein, the PTMs, CLMs, and ULMs can be linked directly or via one or more chemical linkers or combinations thereof. In additional embodiments, when a compound has multiple ULMs, the ULMs can be directed to the same E3 ubiquitin ligase, or each ULM can specifically bind to a different E3 ubiquitin ligase. In yet another embodiment, when a compound has multiple PTMs, the PTMs can bind to the same target protein, or each PTM can specifically bind to a different target protein.

[0048] In another embodiment, the present description provides compounds comprising multiple CLMs linked directly or via chemical linker moieties (L). For example, a compound with two CLMs can be illustrated as follows: (IV) CLM-CLM or (V) CLM-L-CLM

[0049] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are identical. In additional embodiments, compounds comprising multiple CLMs can be linked together, either directly or via a chemical linker (L). and / or both. In certain additional embodiments, the compound comprising multiple CLMs further comprises multiple PTMs. In yet additional embodiments, the PTMs are the same or, optionally, different. In yet other embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target.

[0050] In additional embodiments, the present description provides compounds comprising at least two different CLMs linked directly or via a chemical linker (L), or both. For example, such compounds with two different CLMs can be illustrated as follows: (VI) CLM-CLM' or (VII) CLM-L-CLM' wherein CLM' denotes a cereblon E3 ubiquitin ligase binding moiety that is structurally distinct from CLM. In certain embodiments, a compound may comprise multiple CLMs and / or multiple CLM's. In yet other embodiments, a compound comprising at least two different CLMs, multiple CLMs, and / or multiple CLM's further comprises at least one PTM attached to the CLM or CLM' directly, via a chemical linker, or both. In any embodiment described herein, a compound comprising at least two different CLMs may further comprise multiple PTMs. In yet additional embodiments, the PTMs are the same or, optionally, different. In yet other embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target. In yet other embodiments, the PTM itself is a ULM or CLM (or a ULM' or CLM').

[0051] In preferred embodiments, the CLM comprises a moiety that is a ligand for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM comprises a species from the "imide" class of molecules. In certain additional embodiments, the CLM comprises a phthalimide group or an analog or derivative thereof. In yet further embodiments, the CLM comprises a phthalimide-glutarimide group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0052] In additional embodiments, the present description provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including pharmaceutically acceptable salt forms thereof, such as acid and base salt forms.

[0053] Exemplary Cereblon-Binding and / or Inhibitory Compounds

[0054] In one aspect, the present description provides compounds useful for binding and / or inhibiting the cereblon E3 ubiquitin ligase binding moiety. In certain embodiments, the compounds have a chemical structure comprising at least one of the following (e.g., the compounds have a chemical structure selected from the group consisting of:

[0055] Neoimide Compounds

[0056] In one aspect, the present description provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compounds are selected from the group consisting of the following chemical structures: [ka] [ka] During the ceremony, W in formulas (a) through (e) is independently selected from the group of CH, CHR, C=O, SO, NH, cyclopropyl, cyclobutyl, and N-alkyl; W3 is selected from C or N; Each X in formulas (a) through (e) is absent or independently selected from the group of O and S; Y in formulas (a) through (e) is independently selected from the group of CH, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Each Z in formulas (a) through (e) is absent or independently selected from the group of O and S, except that X and Z cannot both be absent; G and G' of formulas (a) to (e) are independently selected from the group consisting of H, alkyl (linear, branched, optionally substituted), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1-Q4 in formulas (a) through (e) independently represent a carbon C substituted with a group selected from R', N, or N-oxide; A in formulas (a) through (e) is independently selected from the group of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) through (e) includes, but is not limited to: -CONR'R", -OR', -NR'R", -SR', -S0R', -S0NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", -aryl, -hetaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'CO R”, ​​-NR'C(=N-CN)NR'R”, -C(=N-CN)NR'R”, -NR'C(=N-CN)R”, -NR'C(=C-NO2)NR'R”, -SO2NR'COR”, -NO2, -CO2R', -C(C=N-OR')R”, -CR'=CR'R”, -CCR', -S(C=O)(C=N-R')R”, -SF5, and -OCF3; R′ and R″ of formulas (a) through (e) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, —C(═O)R, heterocyclyl, each of which is optionally substituted; n' in formulas (a) through (e) is an integer from 1 to 10 (e.g., 1 to 4); [ka] The above formulas (a) through (e) represent bonds that can be stereospecific ((R) or (S)) or non-stereospecific; [ka] represents a single or double bond; [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and Rn is an optionally substituted straight or branched alkyl (e.g., C1-C6 straight or branched alkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl) optionally substituted with one or more halogens), optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl- containing at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof). aryl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where the alkoxyl may be substituted by one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6.

[0057] Exemplary CLM

[0058] In any compound described herein, the CLM comprises a chemical structure selected from the group consisting of: [ka] [ka] During the ceremony: W in formulas (a) through (f) is independently selected from the group of CH, CHR, C=O, SO, NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl; W3 is selected from C or N; Each X in formulas (a) through (f) is absent or independently selected from the group of O and S; Y in formulas (a) through (f) is independently selected from the group of CH, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Each Z in formulas (a) through (f) is absent or independently selected from an O group and an S group, except that X and Z cannot both be absent; G and G' of formulas (a) to (f) are independently selected from the group consisting of H, alkyl (linear, branched), OH, R'OCOOR, R'OCONRR", CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulas (a) to (f) independently represent a carbon C substituted with a group selected from R', N, or N-oxide; A in formulas (a) through (f) is independently selected from the group of H, alkyl (linear, branched, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) through (f) includes, but is not limited to: -CONR'R", -OR', -NR'R", -SR', -S0R', -S0NR'R", -CR'R"-, -CR'NR'R"-, (-CR'O) n’ R", -aryl, -hetaryl, -alkyl (linear, branched, optionally substituted), -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR'CONR'R", -CONR'CO R”, ​​-NR'C(=N-CN)NR'R”, -C(=N-CN)NR'R”, -NR'C(=N-CN)R”, -NR'C(=C-NO2)NR'R”, -SO2NR'COR”, -NO2, -CO2R', -C(C=N-OR')R”, -CR'=CR'R”, -CCR', -S(C=O)(C=N-R')R”, -SF5, and -OCF3; R′ and R″ of formulas (a) through (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, —C(═O)R, heterocyclyl, each of which is optionally substituted; n' in formulas (a) through (f) is an integer from 1 to 10 (e.g., 1 to 4); [ka] represents a single or double bond; [ka] The above formulas (a) through (f) represent bonds that can be stereospecific ((R) or (S)) or non-stereospecific; Rn is selected from the group consisting of 1 to 4 independent functional groups, optionally substituted linear or branched alkyl (e.g., C1-C6 linear or branched alkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl) optionally substituted with one or more halogens), optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl may be substituted with one or more halogens, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms; and Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6.

[0059] In any aspect or embodiment described herein, each of X and Z of the 6-membered monocyclic silylalkyl or monocyclic heterocycloalkyl of CLM is each independently absent, O, or S, except that X and Z cannot both be absent. In any aspect or embodiment described herein, X on the middle ring is selected from O and S, and each of X and Z of the 6-membered monocyclic silylalkyl or monocyclic heterocycloalkyl of CLM is each independently absent, O, or S, except that X and Z cannot both be absent.

[0060] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the group consisting of: [ka] Formula (g) During the ceremony: W in formula (g) is independently selected from the group of CH2, C=O, NH, and N-alkyl; R in formula (g) is independently H, methyl, alkyl (e.g., a or C1-C6 alkyl (linear, branched, optionally substituted)); In equation (g), [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and Rn is one to four independent functional groups, optionally substituted linear or branched alkyl (e.g., C1-C6 linear or branched alkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl) optionally substituted with one or more halogens), optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or a combination thereof), optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl is one or more substituted aryls). may be substituted with multiple halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyls), or aryls (e.g., C5-C7 aryls), optionally substituted [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), or atoms.

[0061] In any embodiment described herein, W, X, Y, Z, g, G', R, R', R'', Q1-Q4, A, and Rn of formulas (a) through (g) can independently be covalently linked to a linker, and / or a linker attached to one or more PTM, ULM, CLM, or CLM' groups.

[0062] More specifically, non-limiting examples of CLMs are those shown below, as well as "hybrid" molecules thereof that arise from the combination of one or more different features shown in the molecules below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0063] The term "independently" is used herein to indicate that independently applied variants vary independently between applications.

[0064] The term "alkyl" refers, depending on the context, to a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical, or alkyl group, preferably C-C 10 , more preferably C1-C6, or optionally substituted C1-C3 alkyl groups. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, among others. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, the compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes. These compounds generally and contain a side chain (often linked via a polyethylene glycol group) that terminates in an alkyl side chain having a halogen substituent (often chlorine or bromine) at its distal end, which halogen substituent allows compounds containing such moieties to be covalently attached to the protein.

[0065] The term "alkoxy" refers to an alkyl group bonded singly to an oxygen.

[0066] The term "alkenyl" refers to a straight, branched, or cyclic C-C alkyl group containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0067] The term "alkynyl" refers to a straight, branched, or cyclic C-C alkyl group containing at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbons.

[0068] The term "alkylene" as used herein means -(CH2) n "" refers to an - group (n is generally an integer derived from 0 to 6), which may be optionally substituted. When substituted, the alkylene group is preferably substituted on one or more methylene groups with a C1-C6 alkyl group (including a cyclopropyl or t-butyl group), but may also be substituted with one or more halo groups, preferably one to three halo groups, or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or amino acid side chains, 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 is substituted (preferably, but not exclusively, at the distal end of the polyethylene glycol chain) with an alkyl chain substituted with a single halogen, preferably a chlorine, group. 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.

[0069] The term "unsubstituted" shall mean substituted only by hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced by H. Thus, a range of carbon atoms that is C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, H is in place of the carbon.

[0070] The terms "substituted" or "optionally substituted" are intended to mean, independently (i.e., in the case of multiple occurrences of substituents, each substituent is independent of another substituent), one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents, which themselves may contain further substituted substituents, on a portion of a compound according to the present disclosure) at any carbon (or nitrogen) position on the molecule in context, including substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably 1, 2, or 3 halogens, especially on alkyl, especially methyl groups, such as trifluoromethyl), alkyl groups (preferably C1-C2), 10 , more preferably C1-C6), aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy group (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 (where attachment is on the alkylene group rather than to an ester functionality, and the group is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amines (including 5- or 6-membered cyclic alkylene amines, and further including C1-C6 alkylamines or C1-C6 dialkylamines where the alkyl groups may be substituted with one or two hydroxyl groups), or optionally substituted -N(C0-C6 alkyl a)C(O)(O-C1-C6 alkyl) group (optionally substituted with a polyethylene glycol chain, which is further bonded to an alkyl group containing a single halogen, preferably chlorine, substituent); a 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 according to the present disclosure include, for example, -SiR 1sub R 2sub R 3sub groups, where R 1sub and R 2sub each is as otherwise described herein, and R 3sub is H or a C1-C6 alkyl group, preferably R 1sub , R 2sub , R 3sub is 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 alternatively, the substituent may be an optionally substituted -(CH2)2 group, which may be substituted with one or more of the above substituents. m -, or optionally substituted -(OCH2) m -, -(OCH2CH2) m - or -(CH2CH2O) mThe alkylene group -(CH2) may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via a - group. m - group or -(CH2) n The - group or other chains identified above, such as ethylene glycol chains, may be substituted anywhere along the chain. Suitable substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chains of amino acids as described elsewhere herein, and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids as described elsewhere herein. In the present disclosure, a moiety of a molecule may be optionally substituted with up to 5 substituents, preferably up to 3. In most cases in the present disclosure, a substituted moiety will be substituted with 1 or 2 substituents.

[0071] The term "substituted" (each substituent independent of any other substituent) also includes, 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)-NR 1sub R 2sub or -N(R 1sub )-C(O)-OR 1sub , nitro, cyano, and amine (especially C1-C6 alkylene-NR 1sub R 2sub, mono- or di-C1-C6 alkyl substituted with an amine optionally substituted with one or two hydroxyl groups). Each of these groups, unless otherwise indicated, contains between 1 and 6 carbon atoms within the context. In certain embodiments, suitable substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2)-, depending on the context of the use of the substituent. m -( where m and n are 1, 2, 3, 4, 5, or 6 depending on the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R 1sub , -(CH2) n C(O)-NR 1sub R 2sub , -(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)-R 1sub , -(CHO) n C(O)-NR 1sub R 2sub , -S(O)2-R S , -S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR 1sub R 2subR contains a halogen atom (F, Cl, Br, I, preferably F or Cl). 1sub and R 2sub are each, within the context, H or a C1-C6 alkyl group (optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted" is also intended to mean, within the chemical context of the defined compound and the substituents used, an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group, as described elsewhere herein. Alkylene groups, as elsewhere disclosed herein, are also preferably optionally substituted C1-C6 alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), the side chains of amino acid groups, as described elsewhere herein, amide groups, as described herein above, or urethane groups OC(O)-NR 1sub R 2sub A group in which R 1sub and R 2sub may be substituted with groups as otherwise described herein, although numerous other groups may also be used as substituents. The various optionally substituted moieties may be substituted with three or more substituents, preferably no more than three, and preferably one or two substituents. It should be noted that where substitution is required in a compound at a certain position in a molecule (primarily due to valence), but no substitution is indicated, the substituent is to be interpreted or understood as being H unless the context of the substitution suggests otherwise.

[0072] The term "aryl" or "aromatic," when appropriate, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), which can be attached to a compound according to the present disclosure at any available stable position on the ring or as otherwise indicated in the chemical structure provided. Other examples of aryl groups, when appropriate, include heterocyclic aromatic ring systems, i.e., "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (single ring), such as imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, etc., or fused ring systems, such as indole, quinoline, indolizines, azaindolizines, benzofurazans, etc., which can be optionally substituted as described above. Among the heteroaryl groups that may be mentioned are 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 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, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, among others, all of which may be optionally substituted.

[0073] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or multiple fused rings, at least one of which is aromatic, wherein the ring is substituted with one or more substituents. For example, an aryl group can include a substituent selected from the following: -(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, amines, mono- or di-(C1-C6 alkyl)amines in which the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted in the ortho, meta and / or para positions of the phenyl ring, preferably the para position), optionally substituted phenyl groups (the phenyl group itself is preferably and / or 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 ... 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, including methoxybenzylimidazoles, or 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)- or methyl-substituted pyridine or oxapyridine groups, where the pyridine group is linked to the phenyl group by an oxygen; optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans; optionally substituted indoles, indolizines, or azaindolizines (2, 3, or 4-azaindolizines); optionally substituted quinolines;and combinations thereof.

[0074] "Carboxyl" refers to the group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where these generic substituents have the meanings consistent with the definitions of the corresponding groups defined herein.

[0075] The term "heteroaryl" or "hetaryl" refers to an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), Optionally substituted indolizines, optionally substituted azaindolizines (2, 3, or 4-azaindolizines), optionally substituted benzimidazoles, benzodiazoles, benzoxofurans, optionally substituted imidazoles, optionally substituted isoxazoles, optionally substituted oxazoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, optionally substituted thiophenes, optionally substituted thiazoles (preferably methyl and / or thiol substituted), optionally substituted isothiazoles, optionally substituted triazoles (preferably methyl, triisopropylsilyl, optionally substituted -(CH) m -O-C1-C6 alkyl group or optionally substituted -(CH2) m This may mean, but is in no way limited to, 1,2,3-triazole substituted with a -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (2-, 3, or 4-pyridine), or a group according to the following chemical structure: [ka] During the ceremony, 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 by one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C-C alkyl) (preferably substituted by one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups) or optionally substituted —C(O)(C-C 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 is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, perazine, each of which is an optionally substituted heterocycle; and Y C is N or CR YC wherein R YCis 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 an optionally substituted acetylenic group -C≡CR a wherein R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl).

[0076] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and can be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of their use. Exemplary heteroaryl groups are described herein above.

[0077] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, and the like. Among these are lysinyl, 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, oxathiolane, and thiane.

[0078] Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, 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, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocycle" also includes bicyclic groups in which either heterocycle is fused to a benzene ring or a cyclohexane ring or to another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0079] The term "cycloalkyl" can refer to, but is in no way limited to, a monocyclic or polycyclic alkyl group or a monovalent group derived from a cycloalkane as defined herein, for example, a saturated monocyclic hydrocarbon group having from 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, while these general substituents have meanings consistent with the definitions of the corresponding groups as defined in this Description.

[0080] The term "hydrocarbyl" is intended to mean compounds that contain carbon and hydrogen and that may be fully saturated, partially unsaturated, or aromatic, including aryl, alkyl, alkenyl, and alkynyl groups.

[0081] The term "lower alkyl" refers to methyl, ethyl, or propyl.

[0082] The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0083] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds that result from combining features of one or more of the following compounds: [ka] [ka] [ka] During the ceremony: W is independently selected from the group: CH2, CHR, C=O, SO2, NH, and N-alkyl; R 1 is selected from the group consisting of absent, H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl; R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R 4 is methyl or ethyl; R 5 is H or halo; R 6 is H or halo; R in CLM is H; R' is H or an attachment point for a PTM, PTM', chemical linker group (L), ULM, CLM, CLM'; Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl; [ka] is a single or double bond; and Rn includes functional groups or atoms.

[0084] In any embodiment described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, and Rn can independently be covalently attached to a linker and / or a linker attached to one or more PTM groups, ULM groups, ULM′ groups, CLM groups, or CLM′ groups.

[0085] In any embodiment described herein, R 1 , R 2, Q1, Q2, Q3, Q4, and Rn can independently be covalently attached to a linker and / or a linker attached to one or more PTM groups, ULM groups, ULM′ groups, CLM groups, or CLM′ groups.

[0086] In any embodiment described herein, Q1, Q2, Q3, Q4, and Rn can independently be covalently attached to a linker and / or a linker attached to one or more PTM groups, ULM groups, ULM′ groups, CLM groups, or CLM′ groups.

[0087] In any aspect or embodiment described herein, R n is modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0088] Exemplary Linkers

[0089] In certain embodiments, compounds described herein comprise one or more CLMs chemically linked or attached to one or more PTMs (e.g., PTM and / or PTM'), ULMs (e.g., ULM, ULM', and / or CLM') via a chemical linker (L). In certain embodiments, the linker group L is a linker group consisting of one or more covalently linked structural units (e.g., -A L 1…(A L ) q -or-(A L ) q -), wherein A is a group attached to a PTM and A is a group attached to at least one of a ULM, a ULM', a CLM, a CLM', or a combination thereof. In certain embodiments, A L 1 directly links a CLM or CLM' to another ULM, a PTM, or a combination thereof. L1 indirectly connects a CLM or CLM' to another ULM, PTM, or a combination thereof, q Connected through.

[0090] In any aspect or embodiment described herein, the linker group L may be a bond or a group of formula -(A L ) q -, where A is a chemical moiety and q is an integer derived from 1 to 100, and where L is covalently attached to a PTM and a ULM to provide sufficient binding of the PTM to the protein target and sufficient binding of the ULM to an E3 ubiquitin ligase to result in ubiquitination of the target protein.

[0091] In certain embodiments, the linker group is -(A L ) q - in which -(A L ) q - is a group connected to at least one of a ULM moiety, a PTM moiety, or a combination thereof; q of the linker is an integer equal to or greater than 1; Each A L independently, bond, 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 Groups and / or RL2 Optionally by groups Substituted C 3-11 Cycloalkyl, 0 to 9 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 0 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 0 to 8 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 Spiroheterocycloalkyl, 0 to 6 R L1 Groups and / or R L2 aryl optionally substituted by a group, 0 to 6 R L1 Groups and / or R L2 heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently form a cycloalkyl and / or heterocyclyl moiety, optionally linked to other groups, which moieties are optionally joined by 0 to 4 R L5 substituted by a group; and 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, SO2C1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NHSO2NH(C 1-8 alkyl), NHSO2N(C 1-8 alkyl)2, NHSO2NH2.

[0092] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0093] In certain embodiments, for example, when q is greater than 2, A L qis a group attached to a ULM or ULM′ moiety (e.g., CLM or CLM′), and A L 1 and A L q are connected through a structural unit of a linker (L).

[0094] In certain embodiments, for example, when q of the linker is 2, A L q is A L is a group connecting 1 to a ULM or ULM′ moiety (such as a CLM or CLM′).

[0095] In certain embodiments, for example, when the q of the linker is 1, the structure of the linker group L is -A L 1- and A L 1 is a group connecting a ULM or ULM' moiety (such as a CLM or CLM') and a PTM moiety.

[0096] In certain embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(lower alkoxyl)-OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(heterocycloal Kill)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n-(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocycle)-CH2, -NR(CH2CH2) n -(heterocycle)-(heterocycle)-CH, -N(R1R2)-(heterocycle)-CH; n in the linker can be 0 to 10; R of the linker can be H, lower alkyl; The linkers R1 and R2 can form a ring together with the N to which they are connected.

[0097] In certain embodiments, A L The group is represented by a general structure selected from the group consisting of: [ka] [ka] [ka] During the ceremony, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6; 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; If the number is zero, there is no NO or OO bond, R of the linker is H, methyl, and ethyl; X of the linker is H and F; [ka] In the above formula, m of the linker can be 2, 3, 4, or 5; [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein each n and m in the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[0098] In any aspect or embodiment described herein, A L The group is selected from the group consisting of: [ka] [ka] [ka] wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0099] In any aspect or embodiment described herein, A L The group is selected from the group consisting of:

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0100] In any aspect or embodiment described herein, A L The group is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0101] In additional embodiments, the linker (L) is selected from the structures shown below: These include, but are not limited to, structures where the dashed line indicates the point of attachment to a PTM or ULM moiety: [ka] During the ceremony: W L1 and W L2 are each independently absent or optionally R Q and each R is a 4- to 8-membered ring having 0 to 4 heteroatoms substituted with Q are independently H, halo, OH, CN, CF, C-C alkyl (linear, branched, optionally substituted), C-C alkoxy (linear, branched, optionally substituted), or two R Q the groups, together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, a C1-C6 alkyl (linear, branched, optionally substituted) optionally having one or more C atoms substituted by O; or a C1-C6 alkoxy (linear, branched, optionally substituted); n is 0 to 10; and The dashed lines indicate the points of addition of the PTM or ULM moieties.

[0102] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, those shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety: [ka] and During the ceremony: W L1 and W L2 are each independently absent or an aryl, heteroaryl, cyclic, heterocyclic, C 1-6 Alkyl optionally having one or more C atoms replaced by O, C 1-6 Alkenes optionally having one or more C atoms replaced by O, C 1-6 alkyne, optionally with one or more C atoms replaced by O, bicycle, biaryl, biheteroaryl, or biheterocycle, each optionally being selected from the group consisting of R Q and each R Q but, Independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-C6 alkyl (straight chain, branched, optionally substituted), C1-C6 alkoxy (straight chain, branched, optionally substituted), OC 1-3 Alkyl (optionally substituted with one or more -F), OH, NH, NR Y1 R Y2 , CN or two R Q the groups, together with the atom to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted) optionally with one or more C atoms substituted by O; C1-C6 alkoxy (linear, branched, optionally substituted); Q L is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 RQ and each R Q However, independently H, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl) or two R Q the groups, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl) or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0 to 10; and The dashed lines indicate the points of addition of the PTM or ULM moieties.

[0103] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, between 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0104] In any embodiment of the compounds described herein, the linker group can be any suitable moiety as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 and about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, or between about 2 and 4 ethylene glycol units.

[0105] In another embodiment, the disclosure is directed to a compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, comprising a PTM group that binds a target protein or polypeptide to be ubiquitinated by a ubiquitin ligase and is chemically linked either directly to a ULM group (such as a CLM) or via a linker moiety, L; or the PTM is alternatively a ULM' group (such as a CLM') that is also a ubiquitin ligase binding moiety, where the ULM' group may be the same or different from a ULM group described above and is linked directly to the ULM group or via a linker moiety; and L is a linker moiety described above, which may be present or absent, that chemically (covalently) links the ULM to the PTM.

[0106] In certain embodiments, the linker group L is a group comprising one or more covalently linked structural units independently selected from the group consisting of: [ka] X is selected from the group consisting of O, N, S, S(O), and SO2; n is an integer from 1 to 5; R L1 is hydrogen or alkyl, [ka] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; [ka] is a monocyclic or bicyclic cycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; the phenyl ring fragment can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, and cyano. In one embodiment, the linker group L comprises up to 10 covalently connected structural units as described above.

[0107] Although the ULM and PTM groups can be covalently linked to the linker group via any group appropriate and suitable for the linker chemistry, in preferred embodiments of the present disclosure, the linker is independently covalently linked to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which can be inserted anywhere on the ULM and PTM groups to provide for maximal binding of the ULM group to the ubiquitin ligase and the PTM group to the target protein for degradation. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself.) In certain preferred embodiments, the linker can be linked to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group, or heterocyclic group on the ULM and / or PTM group.

[0108] In additional embodiments, q is an integer derived 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.

[0109] In certain additional embodiments, the linker (L) is selected from the group consisting of: [ka] [ka]

[0110] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol having between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, between 1 and 6 ethylene glycol units, between 2 and 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0111] In any embodiment of the compounds described herein, the linker group can be any suitable moiety as described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, between about 2 and about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, or between about 2 and 4 ethylene glycol units.

[0112] Although the CLM (or ULM) and PTM groups can be covalently linked to the linker group via any group appropriate and consistent with the linker chemistry, in preferred embodiments of the present disclosure, the linker is independently covalently linked to the CLM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which can be inserted anywhere on the CLM and PTM groups to provide for maximal binding of the CLM group to the ubiquitin ligase and the PTM group to the target protein for degradation. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation can be the ubiquitin ligase itself.) In certain preferred embodiments, the linker can be linked to an optionally substituted alkyl, alkylene, alkene, or alkyne group, aryl, or heterocyclic group on the CLM and / or PTM groups.

[0113] In certain embodiments, "L" is a straight chain having from 4 to 24 straight chain atoms. The carbon atoms in the linear chain can be substituted with oxygen, nitrogen, amide, fluorocarbon, etc., as shown below: [ka]

[0114] In certain embodiments, "L" can be non-linear and can be an aliphatic or aromatic or heteroaromatic cyclic moiety, some examples of "L" include, but are not limited to: [ka] During the ceremony: "X" in the above structure can be a straight chain containing from 2 to 14 atoms, said chain can contain heteroatoms such as oxygen; and "Y" in the above structure is O, N, S(O) n (n=0, 1, 2).

[0115] Exemplary PTMs

[0116] In preferred embodiments of the present disclosure, the PTM group is a group that binds to a target protein. Targets for the PTM group are highly diverse and are selected from proteins expressed in cells, such that at least a portion of the sequence is found in the cell and can be bound to the PTM group. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length to be able to bind to a PTM group according to the present disclosure. Any protein of a eukaryotic or microbial system, including viruses, bacteria, or fungi, as otherwise described herein, is a target for ubiquitination mediated by compounds according to the present disclosure. Preferably, the target protein is a eukaryotic protein. In certain embodiments, the protein binding moiety is a haloalkane (preferably a C1-C substituted with at least one halo group, preferably at the distal end of the alkyl group, i.e., away from the linker or CLM group). 10 alkyl group), which haloalkane may be covalently attached to a dehalogenase enzyme in a patient or subject or in a diagnostic assay.

[0117] PTM groups according to the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), including, among other non-limiting examples, small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, androgen receptor inhibitors, HDM2 & MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR). The compositions described below exemplify several members of these nine types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding moieties are linked, preferably via a linker, to a ubiquitin ligase binding moiety to present the target protein (to which the protein target moiety is bound) in proximity to a ubiquitin ligase for ubiquitination and degradation.

[0118] Any protein that can be bound to a protein targeting moiety or PTM group and acted upon or degraded by a ubiquitin ligase is a target protein according to the present disclosure. Generally, target proteins include, for example, structural proteins; receptors; enzymes; cell surface proteins; proteins involved in the integrated function of a cell, including 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 transduction factor 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, response to stimuli; and behavior. Proteins of interest may include proteins involved in: 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); pathogenesis; chaperone regulator activity; nucleic acid binding activity; transcription regulator activity; extracellular organization and biosynthetic activity; translation regulator activity. Proteins of interest can include proteins from eukaryotic and prokaryotic organisms, including, among many others, humans as targets for drug therapy, other animals, including livestock animals, microorganisms for determining targets for antibiotics, and other microorganisms and plants, and even viruses.

[0119] In yet other embodiments, the PTM group is a haloalkyl group, where the alkyl group generally ranges 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 carbons to about 8 carbons in length, and more often from about 4 carbons to about 6 carbons in length. Haloalkyl PT groups are generally straight-chain alkyl groups (although branched-chain alkyl groups may also be used) that are end-capped with at least one halogen group, preferably a single halogen group, often a single chloride group. Haloalkyl PT groups for use in the present disclosure preferably have the chemical structure -(CH) v -halo, where v is any integer from 2 to about 12, often from about 3 to about 8, and more often from about 4 to about 6. Halo can be any halogen, but is preferably Cl or Br, and more often Cl.

[0120] In another embodiment, the disclosure provides a library of compounds. The library includes more than one compound, each compound having the formula A-B, where A is a ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin ligase moiety as otherwise disclosed herein) and B is a protein-binding member of a molecular library, where A is linked to B (preferably through a linker moiety), where the ubiquitin pathway protein binding moiety recognizes a ubiquitin pathway protein, specifically an E3 ubiquitin ligase, such as cereblon. In a specific embodiment, the library contains specific cereblon E3 ubiquitin ligase binding moieties linked to random target protein binding elements (e.g., a chemical compound library). Thus, the target protein is not predetermined, and methods can be used to determine the activity and pharmacological value of putative protein binding elements as targets for degradation by ubiquitin ligases.

[0121] The present disclosure may be used to treat numerous disease states and / or conditions, including any disease state and / or condition in which a protein is dysregulated and the patient would benefit from protein degradation.

[0122] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or salt form thereof described herein, a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent.The therapeutic composition can be used to regulate protein degradation in a patient or subject, for example, an animal, such as a human, and treat or alleviate a disease state or condition regulated through protein degradation.In certain embodiments, the therapeutic composition as described herein can be used to cause the degradation of a target protein for the treatment or alleviation of a disease, such as cancer (such as prostate cancer) and Kennedy's disease.In certain additional embodiments, the disease is prostate cancer.

[0123] In an alternative aspect, the present disclosure relates to a method for treating a disease or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide that regulates the disease or condition, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described herein above, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle, and optionally an additional bioactive agent, wherein the composition is effective for treating or ameliorating a disease or disorder or its symptoms in the subject. Using the method of the present disclosure, numerous disease states or conditions, including cancer, can be treated by administering an effective amount of at least one compound described herein. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent, such as a virus, bacteria, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that leads to the disease state and / or condition.

[0124] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0125] The term "target protein" refers to a protein that is conjugated to a compound according to the present disclosure and ubiquitin ligated as described below. The term "small molecule target protein binding moieties" is used to describe proteins or polypeptides that are targets for degradation by enzymes. 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 proteins of interest. These binding moieties are linked to a CLM or ULM group via a linker group, L.

[0126] Target proteins that can bind to a protein targeting moiety and be degraded by a ligase to which the ubiquitin ligase binding moiety binds include any protein or peptide, including fragments, analogs, and / or homologs thereof. Target proteins include proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction functions or activities. In certain embodiments, target proteins include, for example, structural proteins; receptors; enzymes; cell surface proteins; proteins associated with the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell-to-cell communication, regulation of biological processes, development, cell differentiation, response to stimuli; behavioral proteins; cell adhesion proteins; and 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; pathogenesis; chaperone regulator activity; nucleic acid binding activity; transcription regulator activity; extracellular organization and biosynthetic activity; translation regulator activity. Proteins of interest can include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, including humans, microorganisms, viruses, fungi, and parasites, as well as other animals, including livestock animals, microorganisms for determining targets for antibiotics, and other antimicrobials and plants, and even viruses, among many others, as targets for drug therapy.

[0127] More specifically, numerous drug targets used in human therapeutics represent protein targets to which protein targeting moieties can bind and be incorporated into compounds according to the present disclosure. 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 type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxidase 1, cyclooxidase 2, 5HT receptors, dopamine receptors, G proteins i.e. Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, trypanosomal GAPDH, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAWSTAT, RXR and the like, HIV-1 protease, HIV-1 integrase enzymes, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV , NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-1) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transporter inhibitor, 5-alpha-reductase receptor, angiotensin II, glycine receptor, noradrenaline reuptake receptor, endothelin receptor These include receptors, neuropeptide Y and receptors, estrogen receptors, androgen receptors (AR), adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, the NGF receptor TrkA, beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibitor, 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. Additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate phosphate synthase.

[0128] Haloalkane dehalogenase enzymes are another target of specific compounds according to the present disclosure. 12 Alkylhalo groups, often about C2-C 10Compounds according to the present disclosure containing alkylhalo groups may be used to inhibit and / or degrade haloalkane dehalogenase enzymes used in fusion proteins or related diagnostic proteins, as described in PCT / US2012 / 063401 filed December 6, 2011, and WO2012 / 078559 published June 14, 2012, the contents of which are incorporated herein by reference.

[0129] These various protein targets may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into compounds according to the present disclosure, the level of activity of the protein may be altered as a therapeutic end result.

[0130] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to a target protein or other protein or polypeptide of interest, placing / presenting the protein or polypeptide in proximity to a ubiquitin ligase for degradation of the protein or polypeptide by the ubiquitin ligase. Non-limiting examples of small molecule target protein binding moieties 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 the aryl hydrocarbon receptor (AHR). The compositions described below exemplify several members of these nine types of small molecule target proteins.

[0131] Exemplary protein targeting moieties according to the present disclosure include haloalkane halogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0132] The compositions described below contain several of these types of small molecule target protein binding moieties. Examples of such small molecule target protein binding moieties include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that may target proteins of interest. The references cited herein below are incorporated by reference in their entirety.

[0133] I. Heat Shock Protein 90 (HSP90) Inhibitors:

[0134] HSP90 inhibitors as used herein include, but are not limited to:

[0135] 1. HSP90 inhibitors identified in Vallee, et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone (2011) J. Med. Chem. 54: 7206," including YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide). Harmful Agent:

[0136] [ka] wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via a terminal amide group;

[0137] 2. HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

[0138] [ka] wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via a terminal acetylene group;

[0139] 3. Compound 2GJ (5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]) having the following structure: HSP90 inhibitors (modified) identified in Brough, et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J.MED.CHEM. vol: 51, pg: 196 (2008), including [4,5-diarylisoxazole-3-carboxamide]:

[0140] [ka] wherein the linker group L or -(L-CLM) group is derivatized such that it is attached through an amide group (at the amine or at an alkyl group on the amine);

[0141] 4. HSP90 inhibitors (modified) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the following structure: Type):

[0142] [ka] wherein the linker group L or -(L-CLM) is derivatized, e.g., attached via a butyl group; and

[0143] 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 derivative thereof (e.g., 17-alkylamino-17-desmethoxygeldanamycin ("17-AAG") or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin ("17-DMAG")), where the linker group L or -(L-CLM) group is attached, for example, via an amide group.

[0144] II. Kinase and phosphatase inhibitors:

[0145] Kinase inhibitors as used herein include, but are not limited to:

[0146] 1. Erlotinib derivative tyrosine kinase inhibitors: [ka] wherein R is a linker group L or a -(L-CLM) group, attached, for example, via an ether group;

[0147] 2. Kinase inhibitor sunitinib (derivatized):

[0148] [ka] wherein R is derivatized, e.g., to be a linker group L or a -(L-CLM) group attached to the pyrrole moiety;

[0149] 3. Kinase inhibitor sorafenib (derivatized):

[0150] [ka] wherein R is derivatized, e.g., to be a linker group L or a -(L-CLM) group attached to the amide moiety;

[0151] 4. Kinase inhibitor Desatinib (derivatized): [ka] where R is, for example, a linker group L or a -(L-CLM) group attached to the pyrimidine. As in, derivatized;

[0152] 5. Kinase inhibitor Lapatinib (derivatized):

[0153] [ka] wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via the terminal methyl of the sulfonylmethyl group;

[0154] 6. Kinase inhibitor U09-CX-5279 (derivatized):

[0155] [ka] wherein the linker group L or -(L-CLM) group is derivatized such that it is attached to the cyclopropyl group or cyclopropyl group via, for example, an amine (aniline), a carboxylic acid, or an amine alpha;

[0156] 7. Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the kinase inhibitors Y1W and Y1X (derivatized) having the following structures: Treatment of Chronic Obstructive Pulmonary Disease, J.MED.CHEM. vol:54, Kinase inhibitors identified in pag:7797 (2011): [ka]

[0157] YIX (1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea, wherein the linker group L or the a-(L-CLM) group is, for example, i derivatized so that it is attached via a propyl group; [ka] 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-({3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}(benzyl)urea wherein the linker group L or -(L-CLM) group is derivatized, e.g., preferably attached via either an i-propyl group or a t-butyl group;

[0158] 8. Schenkel, including compounds 6TP and 0TP (derivatized) having the following structures: et al., Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors J. Med. Chem., 2011, 54 (24), pp 8440-8450: [ka] 4-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamidothienopyridine 19 wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via a terminal methyl group attached to the amide moiety; [ka] 4-Amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamidothienopyridine 8 wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via a terminal methyl group attached to the amide moiety;

[0159] 9. The kinase inhibitor 07U having the following structure is described 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, identified as kinase inhibitors: [ka] 2-Methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine wherein the linker group L or -(L-CLM) group is derivatized so as to be attached, for example, via a secondary amine or terminal amino group;

[0160] 10. Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2," including the kinase inhibitor YCF, which has the following structure: Kinase inhibitors identified in "Chk2, a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011):

[0161] [ka] wherein the linker group L or the -(L-CLM) group is either a terminal hydroxyl group, e.g. derivatized so as to be attached via;

[0162] 11. 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) Kinase inhibitors include XK9 and NXP (derivatized), which have the following structures: [ka] N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide; [ka] NXP

[0163] N-{4-[(1E)-N-Carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide wherein the linker group L or -(L-CLM) group is derivatized so that it is attached, for example, via a terminal hydroxyl group (XK9) or hydrazone group (NXP);

[0164] 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) (wherein the linker group L or -(L-CLM) group is derivatized, for example, to be attached via an aliphatic amine group);

[0165] 13. The kinase inhibitor fostamatib (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 phosphate disodium hexahydrate) (wherein the linker group L or -(L-CLM) group is derivatized so as to be attached, for example, via a methoxy group);

[0166] 14. Kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

[0167] [ka] wherein the linker group L or -(L-CLM) group is, for example, a methoxy group or an ether group. derivatized so as to be added via;

[0168] 15. The kinase inhibitor lenvatinib (derivatized) (4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (wherein the linker group L or -(L-CLM) group is derivatized so as to be attached, for example, via the cyclopropyl group);

[0169] 16. The kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (wherein the linker group L or -(L-CLM) group is derivatized so as to be attached, for example, via a methoxy group or a hydroxyl group);

[0170] 17. The kinase inhibitor vemurafenib (derivatized) (propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide), derivatized so that a linker group L or a -(L-CLM) group is attached, for example, via a sulfonylpropyl group;

[0171] 18. Kinase inhibitor Gleevec (derivatized):

[0172] [ka] wherein the linker group L or R as a -(L-CLM) group is derivatized, e.g., attached via an amide group or via an aniline amine group;

[0173] 19. Kinase inhibitor Pazopanib (derivatized) (VEGFR3 inhibitor):

[0174] [ka] wherein R is derivatized to be, for example, a linker group L or -(L-CLM) group attached to the phenyl moiety or via the aniline amine group;

[0175] 20. Kinase inhibitor AT-9283 (derivatized) Aurora kinase inhibitor

[0176] [ka] wherein R is a linker group L or a -(L-CLM) group attached to, for example, the phenyl moiety;

[0177] 21. Kinase inhibitor TAE684 (derivatized) ALK inhibitor

[0178] [ka] wherein R is a linker group L or a -(L-CLM) group attached to, for example, the phenyl moiety;

[0179] 22. Kinase inhibitor Nilotinib (derivatized) Abl inhibitor:

[0180] [ka] wherein R is derivatized to be, for example, a linker group L or -(L-CLM) group attached to the phenyl moiety or aniline amine group;

[0181] 23. Kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor

[0182] [ka] wherein R is derivatized to be, for example, a linker group L or -(L-CLM) group attached to the phenyl moiety or diazole group;

[0183] 24. Kinase inhibitor Crizotinib-derivatized Alkyl inhibitor

[0184] [ka] wherein R is derivatized to be, for example, a linker group L or -(L-CLM) group attached to the phenyl moiety or diazole group;

[0185] 25. Kinase inhibitor JNJFMS (derivatized) inhibitor

[0186] [ka] wherein R is derivatized, e.g., a linker group L or a -(L-CLM) group attached to the phenyl moiety;

[0187] 26. Kinase inhibitor Foretinib (derivatized) Met inhibitor

[0188] [ka] wherein R is a linker group L or -(L-CLM) group attached to a hydroxyl or ether group on the phenyl or quinoline moiety, for example;

[0189] 27. Allosteric protein tyrosine phosphatase inhibitor PTP1B (derivatized):

[0190] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at the indicated R;

[0191] 28. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatized):

[0192] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0193] 29.BRaf(BRaf V600E ) / MEK inhibitor (derivatized)

[0194] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0195] 30. Inhibitors of tyrosine kinase ABL (derivatized)

[0196] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0197] 31. Kinase inhibitor OSI-027 (derivatized) mTORC1 / 2 inhibitor

[0198] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0199] 32. Kinase inhibitor OSI-930 (derivatized) c-Kit / KDR inhibitor

[0200] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0201] 33. Kinase inhibitor OSI-906 (derivatized) IGF1R / IR inhibitor

[0202] [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at R;

[0203] In any of the embodiments described in Sections I-XVII, "R" refers to the site for attachment of a linker group L or -(L-CLM) group on the piperazine moiety.

[0204] III.HDM2 / MDM2 inhibitors:

[0205] HDM2 / MDM2 inhibitors as used herein include, but are not limited to:

[0206] 1. The compounds described below, including (or in addition to) Nutlin-3, Nutlin-2, and Nutlin-1 (derivatized), and all derivatives and analogs thereof, are disclosed 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 HDM2 / MDM2 inhibitors identified in the molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908: [ka] wherein the linker group L or -(L-CLM) group is derivatized so as to be attached, for example, at a methoxy group or as a hydroxyl group; [ka] wherein the linker group L or -(L-CLM) group is derivatized, e.g., attached at a methoxy or hydroxyl group; [ka] wherein the linker group L or -(L-CLM) group is derivatized so that it is attached, for example, via a methoxy group or as a hydroxyl group; and

[0207] 2. trans-4-Iodo-4'-boranyl-chalcone [ka]

[0208] where the linker group L or the linker group L or -(L-CLM) group is derivatized such that it is attached, for example, via a hydroxyl group.

[0209] IV. Compounds targeting human BET bromodomain-containing proteins:

[0210] In certain embodiments, a "PTM" can be a ligand that binds to the bromo- and extraneous terminal (BET) proteins BRD2, BRD3, and BRD4. Compounds that target human BET bromodomain-containing proteins include, but are not limited to, compounds related to the targets set forth below, where "R" or "linker" refers to a site for attachment of, for example, a linker group L or a -(L-CLM) group:

[0211] 1.JQ1, Filippakopoulos et al. Selective inhibition of BET bromodomains. Nature (2010): [ka] [ka]

[0212] 2.I-BET, Nicodeme et al. Supression of Inflammation by a Synthetic Histone Mimic. Nature (2010). Chung et al. Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains. J. Med Chem. (2011): [ka]

[0213] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770. [ka]

[0214] 4.I-BET151, Dawson et al. Inhibition of BET Recruitment to Chromatin as an Effective Treatment for MLL-fusion Leukemia. Nature (2011): [ka]

[0215] 5. Carbazole type (U.S. Patent Application Publication No. 2015 / 0256700)

[0216] [ka]

[0217] 6. Pyrrolopyridone type (U.S. Patent Application Publication No. 2015 / 0148342)

[0218] [ka]

[0219] 7. Tetrahydroquinoline type (WO2015 / 074064)

[0220] [ka]

[0221] 8. Triazolopyrazine type (WO2015 / 067770)

[0222] [ka]

[0223] 9. Pyridone type (WO2015 / 022332)

[0224] [ka]

[0225] 10.Quinazolinone type (WO2015 / 015318)

[0226] [ka]

[0227] 11. Dihydropyridopyrazinone type (WO2015 / 011084)

[0228] [ka]

[0229] where R or L or linker in each case refers to the site for attachment of, for example, a linker group L or a -(L-CLM) group.

[0230] In any aspect or embodiment described herein, the claimed structural PTM may comprise a tricyclic diazepine or tricyclic azepine as the BET / BRD4 targeting moiety (PTM-a), where the dashed lines indicate the start of the linker attachment and define three possible sites for linker attachment: [ka] During the ceremony: A and B are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a thiophene, a pyrrole, a pyrazole, a pyridine, a pyrimidine, a pyrazine, optionally substituted by alkyl, alkoxy, halogen, nitrile, or another aromatic or heteroaromatic ring, where A is fused to a central azepine (Y═C) or diazepine (Y═N) moiety; Y1, Y2, and Y3, and Y4 can be carbon, nitrogen, or oxygen to form a fused 5-membered aromatic ring as a triazole or isoxazole; Z1 is a methyl group or a lower alkyl group.

[0231] Fragments of PTM-a as BET / BRD4 targeting moieties are described in the literature (WO2016 / 069578; WO2014 / 001356; WO2016 / 050821; WO2015 / 195863; WO2014 / 128111).

[0232] In any aspect or embodiment described herein that includes the structure CLM-L-PTM-a, PTM-a can be represented by the following general structure, where dashed lines indicate possible linker attachment points: In structures PTM-aa through PTM-ai, the substitution pattern of X and Y can be mono- or di-substituted. [ka] [ka]

[0233] In any aspect or embodiment described herein, the structure of PTM-a as a BET / BRD4 targeting moiety includes the following, where the dashed line indicates the connection point between the BET / BRD4 targeting moiety and the linker: [ka] [ka] [ka]

[0234] V. HDAC inhibitors:

[0235] HDAC inhibitors (derivatized) include, but are not limited to:

[0236] 1.Finnin, MS et al. Structures of Histone Deacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193 (1999). [ka] wherein "R" is derivatized to indicate a site for attachment of, for example, a linker group L or a -(L-CLM) group; and

[0237] 2. Formula (I) of PCT WO0222577 ("DEACETYLASE INHIBITORS") wherein a linker group L or -(L-CLM) group is attached, for example, via a hydroxyl group;

[0238] VI. Human Lysine Methyltransferase Inhibitors:

[0239] Human lysine methyltransferase inhibitors include, but are not limited to, the following:

[0240] 1.Chang et al. Structural Basis for G9a-Like protein Lysine Methyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16(3) 312. [ka]

[0241] (wherein "R" is derivatized to indicate a site for attachment of, for example, a linker group L or a -(L-CLM) group);

[0242] 2.Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Methyltransferase G9a. J. Med. Chem. (2009) 52(24) 7950. [ka]

[0243] (wherein "R" is derivatized to indicate a potential site for attachment of, for example, a linker group L or a -(L-CLM) group);

[0244] 3. Azacitidine (derivatized) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (wherein the linker group L or -(L-CLM) group is derivatized so that it is attached, for example, via a hydroxy group or an amino group); and

[0245] 4. Decitarabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (wherein the linker group L or -(L-CLM) group is derivatized such that it is attached, for example, via either hydroxy group or at the amino group).

[0246] VII. Angiogenesis inhibitors:

[0247] Angiogenesis inhibitors include, but are not limited to:

[0248] 1.Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 GA-1 (derivatized) and derivatives and analogs thereof having the structure set forth in Dec;2(12):1350-8 and attachment to a linker;

[0249] 2. Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211, which may be attached to a linker group L or a -(L-CLM) group (derivatized);

[0250] 3. Estradiol, testosterone (derivatized), and related derivatives, including but not limited to DHT and its derivatives and analogs, having structures generally as described in Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol Cell Proteomics 2003 Dec; 2(12):1350-8, and linked with a linker group L or -(L-CLM) group; and

[0251] 4.Sakamoto, et al., Protacs: chimeric molecules that target proteins Ovalicin, fumagillin (derivatized), and derivatives and analogs thereof having structures and linkages with linker groups L or -(L-CLM) groups generally as described in Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and United States Patent No. 7,208,157.

[0252] VIII. Immunosuppressive compounds:

[0253] Immunosuppressant compounds include, but are not limited to:

[0254] 1. A structure and linker group L or -(L-CLM) group generally as described in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004, 126, 3748-3754. AP21998 (derivatized) with the bond of

[0255] 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, and methylprednisolone) (wherein the linker group L or -(L-CLM) group is derivatized, e.g., to attach to any hydroxyl) and beclomethasone dipropionate (wherein the linker group or -(L-CLM) is derivatized, e.g., to attach to the propionate ester);

[0256] 3. methotrexate (wherein the methotrexate is derivatized so that a linker group or -(L-CLM) group can be attached, for example, to either terminal hydroxyl);

[0257] 4. Cyclosporin (wherein the linker group or -(L-CLM) group is derivatized to allow attachment, for example, at either butyl group);

[0258] 5. Tacrolimus (FK-506) and rapamycin (wherein the linker group L or -(L-CLM) group is derivatized so that it can be attached to, for example, one of the methoxy groups); and

[0259] 6. Actinomycin (wherein the linker group L or -(L-CLM) group is derivatized so that it can be attached to, for example, one of the isopropyl groups).

[0260] IX. Compounds targeting the aryl hydrocarbon receptor (AHR):

[0261] Compounds that target the aryl hydrocarbon receptor (AHR) include, but are not limited to:

[0262] 1. Apigenin (synopsis: 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) derivatized in a manner that will attach to the linker group L or -(L-CLM) group as described above; and

[0263] 2.Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the SR1 and LGC0, as described in Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010:Vol. 329 no. 5997 pp. 1345-1348 06 (derivatized to allow for the attachment of a linker group L or -(L-CLM)).

[0264] X. Compounds that target the RAF receptor (kinase): [ka]

[0265] PLX4032

[0266] (derivatized, where "R" is, for example, a linker group L or -(L-CLM ) groups).

[0267] Any protein that can be bound to a protein targeting moiety or PTM group and acted upon or degraded by a ubiquitin ligase (e.g., RAF) is a target protein according to the present disclosure.

[0268] In any aspect or embodiment described herein, the PTM targets and / or binds to RAF (i.e., a target portion of Raf or BRaf). For example, in any aspect or embodiment described herein, the PTM comprises a chemical group selected from the group of chemical structures consisting of PTM-Ia or PTM-Ib: [ka] During the ceremony: The double point bond is an aromatic bond; V PTM , W PTM , X PTM , Y PTM , Z PTM is one of the following combinations: C, CH, N, N, C; C, N, N, CH, C; C, O, C, CH, C; C, S, C, CH, C; C, CH, C, O, C; C, CH, C, S, C; C, CH, N, CH, C; N, CH, C, CH, C; C, CH, C, CH, N; N, N, C, CH, C; N, CH, C, N, C; C, N, C, CH, N; C, N, C, CH, N; C, N, C, N, C; and C, N, N, N, N, C; XPTM35 , X PTM36 , X PTM37 , and X PTM38 is independently selected from CH and N; R PTM1 is covalently joined to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof; R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM3 is absent or is hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH, NHCH, or M-CH-CH-M, where M is CH, O, and NH, and M is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM5 is selected from the group consisting of: [ka]

[0269] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the group of chemical structures consisting of PTM-IIa or PTM-IIb: [ka] During the ceremony: X PTM1 , X PTM2 , X PTM3 , X PTM4, X PTM5 , and X PTM6 are independently selected from CH or N; R PTM5a is a bond, an optionally substituted amine, an optionally substituted amide (e.g., optionally substituted with an alkyl, methyl, ethyl, propyl, or butyl group), H, [ka] -NHC(O)R PTM5 selected from the group consisting of: R PTM5 is selected from the group consisting of: [ka] R PTM6a and R PTM6b are each independently selected from hydrogen, halogen, or optionally substituted C1-C6 alkyl (linear, branched, optionally substituted); R PTM6 is absent or is hydrogen, halogen, aryl, methyl, ethyl, OCH, NHCH, or M-CH-CH-M, where M is CH, O, and NH, and M is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM7 is absent or is hydrogen, halogen, aryl, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, or NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM8 , R PTM9 , or R PTM10 is independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, NH and M2 is hydrogen, alkyl, cycloalkyl, aryl, or heterocycle; R PTM11is absent or is hydrogen, halogen, methyl, ethyl, OCH, NHCH, or M-CH-CH-M, where M is CH, O, or NH and M is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM8 , R PTM9 , or R PTM10 is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[0270] In certain embodiments, the PTM is a chemical group selected from the group of chemical structures consisting of: May include: [ka] In the formula, R PTM5 , R PTM6a , R PTM6b , R PTM6 , R PTM7 , R PTM8 , R PTM9 , R PTM10 , R PTM11 is as described herein.

[0271] In some embodiments, R PTM9 is the position where the bond is covalently bonded, R PTM7 and R PTM8 is R PTM7 and R PTM8 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0272] In other embodiments, R PTM8 is the position where the bond is covalently bonded, R PTM9 and R PTM10 is R PTM9 and R PTM10 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0273] In yet another embodiment, R PTM10 is the position where the bond is covalently bonded, R PTM8 and R PTM9 is R PTM8 and R PTM9 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0274] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the group of chemical structures consisting of PTM-III: [ka] During the ceremony: X PTM7 , X PTM8 , X PTM9 , X PTM10 , X PTM11 , X PTM12 , X PTM13 , X PTM14 , X PTM15 , X PTM16 , X PTM17 , X PTM18 , X PTM19 , X PTM20 are independently CH or N; R PTM12 , R PTM13 , R PTM14 , R PTM15 , R PTM16 , R PTM17 , R PTM18 , R PTM19 is independently absent or selected from the group consisting of hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH3, NHCH3, or M1-CH2-CH2-M2, where M1 is CH2, O, and NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM20 is a small group containing less than four non-hydrogen atoms; R PTM21is selected from the group consisting of trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH3, NHCH3, dimethylamino, or M1-CH2-CH2-M2, where M1 is CH2, O, or NH and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM12 , R PTM13 , or R PTM16 is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[0275] In some embodiments, R PTM12 is the position where the bond is covalently bonded, R PTM13 and R PTM14 is R PTM13 and R PTM14 and R may be connected together via a covalent bond to form a bicyclic group comprising the ring to which R is attached, and / or PTM15 and R PTM16 is R PTM15 and R PTM16 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0276] In some embodiments, R PTM13 is the position where the bond is covalently bonded, R PTM12 and R PTM16 is R PTM12 and R PTM16 and R may be connected together via a covalent bond to form a bicyclic group comprising the ring to which R is attached, and / or PTM15 and R PTM16 is R PTM15 and R PTM16 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0277] In yet another embodiment, R PTM16 is the position where the bond is covalently bonded, R PTM12 and R PTM13 is R PTM12 and R PTM13 and a ring to which and / or R PTM13 and R PTM14 is R PTM13 and R PTM14 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0278] In any aspect or embodiment described herein, the PTM may comprise a chemical group selected from the group of chemical structures consisting of PTM-IVa or PTM-IVb: [ka] During the ceremony: X PTM21 , X PTM22 , X PTM23 , X PTM24 , X PTM25 , X PTM26 , X PTM27 , X PTM28 , X PTM29 , X PTM30 , X PTM31 , X PTM32 , X PTM33 , X PTM34 are independently CH or N; R PTM22 is selected from the group consisting of: [ka] R PTM25a and R PTM25b are each independently selected from hydrogen, halogen, or C1-C6 alkyl (linear, branched, optionally substituted); R PTM23 , R PTM24 , R PTM28 , R PTM29 , R PTM30 , RPTM31 , R PTM32 is independently absent or selected from the group consisting of a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), methyl, ethyl (optionally substituted), other alkyl (linear, branched, optionally substituted), OCH, NHCH, or M-CH-CH-M, where M is CH, O, and NH and M is hydrogen, alkyl (linear, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted), or heterocycle (optionally substituted); and R PTM25 is absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or SCH3; R PTM26 is absent, hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or SCH3; R PTM27 is absent or selected from the group consisting of hydrogen, halogen, C1-C6 alkyl (linear, branched, optionally substituted), OCH3, NHCH3, or SCH3; and R PTM24 , R PTM29 , or R PTM32 is modified to be covalently attached to a ULM, a chemical linker group (L), a CLM, an ILM, a VLM, an MLM, a ULM', a CLM', an ILM', a VLM', an MLM', or a combination thereof.

[0279] In some embodiments, R PTM24 is the position where the bond is covalently bonded, R PTM31 and R PTM32 is R PTM31 and R PTM32 and R may be connected together via a covalent bond to form a bicyclic group comprising the ring to which R is attached, and / or PTM29 and R PTM30 is RPTM29 and R PTM30 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0280] In some embodiments, R PTM29 is the position where the bond is covalently bonded, R PTM24 and R PTM32 is R PTM24 and R PTM32 and R may be connected together via a covalent bond to form a bicyclic group comprising the ring to which R is attached, and / or PTM31 and R PTM32 is R PTM31 and R PTM32 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0281] In yet another embodiment, R PTM32 is the position where the bond is covalently bonded, R PTM24 and R PTM29 is R PTM24 and R PTM29 and R may be connected together via a covalent bond to form a bicyclic group comprising the ring to which R is attached, and / or PTM29 and R PTM30 is R PTM29 and R PTM30 and the ring to which they are attached can be joined together via a covalent bond to form a bicyclic group.

[0282]

[0023] In any aspect or embodiment described herein, the PTM is selected from the group consisting of the following chemical structures: PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and PTM-8: [ka] [ka]

[0283] XI. Compounds targeting FKBP:

[0284] [ka]

[0285] (derivatized, where "R" refers to the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0286] XII. Compounds targeting the androgen receptor (AR)

[0287] 1. RU59063 Ligand (Derivatized) of the Androgen Receptor

[0288] [ka]

[0289] (derivatized, where "R" refers to the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0290] 2. Androgen receptor SARM ligands (derivatized)

[0291] [ka]

[0292] (derivatized, where "R" refers to the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0293] 3. Androgen receptor ligand DHT (derivatized)

[0294] [ka]

[0295] (derivatized, where "R" refers to the site for attachment of, for example, a linker group L or a -(L-CLM) group).

[0296] 4. MDV3100 Ligand (Derivatized)

[0297] [ka]

[0298] 5.ARN-509 Ligand (Derivatization)

[0299] [ka]

[0300] 6. Hexahydrobenzisoxazoles

[0301] [ka]

[0302] 7. Tetramethylcyclobutanes

[0303] [ka]

[0304] 8. In any aspect or embodiment described herein, the PTM is a chemical moiety that binds to the androgen receptor (AR). Various androgen receptor binding compounds have been described in the literature, including various androgen derivatives such as testosterone, dihydrotestosterone, and metribolone (also known as methyltrienolone or R1881), as well as non-steroidal compounds such as bicalutamide and enzalutamide, some of which have been described above. Those skilled in the art will recognize that these androgen receptor binding compounds may be used as androgen binding moieties (ABMs) in PROTAC compounds. Such literature includes, but is not limited to, GF Allan et al., Nuclear Receptor Signaling, 2003, 1, e009; RH Bradbury et al., Bioorganic & Medicinal Chemistry Letters, 2011 5442-5445; C. Guo ... Chemistry Letters, 2012 2572-2578; PK Poutiainen et. al, J. Med. Chem. 2012, 55, 6316 - 6327 A. Pepe et. al, J. Med. Chem. 2013, 56, 8280-8297; ME Jung et al, J. Med. Chem. 2010, 53, 2779-2796, which are incorporated herein by reference.

[0305] In any aspect or embodiment described herein, the ABM comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment of a linker moiety or ULM, such as a CLM: [ka] [ka] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently containing one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (linear, branched, optionally substituted; e.g., optionally with one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (linear, branched, optionally substituted; e.g., optionally substituted with one or more halo), C 2-6 Alkenyl, C 2-6 substituted by alkynyl, or CF3; Y 1 , Y 2 are each independently NR Y1 ,O,S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is optionally 0 to 6 R Q and each R is a 3- to 6-membered ring having 0 to 4 heteroatoms substituted by Q However, independently, H, C 1-6 Alkyl (linear, branched, optionally substituted, e.g., optionally halo, C 1-6 substituted by alkoxyl), halogen, C 1-6 Alkoxy or two R Q the groups, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R 1 , R 2 , R a , R b , R Y1 , R Y2 are independently H, C 1-6Alkyl (linear, branched, optionally substituted; e.g., optionally with one or more halo, C 1-6 substituted by alkoxyl), halogen, C 1-6 alkoxy, cyclic, heterocyclic, or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C 1-6 Alkyl, C 1-6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocycle, biheterocycle, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 is replaced by; Each R W2 are independently H, halo, and C 1-6 alkyl (linear, branched, optionally substituted; e.g., optionally substituted with one or more F), -OR W2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC 1-3 Alkyl (optionally substituted), OH, NH2, NR Y1 R Y2 , CN; and R W2A is H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (linear, branched), each optionally selected from cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC; 1-3 Substituted by alkyl.

[0306] In any aspect or embodiment described herein, W 2is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0307] In any aspect or embodiment described herein, W 1 teeth: [ka] and In the formula, each R 22 is independently halo, H, optionally substituted alkyl, haloalkyl, cyano, or nitro; and each R 23 is independently H, halo, CF3, optionally substituted alkyl, alkoxy, haloalkyl, cyano, or nitro.

[0308] In any aspect or embodiment described herein, W 1 is selected from the group consisting of: [ka]

[0309] In any aspect or embodiment described herein, the ABM comprises a structure selected from the following structures shown below, wherein: [ka] indicates the point of attachment of the linker or ULM: [ka] During the ceremony: R Q2 is H, halogen, CH3, or CF3; R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl), C 1-6Alkoxyl (linear, branched, optionally substituted with one or more halo), C 2-6 Alkenyl, C 2-6 alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C═O, heteroaryl, or aryl; R Y1 , R Y2 are each independently H or C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxy, cyclic or heterocyclic; and R Q are each independently H, C1-C6 alkyl (linear, branched, optionally with one or more halo, or C 1-6 substituted by alkoxyl) or two R Q together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms.

[0310] In any aspect or embodiment described herein, each R Q is independently H or CH. In another embodiment, R Q3 is CN.

[0311] In any aspect or embodiment described herein, the ABM may have the following structure shown below: and a structure selected from the group consisting of: [ka] indicates the point of attachment of the linker or ULM: [ka] During the ceremony: R Q2 is H, halogen, CN, CH3, or CF3; and R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (linear, branched, optionally substituted with one or more halo), C 2-6 Alkenyl, C 2-6 alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C═O, heteroaryl, or aryl; and R Y1 , R Y2 are each independently H or C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxy, cyclic or heterocyclic; and X is N or C.

[0312] In any aspect or embodiment described herein, R Q3 is CN.

[0313] In any aspect or embodiment described herein, the ABM comprises the structure shown below, where the dashed line indicates the point of attachment of a linker moiety or a ULM or CLM: [ka] During the ceremony: W 1 teeth, [ka] and; Each R 22 are independently H or -CN; Each R 23are independently H, halo, C-C alkyl (linear, branched, optionally substituted), C-C alkoxy, or -CF; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 are each independently H, or C1-C6 alkyl (linear or branched, optionally substituted; e.g., optionally with one or more halo, or C 1-6 substituted by alkoxyl); W 2 is a bond, C 1-6 Aryl, C1-6 heteroaryl, C 1-6 alicyclic, or C heterocycle, biheterocycle, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 is replaced by; and Each R W2 are independently H or halo; and [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0314] In any aspect or embodiment described herein, W 2 is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0315] In any aspect or embodiment described herein, W 1 is selected from the group consisting of: [ka]

[0316] In any aspect or embodiment described herein, W 2 is selected from the group consisting of: [ka]

[0317] In any aspect or embodiment described herein, the ABM comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment of the linker moiety or ULM: [ka] During the ceremony: W 1 teeth, [ka] and; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 1 , Y 2 are each independently O or S; R 1 , R 2 are each independently H or a methyl group; W 2 is a bond, C 1-6 aryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6 alkyl (optionally substituted with one or more F), OC 1-3 alkyl (optionally substituted with one or more -F).

[0318] In any embodiment described herein, W 2is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0319] In certain additional embodiments, W 1 is selected from the group consisting of: [ka]

[0320] In any aspect or embodiment described herein, W2 is selected from the group consisting of: [ka]

[0321]

[0033] In any aspect or embodiment described herein, the ABM is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] .

[0322]

[0023] In any aspect or embodiment described herein, the ABM comprises the following structure: [ka] During the ceremony: W 1 are aryl, or heteroaryl, each independently selected from one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (linear, branched, optionally substituted with one or more halo), C 2-6 Alkenyl, C 2-6 substituted by alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is a 4-membered alicyclic or aromatic ring having 0-2 heteroatoms, and optionally 0-6 R Q and each R Q However, independently H, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl) or two R Q the groups, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R Y1 , R Y2 are independently H, C 1-6 Alkyl (straight chain, branched, optionally One or more halos in C 1-6 substituted by alkoxyl); and W 2 is a bond, C 1-6 Alkyl, C 1-6 Heteroalkyl, O, C 1-6 alicyclic, heterocyclic, aryl, biheterocyclic, biaryl or biheteroaryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6 Alkyl (linear, branched, optionally substituted with one or more F), C1-6 heteroalkyl (linear, branched, optionally substituted), -OR W2A , O.C. 1-3 alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 cycloheteroalkyl (optionally substituted), C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), heteroaryl (optionally substituted), bicyclic heteroaryl (optionally substituted), bicyclic aryl, OH, NH, NR Y1 R Y2 , or CN; and R W2A is H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (linear, branched), each optionally selected from cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC; 1-3 Substituted by alkyl.

[0323] In any aspect or embodiment described herein, the description provides an androgen receptor binding compound comprising the following structure: [ka] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently containing one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (linear, branched, optionally substituted with one or more halo), C 2-6 Alkenyl, C 2-6 substituted by alkynyl, or CF3; Y 1 , Y 2are each independently NR Y1 , O, or S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is a 3-6 membered alicyclic or aromatic ring having 0-4 heteroatoms, and optionally 0-6 R Q and each R Q However, independently H, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl) or two R Q the groups, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R 1 , R 2 , R a , R b , R Y1 , R Y2 are independently H, C 1-6 Alkyl (linear, branched, optionally with one or more halo, C 1-6 substituted by alkoxyl) or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C 1-6 Alkyl, C 1-6 Heteroalkyl, O, C 1-6 alicyclic, heterocyclic, aryl, biheterocyclic, biaryl or biheteroaryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by ; Each R W2 are independently H, halo, and C 1-6 Alkyl (straight chain, branched, optionally one or or replaced by multiple F), C 1-6heteroalkyl (linear, branched, optionally substituted), -OR W2A , O.C. 1-3 alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH, NR Y1 R Y2 , CN; and R W2A is H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (linear, branched), each optionally selected from cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC; 1-3 Substituted by alkyl.

[0324]

[0041] In any aspect or embodiment described herein, the androgen receptor binding moiety has the following structure: [ka] During the ceremony: W 1 teeth, [ka] and; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 3 is a bond or O; Q is optionally 0 to 4 R Q and each R Q are independently H or methyl; Y4 is a bond or NH; Y5 is a bond, C=O, or C=S; and Each W 2 are independently a bond, C aryl or heteroaryl, each optionally having 1, 2, or 3 R W2 and each R W2 are independently H, halo, a 6-membered alicyclic ring having 1 or 2 heteroatoms, or a 5-membered aromatic ring having 1, 2, or 3 heteroatoms.

[0325] In any aspect or embodiment described herein, W 2 is selected from the group consisting of: [ka]

[0326] In any aspect or embodiment described herein, W 2 is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0327] In any aspect or embodiment described herein, W 1 is selected from the group consisting of: [ka]

[0328]

[0041] In any aspect or embodiment described herein, the androgen binding moiety has the following structure: [ka] During the ceremony: W 1 is independently aryl substituted with one or more halo, CN; Y 3 are each independently a bond, NR Y2 , C.R. Y1 RY2 , C=O; Q is a 5-membered aromatic ring containing 1 or 2 heteroatoms; R Y1 , R Y2 are independently H, C 1-6 Alkyl (linear, branched); W 2 is a bond, aryl, or heteroaryl, each optionally having one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6 alkyl (optionally substituted with one or more F), OC 1-3 alkyl (optionally substituted with one or more -F).

[0329] In any aspect or embodiment described herein, W 2 is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0330] In any aspect or embodiment described herein, W 1 teeth: [ka] and; Each R 22 are independently halo or CN; and Each R 23 are independently H or halo;

[0331] In any aspect or embodiment described herein, W 1 is selected from the group consisting of: [ka]

[0332] In any aspect or embodiment described herein, Q is: [ka] is.

[0333] In any aspect or embodiment described herein, W 2 teeth: [ka] is.

[0334] In any aspect or embodiment described herein, (Y 3 ) 0-5 teeth: [ka] is.

[0335] In any aspect or embodiment described herein, the ABM comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment of a linker moiety or ULM, such as a CLM: [ka] During the ceremony: W 1 teeth, [ka] and; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 1 , Y 2 are each independently O or S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2, C=O, C=S, SO, or SO2; R 1 , R 2 are each independently H or a methyl group; W 2 is a bond, C 1-6 aryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6 alkyl (optionally substituted with one or more F), C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, OC 1-3 alkyl (optionally substituted with one or more -F).

[0336] In any aspect or embodiment described herein, W 2 is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0337] In any aspect or embodiment described herein, W 1 is selected from the group consisting of: [ka]

[0338] In any aspect or embodiment described herein, W2 is selected from the group consisting of: [ka]

[0339] In any aspect or embodiment described herein, the ABM comprises the structure shown below, where the dashed line indicates the point of attachment of a linker moiety or a ULM or CLM: [ka] During the ceremony: W 1 teeth, [ka] and; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 are each independently H, or C1-C6 alkyl (linear or branched, optionally with one or more halo, or C 1-6 substituted by alkoxyl); W 2 is a bond, C 1-6 Aryl, C1-6 heteroaryl, C 1-6 alicyclic, or C heterocyclic, each optionally containing 1 to 10 R W2 is replaced by; and Each R W2 are independently H or halo; and

[0340] [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0341] In any embodiment described herein, W 2 is covalently joined to one or more ULM or CLM groups or a linker attached to one or more ULM or CLM groups, as described herein.

[0342] In certain additional embodiments, W 1 is selected from the group consisting of: [ka]

[0343] In certain additional embodiments, W 2 is selected from the group consisting of: [ka] [ka]

[0344] In certain embodiments, the androgen receptor binding compound of the ABM is selected from the group consisting of: trans-2-chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile; cis-2-chloro-4-[3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile; trans 6-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridazine-3-carboxamide; trans tert-butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamate; trans 4-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; trans 5-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrazine-2-carboxamide; trans 2-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrimidine-5-carboxamide; 4-Methoxy-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; trans 1-(2-hydroxyethyl)-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]-1H-pyrazole-4-carboxamide; trans 6-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide; trans 4-[(5-hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; and trans tert-butyl 2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]carbamoyl}phenyl)aminopentyl}oxy)acetate; and N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenzamide.

[0345] XIII. Compound ICI-182780 targeting the estrogen receptor (ER)

[0346] 1. Estrogen receptor ligands

[0347] [ka]

[0348] (derivatized, where "R" refers to the site for attachment of a linker group L or a -(L-CLM) group).

[0349] In any embodiment or aspect described herein, the PTM may be represented by the formula PTM-I: [ka] During the ceremony: XPTM is O or C=O; X PTM1 and X PTM2 each of is independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is an alkyl or aryl group in the ester; At least one R PTM2 are each independently selected from H, OH, halogen, CN, CF, SO-alkyl, O-lower alkyl; At least one R PTM3 are each independently selected from H, halogen; and The dashed lines mark the site of addition of at least one of a linker, a CLM, a CLM', a PTM, a PTM', or a combination thereof.

[0350] In any embodiment or aspect described herein, the PTM may be represented by the formula PTM-I: [ka] During the ceremony: X PTM is O or C=O; X PTM1 and X PTM2 each of is independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is an alkyl or aryl group in the ester; Each R PTM2 are independently selected from H, OH, halogen, CN, CF, SO-alkyl, O-lower alkyl; Each R PTM3 are independently selected from H, halogen; PTM-I is at least R PTM2 , at least one R PTM3or combinations thereof in each ring; and The dashed lines mark the site of addition of at least one of a linker, a CLM, a CLM', a PTM, a PTM', or a combination thereof.

[0351] In any embodiment or aspect described herein, PTM-I may comprise two R PTM2 , two R PTM3 or a combination thereof.

[0352] In any embodiment or aspect described herein, the PTM may be represented by the formula PTM-II: [ka] During the ceremony: X PTM is O or C=O; X PTM1 and X PTM2 each of is independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is an alkyl or aryl group in the ester; R PTM2 and R PTM4 is independently selected from H, OH, halogen, CN, CF, SO-alkyl, O-lower alkyl; R PTM3 and R PTM5 are independently selected from H, halogen; and The dashed lines mark the site of addition of at least one of a linker, a CLM, a CLM', a PTM, a PTM', or a combination thereof.

[0353] In aspects or embodiments described herein, O(CO)R PTM functions as a prodrug of the corresponding phenol in formula PTM-I or PTM-II.

[0354] In any embodiment or aspect described herein, the O-lower alkyl of PTM-I or PTM-II is an alkyl chain having 1 to 3 carbon atoms.

[0355] In aspects or embodiments described herein, the present disclosure provides a compound of formula (I PTM ) a compound or PTM of: [ka] Formula (I PMT ) During the ceremony: each X PTM are independently CH, N; [ka] indicates the site of attachment of at least one of a linker, a CLM, a CLM', a PTM, a PTM', or a combination thereof. Each R PTM1 are independently OH, halogen, O(CO)R PTM where R PTM is an alkyl or cycloalkyl group having 1 to 6 carbons or an aryl group, which may be mono-, di-, or tri-substituted; Each R PTM2 are independently H, halogen, CN, CF, alkoxy, and the substitutions can be mono- or di-substituted; and Each R PTM3 are independently H, halogen, and the substitution can be mono- or di-substituted.

[0356] In any aspect or embodiment described herein, the PTM is represented by formula (II PTM ) is represented by: [ka] Formula (II PMT ) During the ceremony: X PTM is CH,N; [ka] indicates the site of attachment of at least one of a linker, CLM, CLM', PTM, PTM', ULM, ILM, VLM, MLM, ULM', ILM', VLM', MLM', or combinations thereof; Each R PTM1 are independently OH, halogen (e.g., F); Each R PTM2 are independently H, halogen (e.g., F), CF3, and the substitutions can be mono- or di-substituted; and Each R PTM3 are independently halogen (e.g., F), and the substitution can be mono- or di-substituted.

[0357] In certain embodiments, at least one of the following: Formula (II PTM )X PTM is CH; Formula (II PTM )R PTM1 is OH; Formula (II PTM )R PTM2 is H; Formula (II PTM ) each R PTM3 are independently H or F; or A combination of them.

[0358] XIV. Compounds Targeting Thyroid Hormone Receptors (TRs)

[0359] 1. Thyroid hormone receptor ligands (derivatized)

[0360] [ka]

[0361] (derivatized, where "R" refers to the site for attachment of a linker group L or -(L-CLM) group, and MOMO denotes a methoxymethoxy group).

[0362] XV. Compounds that target HIV protease

[0363] 1. HIV protease inhibitors (derivatized)

[0364] [ka]

[0365] (derivatized, where "R" refers to the site for attachment of a linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0366] 2. HIV protease inhibitors

[0367] [ka]

[0368] (derivatized, where "R" refers to a potential site for attachment of a linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 521-538.

[0369] XVI. Compounds that target HIV integrase

[0370] 1. HIV integrase inhibitors (derivatized)

[0371] [ka]

[0372] (derivatized, where "R" refers to the site for attachment of a linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0373] 2. HIV integrase inhibitors (derivatized)

[0374] [ka]

[0375] 3. HIV integrase inhibitor Isentress (derivatized)

[0376] [ka]

[0377] (derivatized, where "R" refers to the site for attachment of a linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53, 6466.

[0378] XVII. Compounds targeting HCV protease

[0379] 1. HCV protease inhibitors (derivatized)

[0380] [ka]

[0381] (derivatized, where "R" refers to the site for attachment of a linker group L or a -(L-CLM) group).

[0382] XVIII. Compounds Targeting Acyl-Protein Thioesterase-1 and -2 (APT1 and APT2)

[0383] 1. APT1 and APT2 inhibitors (derivatized)

[0384] [ka]

[0385] (derivatized, where "R" refers to the site for attachment of a linker group L or -(L-CLM) group). See Angew. Chem. Int. Ed. 2011, 50, 9838-9842 and in which L is a linker group as otherwise described herein, and the CLM group is as otherwise described herein, such that -(L-CLM) connects the CLM group to the PTM group as otherwise described herein.

[0386] VIV. Compounds targeting the Tau protein

[0387] In any aspect or embodiment described herein, the PTM may comprise a Tau protein-binding moiety. For example, the PTM may be represented by Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, or Formula XI: [ka] During the ceremony: A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- or 7-membered cycloalkyl or heterocycloalkyl, where contact between circles indicates ring fusion; and L PTM is selected from a bond, alkyl, alkenyl, or alkynyl, or is optionally interrupted by one or more rings (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), or is selected from -O-, -S-, -NR 1 PTM -(In the formula, R 1 PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO2-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO2-, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, said functional groups optionally being phosphorus Located at either end of the car.

[0388] In any aspect or embodiment described herein, the aryl and heteroaryl rings of A, B, C, D, E, and F of PTM are optionally substituted with 1 to 3 substituents, each independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, wherein the alkyl and alkenyl groups are further optionally substituted.

[0389] In any aspect or embodiment described herein, at least one ring of A, B, C, F, or a combination thereof is selected from an optionally substituted 5- or 6-membered aryl or heteroaryl ring;

[0390] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I, wherein: Rings A, B, and C are independently 5- or 6-membered fused aryl or heteroaryl rings; L PTM is selected from a bond or alkyl, and D is selected from a 6-membered aryl, heteroaryl, or heterocycloalkyl; wherein A, B, C, and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0391] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula I, wherein: A and C are phenyl or a 6-membered heteroaryl ring; B is a 5-membered heteroaryl ring; L PTM is a bond; and D is a 6-membered heteroaryl ring or a 6-membered heterocycloalkyl ring; wherein each of A, B, C, and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano, and wherein a nitrogen atom in any of the A, B, C, and D rings is not directly connected to a heteroatom or carbon atom to which another heteroatom is directly attached.

[0392] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula III or IV, where A, B, and C are 5- or 6-membered fused aryl or heteroaryl rings, and L PTM is selected from a bond or alkyl, and D and E are 5- or 6-membered fused aryl or heteroaryl rings, wherein A, B, C, D, and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0393] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure: [ka] [ka] During the ceremony: R 1 , R 2 , and R 3 is independently selected from H, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; R 4 and R 5 is independently selected from H, methyl, ethyl, and halogen; and R 6 are 1 to 2 substituents independently selected from H, methyl, ethyl, and halogen; wherein the PTM is attached to the ULM via L.

[0394] In any embodiment described herein, the PTM is covalently joined to one or more ULM (VLM or CLM) groups or to a linker attached to one or more ULM (VLM or CLM) groups, as described herein.

[0395] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure: [ka] [ka] [ka] During the ceremony: R 1 , R 2 , and R 3 is independently selected from H, optionally substituted alkyl, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; and R 7 , R 8 , R 9 , and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, aceylamino, trifluoromethyl, or cyano, where the PTM is linked to the ULM (VLM or CLM) via L.

[0396] In any aspect or embodiment described herein, the PTM is represented by the following chemical structure: [ka] [ka] [ka]

[0397] In any aspect or embodiment described herein, the point of attachment of the linker to the PTM is as marked by the dotted line: [ka]

[0398] therapeutic compounds

[0399] Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein in combination with one or more other compounds described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent yet another aspect of the present disclosure.

[0400] The present disclosure includes compositions containing pharmaceutically acceptable salts, where available, specifically acid or base addition salts of the compounds described herein. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds described above useful in this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as hydrochloride, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt), among others.

[0401] Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms of compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.

[0402] The compounds described herein may be administered orally, parenterally, or topically in single or divided doses in accordance with the present disclosure. Administration of the active compounds may range from continuous administration (intravenous infusion) to multiple oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, sublingual, and suppository administration, among other routes of administration. Enteric-coated oral tablets may also be used to enhance the bioavailability of the compounds from oral administration. The most effective dosage form will depend on the pharmacokinetics of the specific agent selected and the severity of the patient's disease. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration may also be used. Therefore, the present disclosure is directed to pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle. The compounds according to the present disclosure may be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Sustained or controlled release forms are preferably administered orally, but also via suppositories and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0403] The compositions described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and may also be administered in controlled-release formulations. 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, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0404] 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.

[0405] The sterile injectable form of the compositions described herein may be aqueous or oily suspension.These suspensions may be formulated according to methods known in the art using suitable dispersants or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution.In addition, sterile, fixed oils are conventionally used as solvents or suspending media.For this purpose, any non-irritating, non-volatile oil may be used. Natural oils can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as Ph. Helv or similar alcohols.

[0406] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants, such as magnesium stearate, are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings, or coloring agents can also be added.

[0407] 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.

[0408] The pharmaceutical compositions described herein can also be administered topically.Suitable topical formulations are easily prepared for each of these areas or organs.Topical application for the lower gastrointestinal tract can be provided in a rectal suppository formulation (see above) or in a suitable enema formulation.Topically acceptable transdermal patches can also be used.

[0409] For topical application, pharmaceutical compositions can be formulated into suitable ointments, which contain the active ingredients suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of this invention include but are not limited to mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, water.In a particular preferred embodiment of the present invention, the compound can be coated on the stent that is surgically implanted in the patient, so as to prevent or reduce the possibility of the stent becoming blocked in the patient.

[0410] Alternatively, the pharmaceutical compositions can be formulated into 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.

[0411] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment such as petrolatum.

[0412] The pharmaceutical compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may contain additives such as benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, or the like. The compound may be prepared as a solution in saline employing bon, and / or other conventional solubilizing or dispersing agents.

[0413] The amount of the compounds in the pharmaceutical compositions described herein that may be combined with carrier materials to produce a single dosage form will vary depending on the host and disease being treated, and the particular mode of administration. Preferably, the compositions should be formulated to contain between about 0.05 milligrams to about 750 milligrams or more of the active ingredient, alone or in combination with at least one other compound of the present disclosure, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams.

[0414] It should be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0415] Patients or subjects in need of therapy with compounds according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including a pharmaceutically acceptable salt, solvate, or polymorph, optionally in a pharmaceutically acceptable carrier or diluent, either alone or in combination with other known erythropoiesis stimulating agents as otherwise specified herein.

[0416] These compounds can be administered by an appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, for example, transdermally, in liquid, cream, gel, or solid form, or in aerosol form.

[0417] 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 indicated condition without causing serious toxic effects to the patient being treated. Suitable doses of the active compound for all conditions described herein range from about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally from 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical dosages will range from 0.01 to 5% wt / wt in a suitable carrier.

[0418] The compounds are conveniently administered in any suitable unit dosage form, including, but not limited to, those containing less than 1 mg, 1 mg to 3000 mg, and preferably 5 to 500 mg of active ingredient per unit dosage form. Oral dosages of about 25 to 250 mg are often convenient.

[0419] 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 may be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or may be administered as a bolus of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0420] The concentration of the active compound in the drug composition will depend on the absorption rate, distribution rate, inactivation rate and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage value will also vary depending on the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges specified herein are merely exemplary and should not be construed as limiting the scope of the claimed compositions. It will be further understood that the scope or practice of the present invention is not intended to limit the scope or practice of the present invention. The active ingredient may be administered immediately, or may be divided into several smaller doses to be administered at varying intervals of time.

[0421] Oral compositions generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound, or its prodrug derivative, can be incorporated with excipients into tablets, troches, or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition.

[0422] Tablets, pills, capsules, troches, etc. may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents 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 can contain a liquid carrier such as fatty oil. Furthermore, the unit dosage form can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric agents.

[0423] 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 compounds, sucrose as a sweetening agent and certain preservatives, dyes and coloring and flavoring agents.

[0424] The active compounds or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as erythropoietin stimulating agents, including EPO and darbapoietin alpha, among others. In certain preferred embodiments of the invention, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an erythropoietin stimulating agent or a wound healing agent, including antibiotics, as described elsewhere herein.

[0425] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibiotics such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for adjusting isotonicity such as sodium chloride or dextrose. The parent preparation can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0426] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0427] 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, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, Polylactic acid, terephthalate, and polylactic acid can be used. Methods for the preparation of such formulations will be apparent to those skilled in the art.

[0428] Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811 (incorporated herein by reference in its entirety). For example, liposomal preparations can be prepared by dissolving an appropriate lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachadoylphosphatidylcholine, and cholesterol, etc.) in an inorganic solvent, and then evaporating the lipid, leaving a thin film of dry lipid on the surface of the container. An aqueous solution of the active compound is then poured into the container. The container is then manually swirled to remove lipid material from the sides of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0429] Treatment method

[0430] In an additional aspect, the present description provides a therapeutic composition comprising an effective amount of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal such as a human, to treat or ameliorate a disease state or condition modulated through protein degradation.

[0431] As used herein, the terms "treat," "treating," and "treatment" refer to any effect that benefits a patient to whom the compounds of the present disclosure may be administered, including the treatment of any disease state or condition that is modulated via a protein to which the compounds of the present disclosure bind. Disease states or conditions, including cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0432] The present disclosure provides therapeutic compositions as described herein for causing the degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Thus, in yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound as described herein, e.g., comprising a CLM and a PTM, preferably linked via a linker moiety as otherwise described herein, where the CLM is linked to the PTM, the CLM recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase such as cereblon), and the PTM recognizes the target protein, such that, when the target protein is brought into proximity with the ubiquitin ligase, degradation of the target protein occurs, thereby resulting in degradation / inhibition of the target protein's action and suppression of protein levels. This suppression of protein levels provided by the present disclosure reduces the level of the target protein in a cell, e.g., a patient's cell, thereby providing treatment for a disease state or condition regulated through that protein. In certain embodiments, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0433] In an additional aspect, the present description provides a method for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein or a salt form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder or symptom thereof in the subject. be.

[0434] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0435] In another embodiment, the present disclosure is directed to a method of treating a human patient in need of a disease state or condition mediated by a protein, where degradation of the protein provides a therapeutic benefit to the patient, comprising administering to the patient in need an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein that leads to the disease state and / or condition.

[0436] The term "disease state or condition" is used to describe any disease state or condition in which dysregulation of a protein occurs (i.e., the amount of a protein expressed in a patient is elevated) and degradation of one or more proteins in the patient may provide beneficial therapy or symptomatic relief to a patient in need thereof. In certain cases, the disease state or condition may be cured.

[0437] Conditions that may be treated using compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, 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.

[0438] Further disease states or conditions that may be treated by the compounds according to the present disclosure 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, diabetes mellitus type 1, diabetes mellitus type 2, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette's syndrome, and vasculitis.

[0439] Still further disease states or conditions that can be treated by the compounds of the present disclosure include aceruloplasminemia, achondroplasia type 2, achondroplasia, acrocephaly, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric ochrodialysis, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitors, and emphysema. , amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, diffuse truncal angiokeratomatous anemia, 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 group, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bonneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux / hallus syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis of the liver (hemochromatosis), spinal and bulbar muscular atrophy (Kennedy disease), Byrga -Grütz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disorder, chiropterus dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-cat syndrome, CAVD (congenital absence of the vas deferens), Cuyler cardiofacial syndrome (CBAVD), CEP (congenital hematopoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia), autosomal dominant otospondylomegaly epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal skeletal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome,(familial adenomatous polyposis), congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, conotruncal dysfacial syndrome, Cooley anemia (beta-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) Fee), Behle-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophies (DBMD), neurodegenerative disorders including Usher syndrome, de Grouchy syndrome and Dejerine-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), Di George syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protease Erythropoietic porphyria, erythroid 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial neuropathy with liability to pressure palsy, primary pulmonary hypertension (PPH), pancreatic fibrous cysts, fragile X syndrome, galactosemia, genetic brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grenblatt-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), Helicobacter pylori syndrome (Human ulcerative colitis), Mochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau syndrome (von Hippel-Lindau disease), Huntington's disease, Hutchison-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Kennedy syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter's syndrome,Metabolic disorders including Kniest dysplasia, lacunar infarct dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Münke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, multiple myeloma 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, prion disease, progeria (Hutchison-Gilford progeria syndrome), chronic hereditary (Huntington's) progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PX E (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-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome and resulting breast sarcoma, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis complex (tuberous sclerosis complex), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia congenita) syndrome, Strudwick type), SEDc (spondyloepiphyseal dysplasia congenita), Strudwick type SEMD (spondyloepiphyseal dysplasia, Strudwick type), Shprintzen syndrome, skin pigmentation disorders, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variant porphyria), infantile-onset ascending hereditary spastic paralysis, speech 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-Shaw-Fredelius syndrome, Weisenbacher-Zweimüller syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weisenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0440] The term "neoplasia" or "cancer" is used throughout this specification to refer to the formation and growth of cancerous or malignant neoplasia, i.e., a pathological process resulting in abnormal tissue that grows by cellular proliferation, often faster than normal, and continues to grow after the stimulus that initiated the new growth has ceased. Malignant neoplasias exhibit partial or complete loss of structural organization and functional coordination with normal tissue, often invade surrounding tissues, metastasize to multiple sites, tend to recur after attempted removal, and cause patient death unless properly treated. As used herein, the term neoplasia is used to describe all cancerous conditions and includes or encompasses the pathological processes associated with malignant hematopoietic tumors, ascites tumors, and solid tumors. Exemplary cancers that may be treated by the compounds of the present application, alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder, colon, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and fatty liver disease. Sarcomas, including sarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pinealocytoma, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal 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, colorectal cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoblastoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0441] The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the compound as an agent having biological activity to aid in effecting the intended therapy, inhibition and / or prevention / prophylaxis for which the compound is used. Suitable bioactive agents for use herein include those that are not intended for use or administration by the compound. Examples of such agents include those that have the same pharmacological activity as when administered, such as anticancer agents, antiviral agents, particularly anti-HIV agents and anti-HCV agents, antimicrobial agents, and antifungal agents.

[0442] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that may be combined with a compound according to the present disclosure to treat cancer. Examples of these agents include everolimus, trabectedin, Abraxane, TLK286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON 0910.Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimema Lucen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, jamatecan, IL13-PE38QQR, INO1001, IPdR1, KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta744, Sdx102, talampanel, atrasentan, Xr311, 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, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG -013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamate analide hydroxamic acid), valproic acid, trichostatin A, FK-228, SU11248, so; Rafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melfala methadone, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard , estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiotensin II Tatin, Vitaxin, Droloxifene, Idoxifene, Spironolactone, Finasteride, Cimitidine, Trastuzumab, Denileukin Diftitox, Gefitinib, Bortezimib, Paclitaxel, Cremophor-Free Paclitaxel, Docetaxel, Epithilon B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasophor Xifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, PEG-filgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0443] The term "anti-HIV agent" or "additional anti-HIV agent" includes, for example, nucleoside reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., not representative of the present disclosure), protease inhibitors, fusion inhibitors, among others, exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), among others. Fusion inhibitors such as tenofovir (PMPA), D-D4FC (Reverset), D4T (stavudine), rasibir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz), SQVM (saquinavir mesinate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), and T20 These include agents, fusions and mixtures thereof, and may include anti-HIV compounds currently in clinical trials or development.

[0444] Other anti-HIV agents that may be used for co-administration with compounds according to the present disclosure include, for example, other NNRTIs (i.e., other than NNRTIs according to the present disclosure), including, among others, 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-furancarbotiamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinone), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY097, DMP266, baicalin (TJN-151), ADAM-II (methyl 3',3'-dichloro-4',4"-dimethoxy-5',5"-bis(methoxycarbonyl)-6,6-diphenylhexenoate), methyl 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hept-1-enyl)-2-methoxybenzoate (alkenyl diarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide), AAP-BHAP (U-104489 or PNU-104489), capravirin (AG-1549,S-1153), Ateviridine (U-87201E), Aurintricarboxylic Acid (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N-(methyl)methylsulfonylamido]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine , 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl)sulfone (NSC633001), calanolide A (NSC675451), calanolide B, 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-5 46), DPC961, 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), Inophylum P, L-737, 126, Mikellamine A (NSC650898), Kelamine B (NSC649324), Mikelamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethyoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC648400), Oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea (PETT 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(pyridin-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methoxy, -5,6-dimethyl-3-pyridyl)methyl]amine]-5-ethyl-6-methyl(pyridine-2(1H)-thione, R82150, R82913, R87232, R88703, R89439 (Roviride), R90385, S-2720, suramin sodium, TBZ (thiazolobenzimidazole, NSC625487), 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.

[0445] The term "pharmaceutically acceptable salt" is used throughout this specification to describe one or more salt forms of the compounds described herein, where applicable, which are present to increase the solubility of the compound in the gastric juices of a patient's gastrointestinal tract to facilitate dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium salts, magnesium salts, and ammonium salts, among many other acids and bases known in the pharmaceutical art. Sodium and potassium salts are particularly suitable as neutralized salts of phosphoric acid according to the present disclosure.

[0446] The term "pharmaceutically acceptable derivative" refers to a pharmaceutically acceptable prodrug form, e.g., used throughout this specification to describe groups such as esters, amides, and other prodrug groups; They provide, directly or indirectly, the compounds of the present application or active metabolites of the compounds of the present application when administered to a patient.

[0447] General synthetic approach

[0448] The synthetic realization and optimization of the bifunctional molecules described herein can be approached in a stepwise or modular manner. For example, the identification of compounds that bind to a target molecule may involve high- or medium-throughput screening efforts when suitable ligands are not readily available. When identified by data from appropriate in vitro pharmacological and / or ADMET assays, it is not uncommon for the starting ligand to require iterative design and optimization cycles to improve suboptimal aspects. Part of the optimization / SAR effort will be probing ligand positions that are tolerant to substitution and that may be suitable locations for adding linker chemistries as previously mentioned herein. When crystallographic or NMR structural data are available, they can be used to focus such synthetic efforts.

[0449] In a very similar way, ligands for E3 ligases, i.e., ULM / CLM, can be identified and optimized.

[0450] With PTMs and ULMs (e.g., CLMs) at their disposal, one of skill in the art can use known synthetic methods for their combinations with or without linker moieties. Linker moieties can be synthesized with a variety of compositions, lengths, and flexibility, and can be functionalized to allow for the sequential addition of PTM and ULM groups to the distal end of the linker. Thus, libraries of bifunctional molecules can be generated in vitro and in vivo. They can be embodied and profiled in vivo pharmacological and ADMET / PK studies. The final bifunctional molecules, as well as PTM and ULM groups, can be subjected to iterative design and optimization cycles to identify molecules with desirable properties.

[0451] Abbreviation: ACN: acetonitrile AcOH, acetic acid ADDP: 1,1'-(azodicarbonyl)dipiperidine aq., aqueous BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride BINAP, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Boc, tert-butoxycarbonyl Boc2O, di-tert-butyl decarbonate BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BPO: Benzoyl peroxide Cbz: carbonylbenzyloxy CDCl3, deuterated chloroform CD3OD, deuterated methanol CH3CN, acetonitrile CH3OH, methanol CsF, cesium fluoride Cs2CO3, cesium carbonate Cu(OAc)2, copper(II) acetate Cy2NMe, dicyclohexylmethylamine DAST: Diethylaminosulfur trifluoride DBE: 1,2-dibromoethane DCM: dichloromethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIBAL: dithiobutylaluminum hydride DIEA or DIPEA: Diisopropylethylamine DMA: N,N-dimethylacetamide DMAP, N,N-dimethylaminopyridine DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMSO, dimethyl sulfoxide DMSO-d6, hexadeuterated dimethyl sulfoxide EA: Ethyl acetate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2NH, diethylamine EtOAc or EA, ethyl acetate HCl, hydrochloric acid H2O, water HBTU: N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HMDS: Bis(9-trimethylsilyl)amine HMPA: hexamethylphosphoramide HPLC, high-performance liquid chromatography IBX, 2-iodoxybenzoic acid KOAc, potassium acetate LCMS, liquid chromatography / mass spectrometry LDA: lithium diisopropylamide LiOH, lithium hydroxide MCPBA: meta-chloroperoxybenzoic acid MeOH, methanol MsCl: methanesulfonyl chloride MW: Microwave N2, nitrogen NaH, sodium hydride NaBH3CN, sodium cyanoborohydride NaBH(OAc)3, sodium borohydride triacetate NaCl, sodium chloride NaHCO3, sodium bicarbonate NaI, sodium iodide Na2SO4, sodium sulfate NBS: N-bromosuccinimide n-BuLi, n-butyllithium NH3, ammonia NH4Cl, ammonium chloride NH2OH . HCl, hydroxylamine hydrochloride NMP, N-methylpyrrolidone NMR, nuclear magnetic resonance O2, oxygen PCC: Pyridinium chlorochromate Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium Pd(aMPhos)Cl2, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium Pd(dba)2: Bis(dibenzylideneacetone)palladium Pd(OH)2, palladium hydroxide Pd(PPh3)4, tetrakis(triphenylphosphine)palladium(0) PE, petroleum ether Ph3P, triphenylphosphine PPTS: Pyridinium p-toluenesulfonate PTSA: p-toluenesulfonic acid Py, pyridine PyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate rt, room temperature RuPhos-Pd-G3: XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) SFC: Supercritical fluid chromatography TBAF, tetra-n-butylammonium fluoride TBDPSCl, tert-butyldiphenylsilyl chloride TBS, tert-butyldimethylsilyl tBuOK, potassium tert-butoxide [tBu3PH]BF4, tri-tert-butylphosphonium tetrafluoroborate t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA: Trimethylamine TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography TMP: 2,2,6,6-tetramethylpiperidine TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide TMSOTf, trimethylsilyl trifluoromethanesulfonate TosCl or TsCl: p-toluenesulfonyl chloride TsCl, p-toluenesulfonyl chloride TsOH: p-toluenesulfonic acid XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 12354-85-7: Bis(pentamethylcyclopentadienylrhodium dichloride)

[0452] A. Exemplary Synthetic Schemes for Exemplary Estrogen Receptor Binding Moiety-Based Compounds

[0453] Synthetic Schemes A-1, A-2 to A-5, A-6, and A-7 depict routes used to prepare CRBN ligands, as well as CRBN ligands attached with partial linker moieties.

[0454] General synthetic scheme A-1 for preparing intermediates [ka]

[0455] General synthetic scheme A-2 for preparing intermediates [ka]

[0456] General synthetic scheme A-3 for preparing intermediates [ka]

[0457] General synthetic scheme A-4 for preparing intermediates [ka]

[0458] General synthetic scheme A-5 for preparing intermediates [ka]

[0459] General synthetic scheme A-6 for preparing intermediates [ka]

[0460] General synthetic scheme A-7 for preparing intermediates [ka]

[0461] Synthetic Schemes A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, and A-17 depicting routes used to prepare representative chimeric compounds claimed herein.

[0462] General synthetic scheme A-8 for preparing claimed compounds [ka]

[0463] General synthetic scheme A-9 for preparing claimed compounds [ka]

[0464] General synthetic scheme A-10 for preparing claimed compounds [ka]

[0465] General synthetic scheme A-11 for preparing claimed compounds [ka]

[0466] General synthetic scheme A-12 for preparing claimed compounds [ka]

[0467] General synthetic scheme A-13 for preparing claimed compounds [ka]

[0468] General synthetic scheme A-14 for preparing claimed compounds [ka]

[0469] General synthetic scheme A-15 for preparing claimed compounds [ka]

[0470] General synthetic scheme A-16 for preparing claimed compounds [ka]

[0471] General synthetic scheme A-17 for preparing claimed compounds [ka]

[0472] Exemplary Synthesis of Exemplary Compound 2: 3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione

[0473] Step 1: Preparation of 5-bromopentanal [ka]

[0474] To a solution of oxalyl chloride (9.12 g, 72 mmol, 6 mL, 4.00 equiv.) in dichloromethane (50 mL), a solution of dimethyl sulfoxide (5.61 g, 72 mmol, 4.00 equiv.) in dichloromethane (10 mL) was added over 30 minutes at −70° C., followed by the addition of 5-bromopentan-1-ol (3.00 g, 18 mmol, 1.00 equiv.) below −60° C. The resulting mixture was stirred at −70° C. for 1 hour. Thin layer chromatography (petroleum ether:ethyl acetate=10:1) indicated the reaction was complete. Triethylamine (14.54 g, 144 mmol, 20 mL, 8.00 equiv.) was added to the mixture, and the reaction was stirred at −60° C. for 30 minutes. The mixture was poured into water (20 mL) and stirred for 1 minute. The aqueous phase was extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was used directly in the next step without further purification. -Bromopentanal (2.80 g, 17 mmol, 94% yield) was obtained as a colorless oil.

[0475] Step 2: Preparation of 5-bromo-1,1-dimethoxypentane [ka]

[0476] To a solution of 5-bromopentanal (2.80 g, 16.97 mmol, 1.00 equiv.) in methanol (50 mL) was added trimethoxymethane (9.00 g, 85 mmol, 9 mL, 5.00 equiv.) and 4-methylbenzenesulfonic acid hydrate (161 mg, 0.85 mmol, 0.05 equiv.) at 25 °C. The resulting mixture was stirred at 25 °C for 16 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 10:1) showed a new, predominant spot. The mixture was poured into water (40 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1). 5-Bromo-1,1-dimethoxy-pentane (3.50 g, 16.58 mmol, 97% yield) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ 4.37 (t, J=5.6 Hz, 1H), 3.41 (s, 2H), 3.33 (s, 6H), 1.95 - 1.84 (m, 2H), 1.67 - 1.59 (m, 2H), 1.54 - 1.45 (m, 2H).

[0477] Step 3: Preparation of (1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin [ka]

[0478] To a solution of 4-[(1R,2S)-6-benzyloxy-2-phenyl-tetralin-1-yl]phenol (500 mg, 1.23 mmol, 1.00 equiv.) in dimethylformamide (5 mL) was added cesium carbonate (1.2 g, 3.69 mmol, 3.00 equiv.) and 5-bromo-1,1-dimethoxypentane (390 mg, 1.84 mmol, 1.50 equiv.). The mixture was stirred at 100°C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to give (1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin (500 mg, 0.93 mmol, 76% yield) as a white solid. LC / MS (ESI) m / z: 559.2 [M+23] + , 1 H NMR (400MHz, CDCl3) δ 7.49 - 7.45 (m, 2H), 7.44 - 7.38 (m, 2H), 7.37 - 7.31 (m, 1H), 7.21 - 7.13 (m, 3H), 6.90 - 6.85 (m, 2H), 6.82 (dd, J=2.0, 7.2 Hz, 2H), 6.76 (dd, J=2.4, 8.4 Hz, 1H), 6.53 (d, J=8.8 Hz, 2H), 6.32 (d, J=8.8 Hz, 2H), 5.07 (s, 2H), 4.38 (t, J=5.6 Hz, 1H), 4.25 (d, J=4.8 Hz, 1H), 3.84 (t, J=6.4 Hz, 2H), 3.41 - 3.28 (m, 7H), 3.17 - 2.99 (m, 2H), 2.28 - 2.13 (m, 1H), 1.87 - 1.71 (m, 3H), 1.69 - 1.60 (m, 2H), 1.54 - 1.42 (m, 2H).

[0479] Step 4: Preparation of (1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol [ka]

[0480] To a solution of (1R,2S)-6-benzyloxy-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin (500 mg, 0.93 mmol, 1.00 equiv.) in methanol (20 mL) and tetrahydrofuran (20 mL) was added palladium on carbon (200 mg, 10% purity) under a nitrogen atmosphere. The suspension was degassed three times with hydrogen. The mixture was stirred under hydrogen (15 psi) at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to give (1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol (420 mg, crude) as a white solid. LC / MS (ESI) m / z: 469.1 [M+23] +。

[0481] Step 5: Preparation of 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal [ka]

[0482] To a solution of (1R,2S)-1-[4-(5,5-dimethoxypentoxy)phenyl]-2-phenyl-tetralin-6-ol (420 mg, 0.94 mmol, 1.00 equiv.) in tetrahydrofuran (75 mL) was added sulfuric acid (2 M in water, 18 mL, 40.00 equiv.). The mixture was stirred at 70 °C for 0.5 h. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete and a new spot had formed. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium bicarbonate (15 mL) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (370 mg, 0.92 mmol, 98% yield) as a white solid.

[0483] Step 6: Preparation of tert-butyl 4-(7-methoxy-1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1-carboxylate [ka]

[0484] To a mixture of 5-fluoro-7-methoxy-3H-isobenzofuran-1-one (1 g, 5.49 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (2.05 g, 10.98 mmol, 2 equiv.) in 1-methylpyrrolidin-2-one (6 mL), N-ethyl-N-isopropylpropan-2-amine (2.84 g, 21.96 mmol, 3.83 mL, 4 equiv.) was added in one portion. The mixture was stirred at 100° C. for 12 hours. TLC (ethyl acetate / petroleum ether=1 / 1, R f=0.1) indicated the formation of a new spot. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic layers were washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1:1). tert-Butyl 4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (1 g, 2.87 mmol, 52% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 349.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ 6.38 (s, 1H), 6.30 (s, 1H), 5.13 (s, 2H), 3.99 (s, 3H), 3.62-3.59 (m, 4H), 3.42-3.35 (m, 4H), 1.48 (s, 9H).

[0485] Step 7: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)-6-methoxybenzoic acid [ka]

[0486] To a mixture of tert-butyl 4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (1 g, 2.87 mmol, 1 equiv.) in methyl alcohol (10 mL) and tetrahydrofuran (10 mL) was added a solution of sodium hydroxide (459 mg, 11.48 mmol, 4 equiv.) in water (2 mL). The mixture was stirred at 20° C. for 1 hour. TLC (ethyl acetate / petroleum ether=1 / 1, R f= 0) indicated the formation of a new spot. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The aqueous phase was adjusted to a pH value of 4-5 with hydrochloric acid (1.5 N), then filtered to collect the solid. This solid was used in the next step without further purification. 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzoic acid (700 mg, 1.68 mmol, 58% yield, 88% purity) was obtained as a white solid. LC / MS (ESI) m / z: 367.3 [M+1] + .

[0487] Step 8: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-6-methoxybenzoic acid [ka]

[0488] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-6-methoxy-benzoic acid (650 mg, 1.77 mmol, 1 equiv.) in methyl alcohol (20 mL) was added manganese dioxide (1.54 g, 17.74 mmol, 10 equiv.) in one portion at 20° C. under nitrogen. The mixture was stirred at 50° C. for 12 hours. LC / MS indicated that the reaction was complete and the desired product had formed. The reaction mixture was filtered, and the solution was concentrated in vacuo. This reaction was used in the next step without further purification. 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic acid (600 mg, 1.65 mmol, 92% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 365.3 [M+1] + .

[0489] Step 9: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)amino)methyl)-6-methoxybenzoic acid [ka]

[0490] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxybenzoic acid (600 mg, 1.65 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione (407 mg, 2.47 mmol, 1.5 equiv., HCl) in methyl alcohol (10 mL), sodium acetate (203 mg, 2.47 mmol, 1.5 equiv.) and sodium cyanoborohydride (310 mg, 4.94 mmol, 3 equiv.) were added in one portion at 20 °C. LC / MS indicated the reaction was complete and the desired product had formed. The reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase flash silica gel chromatography (120 g SepaFlash silica gel column, elution with 0–60% acetonitrile in water at a flow rate of 30 mL / min). 4-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 38% yield) was obtained as a white solid. LC / MS (ESI) m / z: 477.4 [M+1] + .

[0491] Step 10: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1-oxoisoindolin-5-yl)piperazine-1-carboxylate [ka]

[0492] To a mixture of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 1 equiv.) in dichloromethane (10 mL), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (181 mg, 0.94 mmol, 1.5 equiv.), N-hydroxybenzotrizole (128 mg, 0.94 mmol, 1.5 equiv.), and triethylamine (191 mg, 1.89 mmol, 3 equiv.) were added. The mixture was stirred at 20 °C for 1 hour. LC / MS indicated that the reaction was complete and the desired product had formed. The reaction mixture was quenched by the addition of water (15 mL) and then extracted with dichloromethane (40 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methyl alcohol = 10:1, R f =0.60) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (260 mg, 0.57 mmol, 90% yield) as a white solid. LC / MS (ESI) m / z: 459.4 [M+1] + .

[0493] Step 11: Preparation of 3-(7-methoxy-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0494] To a mixture of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (300 mg, 0.65 mmol, 1 equiv.) in dioxane (10 mL), hydrogen chloride / dioxane (4 M, 17 mL, 105.81 equiv.) was added in one portion. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was used in the next step without further purification. 3-(7-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (216 mg, 0.55 mmol, 83% yield, HCl salt) was obtained as a white solid. LC / MS (ESI) m / z: 359.2 [M+1] + ; 1 H-NMR (400MHz, MeOD) δ: 6.72 (s, 1H), 6.60 (s, 1H), 5.08-5.04 (m, 1H), 4.36-4.35 (m, 2H), 3.92 (s, 3H), 3.66-3.65 (m, 5H), 3.38-3.35 (m, 4H), 2.89-2.78 (m, 1H), 2.77-2.67 (m, 1H), 2.45-2.42 (m, 1H), 2.14-2.14 (m, 1H).

[0495] Step 12: 3-{5-[4-(5-{4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenoxy}pentyl)piperazin-1-yl]-7-methoxy-1-oxo-2,3-dihydro-1H-isothiazolinone Preparation of {indol-2-yl}piperidine-2,6-dione (exemplary compound 2) [ka]

[0496] To a mixture of 3-(7-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione hydrochloride (89 mg, 0.23 mmol) in methyl alcohol (5 mL) and dichloromethane (1 mL) was added sodium acetate (102 mg, 1.25 mmol, 5 equiv.) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 hour, and then 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (100 mg, 0.25 mmol, 1 equiv.) was added to the reaction mixture and stirred for 1 hour. Sodium cyanoborohydride (31 mg, 0.50 mmol, 2 equiv.) and acetic acid (0.05 mL) were added to the reaction mixture. The resulting solution was stirred at 20 °C for 5 hours. LC / MS indicated the reaction was complete and the desired product had formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 x 10 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: 35%-55%, 7.8 min). 3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-7-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (109.9 mg, 0.14 mmol, 56% yield, 100% purity, HCl salt) was obtained as a white solid. LC / MS (ESI) m / z: 743.7 [M+1] + ; 1 H-NMR (400MHz, DMSO-d6) δ 10.93 (s, 1H), 10.56-10.43 (m, 1H), 9.18-9.13 (m, 1H), 7.16-7.13 (m, 3H), 6.84-6.83 (d, J = 6.4Hz, 2H), 6.69 (s, 1H), 6.62-6.61 (m, 2H), 6.55-6.52 (m, 3H), 6.28-6.26 (d, J = 8.4Hz, 2H), 4.99-4.97 (m, 1H), 4.29-4.25 (m, 1H), 4.23-4.18 (m, 1H), 4.17-4.15 (m, 1H), 4.06-4.00 (m, 2H), 3.85-3.83 (m, 5H), 3.56-3.53 (m, 1H), 3.34-3.33 (m, 4H), 3.10-3.02 (m, 4H), 3.00-2.85 (m, 2H), 2.60-2.58 (m, 3H), 2.16-2.08 (m, 1H), 1.91-1.88 (m, 1H), 1.76-1.69 (m, 5H), 1.43-1.41 (m, 2H).

[0497] Exemplary Synthesis of Exemplary Compound 3: 3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

[0498] Step 1: Preparation of 5-bromo-4-iodo-3H-isobenzofuran-1-one [ka]

[0499] 5-Bromo-3H-isobenzofuran-1-one (50 g, 234.71 mmol, 1 To a solution of 1-iodopyrrolidine-2,5-dione (55.45 g, 246.45 mmol, 1.05 equiv.) in trifluoromethanesulfonic acid (680 g, 4.53 mol, 400 mL, 19.30 equiv.) was added 1-iodopyrrolidine-2,5-dione (55.45 g, 246.45 mmol, 1.05 equiv.) in one portion at 0° C. The mixture was allowed to warm to 15° C. and held for 16 h. TLC (petroleum ether:ethyl acetate=5:1) showed no starting material remaining and two new spots (R f=0.4, 0.5). The reaction mixture was poured into ice water (1 L), causing precipitation of a yellow solid. The mixture was filtered, and the filter cake was washed with water. The filter cake was dissolved in ethyl acetate (500 mL), and the resulting orange solution was dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a yellow solid. The residue was triturated with ethyl acetate (50 mL), filtered, and washed with ethyl acetate (10 mL × 2). 5-Bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02 mmol, 50% yield) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H).

[0500] Step 2: Preparation of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one [ka]

[0501] To a mixture of 5-bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02 mmol, 1 equiv.), sodium hydroxide (23.60 g, 590.10 mmol, 5 equiv.) in water (400 mL) and N,N-dimethylacetamide (200 mL) was added cuprous oxide (3.38 g, 23.60 mmol, 2.4 mL, 0.2 equiv.). The reaction mixture was heated to 80° C. and maintained for 16 h. TLC (petroleum ether:ethyl acetate=1:1, R fA pH of 0.05 (=0.3) indicated the reaction was complete. The reaction mixture was poured into 1N hydrochloric acid solution (400 mL) and extracted with ethyl acetate (400 mL x 2). The combined organic layers were concentrated, dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate (150 mL), brine (150 mL), and then dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give a residue. The residue was triturated with ethyl acetate (20 mL), filtered, and washed with ethyl acetate (10 mL) to give a solid. The filtrate was further concentrated and triturated with ethyl acetate to give 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (14.5 g, 60.15 mmol, 50% yield, 95% purity) as a white solid. 1 H NMR (400MHz, DMSO) δ 10.90 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.35 (s, 2H).

[0502] Step 3: Preparation of 5-bromo-4-methoxy-3H-isobenzofuran-1-one [ka]

[0503] To a mixture of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (3 g, 13.10 mmol, 1 equiv.) in acetone (20 mL) was added iodomethane (17.5 g, 123.29 mmol, 7.7 mL, 9.41 equiv.) and potassium carbonate (5.43 g, 39.30 mmol, 3 equiv.). The mixture was stirred at 20° C. for 15 hours. TLC (Ethyl acetate:petroleum ether = 1:3, R fThe pH (R = 0.37) indicated the reaction was complete. The reaction mixture was quenched by the addition of water (10 mL) and then extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate (10 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. 5-Bromo-4-methoxy-3H-isobenzofuran-1-one (2.9 g, 11.93 mmol, 91% yield) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 5.44 (s, 2H), 4.00 (s, 3H).

[0504] Step 4: Preparation of tert-butyl 4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate [ka]

[0505] A vial was charged with 5-bromo-4-methoxy-3H-isobenzofuran-1-one (500 mg, 2.06 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (383 mg, 2.06 mmol, 1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (188 mg, 0.20 mmol, 0.1 equiv.), XantPhos (119 mg, 0.20 mmol, 0.1 equiv.), potassium phosphate (873 mg, 4.11 mmol, 2 equiv.), and dioxane (5 mL). The mixture was degassed with nitrogen and heated at 100 °C for 16 h. TLC (ethyl acetate:petroleum ether = 1:3) indicated the reaction was complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with brine (30 mL) and dried over sodium sulfate. The crude product was purified by silica gel chromatography (ethyl acetate:petroleum ether = 1:20 to 1:6). tert-Butyl 4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700 mg, 2.01 mmol, 97% yield) was obtained as a yellow solid. LC / MS (ESI) m / z: 349.2 [M+1] + .

[0506] Step 5: Preparation of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxylmethyl)-3-methoxy-benzoic acid [ka]

[0507] To a solution of tert-butyl 4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700 mg, 2.01 mmol, 1 equiv.) in tetrahydrofuran (4 mL) and water (4 mL) was added sodium hydroxide (401 mg, 10.05 mmol, 5 equiv.). The mixture was stirred at 20 °C for 16 h. TLC (ethyl acetate:petroleum ether = 1:2) showed the reaction was complete. The mixture was adjusted to pH = 4 with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with brine (20 mL) and dried over sodium sulfate. The crude material was not further purified. 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzoic acid (700 mg, crude) was obtained as a yellow solid.

[0508] Step 6: Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic acid [ka]

[0509] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxybenzoic acid (700 mg, 1.91 mmol, 1 equiv.) in dichloromethane (10 mL) was added manganese dioxide (2.49 g, 28.66 mmol, 15 equiv.). The mixture was stirred at 20° C. for 1 hour. TLC (dichloromethane:methanol=20:1) indicated that the reaction was complete. The mixture was diluted with dichloromethane (10 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1 to 60:1). 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formyl-3-methoxybenzoic acid (300 mg, 0.82 mmol, 43% yield) was obtained as a pale yellow solid.

[0510] Step 7: Preparation of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic acid [ka]

[0511] To a mixture of 3-aminopiperidine-2,6-dione (135 mg, 0.82 mmol, 1 equiv., HCl salt) in methanol (2 mL) and dichloromethane (4 mL) was added sodium acetate (270 mg, 3.29 mmol, 4 equiv.). The mixture was stirred at 20 °C for 10 min, and then 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-3-methoxybenzoic acid (300 mg, 0.82 mmol, 1 equiv.) was added and the mixture was stirred for 10 min. Sodium cyanoborohydride (103 mg, 1.65 mmol, 2 equiv.) was added and the mixture was stirred for an additional 40 min. LCMS indicated the reaction was complete. The mixture was adjusted to pH 4-5 with aqueous hydrochloric acid solution (1 M) and extracted with ethyl acetate (10 mL × 3). The organic layer was dried over sodium sulfate. The crude product was not further purified. 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic acid (400 mg, crude) was obtained as a white solid. LC / MS (ESI) m / z: 477.1 [M+1] + .

[0512] Step 8: Preparation of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate [ka]

[0513] To a solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic acid (400 mg, 0.84 mmol, 1 equiv.) in dimethylformamide (5 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (383 mg, 1.01 mmol, 1.2 equiv.). The solution was stirred for 10 minutes, and then N,N-diisopropylethylamine (325 mg, 2.52 mmol, 3 equiv.) was added. The solution was stirred at 20 °C for 20 minutes. LCMS indicated the reaction was complete. The solution was diluted with ethyl acetate (40 mL) and washed with water (30 mL × 5) and brine (40 mL). The organic layer was dried over sodium sulfate. tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (400 mg, crude) was obtained as a pale yellow solid. LC / MS (ESI) m / z: 459.1 [M+1] + .

[0514] Step 9: Preparation of 3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione [ka]

[0515] To a mixture of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (400 mg, 0.87 mmol, 1 equiv.) in dioxane (2 mL) was added hydrochloric acid in dioxane (4 M, 4 mL, 18.34 equiv.). The mixture was stirred at 20° C. for 10 minutes, and the solvent was removed under vacuum. 3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (350 mg, crude, HCl salt) was obtained as a white solid. LC / MS (ESI) m / z: 359.1 [M+1] +.

[0516] Step 10: Preparation of 3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (exemplary compound 3) [ka]

[0517] To a mixture of 3-(4-methoxy-1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.25 mmol, 1 eq., HCl salt) in dichloromethane (4 mL) and methanol (1 mL) was added sodium acetate (83 mg, 1.01 mmol, 4 eq.). The mixture was stirred at 20° C. for 10 minutes. Then, 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (101 mg, 0.25 mmol, 1.00 eq.) was added, and the mixture was stirred for 10 minutes. Sodium cyanoborohydride (31 mg, 0.51 mmol, 2 eq.) was added to the mixture, and stirring was maintained for 40 minutes. LCMS and TLC (dichloromethane:methanol = 10:1) showed the reaction was complete. The solvent was removed under vacuum. The crude product was purified by preparative TLC (dichloromethane:methanol = 10:1). 3-[5-[4-[5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentyl]piperazin-1-yl]-4-methoxy-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (55 mg, 0.07 mmol, 29% yield, 99% purity) was obtained as a white solid. LC / MS (ESI) m / z: 743.3 [M+1] + ; 1H-NMR (400MHz, DMSO-d6) δ 10.96 (s, 1H), 9.12 (s, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 - 6.98 (m, 4H), 6.83 (d, J=6.8 Hz, 2H), 6.72 - 6.43 (m, 5H), 6.26 (d, J=8.6 Hz, 2H), 5.06 (dd, J=5.0, 13.2 Hz, 1H), 4.56 - 4.11 (m, 3H), 3.94 - 3.70 (m, 5H), 3.30 - 3.25 (m, 1H), 3.21 - 2.77 (m, 8H), 2.64-2.55 (m, 5H), 2.46 - 2.26 (m, 2H), 2.16 - 1.94 (m, 2H), 1.80 - 1.22 (m, 7H).

[0518] B. Exemplary Synthetic Schemes for Exemplary Androgen Receptor Binding Moiety-Based Compounds

[0519] General synthetic scheme B-1 [ka]

[0520] General synthetic scheme B-2 [ka]

[0521] Exemplary synthesis scheme for exemplary compound 32: [ka]

[0522] Synthesis of 1,5-bromo-3-methoxybenzene-1,2-dicarboxylic acid

[0523] In a 100 mL round-bottom flask, 4-bromo-2-methoxy-6-methylbenzonitrile (800 mg, 3.54 mmol, 1.00 equiv.), water (10 mL), sodium hydroxide (708 mg, 17.70 mmol, 5.00 equiv.), and KMnO4 (1.12 g, 7.09 mmol, 2.00 equiv.) were placed. The resulting solution was stirred in an oil bath at 100 °C for 16 h. The solid matter was filtered off. The pH of the solution was adjusted to 3 with hydrogen chloride (2 mol / L). The resulting solution was extracted with dichloromethane (15 mL × 3), and the aqueous layers were combined. The resulting solution was extracted with ethyl acetate / methanol = 10:1 (15 mL × 3), and the organic layers were combined, dried in an oven under reduced pressure, and concentrated in vacuo. This gave 330 mg (34%) of 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid as a white solid.

[0524] 2. Synthesis of 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate

[0525] In a 100 mL round-bottom flask, 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid (330 mg, 1.20 mmol, 1.00 equiv.), methanol (20 mL), and sulfuric acid (5 mL) were placed. The resulting solution was stirred in an oil bath at 70 °C for 16 hours. The resulting solution was diluted with water (40 mL). The pH of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This afforded 340 mg (93%) of 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate as a white solid.

[0526] LC-MS (ES+): m / z 302.85 [MH+], t R = 0.906 min (2.0 min run).

[0527] 3. Synthesis of 1,2-dimethyl-5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate

[0528] A 100 mL round-bottom flask was charged with 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (277 mg, 1.49 mmol, 1.50 equiv), RuphosPd (39 mg, 0.05 mmol, 0.05 equiv), CsCO (978 mg, 3.00 mmol, 3.00 equiv), and toluene (15 mL). The resulting solution was stirred in an oil bath at 100 °C for 12 h. The resulting solution was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / ethyl acetate (10:1). This gave 340 mg (84%) of 1,2-dimethyl 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate as a pale yellow oil.

[0529] LC-MS (ES+): m / z 409.05 [MH+], t R = 0.963 min (2.0 min run).

[0530] 4. Synthesis of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylic acid

[0531] In a 100-mL round-bottom flask, 1,2-dimethyl 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate (340 mg, 0.83 mmol, 1.00 equiv.), methanol / HO / THF (8 mL), and sodium hydroxide (100 mg, 2.50 mmol, 3.00 equiv.) were placed. The resulting solution was stirred at 25 °C for 12 h. The resulting solution was diluted with water (30 mL). The pH of the solution was adjusted to 8 with hydrogen chloride (2 mol / L). The pH was adjusted to 3 with citric acid monohydrate. The resulting solution was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This gave 300 mg (95%) of 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylic acid as a colorless oil.

[0532] LC-MS (ES+): m / z 306.95 [MH+], t R = 0.853 min (2.0 min run).

[0533] 5. Synthesis of tert-butyl-4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate

[0534] In a 100 mL round-bottom flask, tert-butyl 4-(7-methoxy-1,3-dioxo-1,3-dihydro-2-benzofuran-5-yl)piperazine-1-carboxylate (260 mg, 0.72 mmol, 1.00 equiv.), 3-aminopiperidine-2,6-dione hydrochloride (153.6 mg, 0.93 mmol, 1.30 equiv.), and pyridine (10 mL) were placed. The resulting solution was stirred in an oil bath at 120° C. for 4 hours. The resulting solution was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane / methanol (100:1). This gave 280 mg (83%) of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate as a yellow solid.

[0535] LC-MS (ES+): m / z 417.05 [MH+], t R = 0.852 min (2.0 min run).

[0536] 6. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dione

[0537] A 50 mL round-bottom flask was charged with tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (270 mg, 0.57 mmol, 1 equiv.), dichloromethane (6 mL, 0.07 mmol, 0.124 equiv.), and TFA (2 mL, 0.02 mmol, 0.031 equiv.). The resulting solution was stirred at 25° C. for 2 hours. The resulting mixture was concentrated to give 2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)isoindoline-1,3-dione as a brown oil.

[0538] LC-MS (ES+): m / z 373.05 [MH+], t R = 0.155 min (2.0 min run).

[0539] 7. Synthesis of 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide

[0540] In a 100 mL round-bottom flask were placed 2,2,2-trifluoroacetaldehyde, 2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (130 mg, 0.28 mmol, 1.078 equiv.), dichloromethane (10 mL, 0.12 mmol), 6-(4-formylpiperidin-1-yl)-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (120 mg, 0.26 mmol, 1 equiv.), and NaBH(OAc) (163.4 mg, 0.77 mmol, 3.006 equiv.). The resulting solution was stirred at 25 °C for 2 h. The resulting solution was diluted with dichloromethane (30 mL). The resulting mixture was washed with H2O (30 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane / ethyl acetate (3:1). The crude product was purified by preparative HPLC with the following conditions: Column, XBridge Prep C18 OBD column, 5 μm, 19*150 mm; mobile phase, water (10 mmol / L NH4HCO3) and acetonitrile (43% B phase up to 65% in 8 min); detector, UV. This gave 70 mg (33.11%) of 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide as a yellow solid.

[0541] 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 7.87-7.79 (m, 2H), 7.39-7.32 (m, 2H), 7.15-7.12 (m, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 5.04-4.98 (m, 1H), 4.50-4.47 (m, 3H), 4.93-3.85 (m, 4H), 3.35-3.33 (m, 5H), 3.07 - 2.81 (m, 3H), 2.51 (s, LC-MS (ES+): m / z 824.25 / 826.25 [MH+], t R = 182 minutes (3.0 minute run).

[0542] Chemical formula:C 42 H 46 ClN9O7[823.32 / 825.32]

[0543] Total H number obtained from HNMR data: 46.

[0544] Exemplary Synthesis of Exemplary Compound 34: [ka] rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2'-(2,6-dioxopiperidin-3-yl)-3'-oxospiro[cyclopropane-1,1'-isoindoline]-6'-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide

[0545] Synthesis scheme: [ka]

[0546] Step 1: Synthesis of dimethyl 2-bromopentanedioate [ka]

[0547] To a solution of glutaric acid (30 g, 227.07 mmol, 1 equiv.) in chloroform (90 mL) was added thionyl chloride (59 g, 499.56 mmol, 36 mL, 2.2 equiv.). The mixture was stirred at 70 °C for 1 h. Liquid bromine (36.29 g, 227.07 mmol, 1 equiv.) was added dropwise to the mixture. The mixture was stirred at 70 °C for 12 h. The mixture was cooled to 0 °C, and methanol (58 g, 1.82 mol, 73 mL, 8 equiv.) was added dropwise to the mixture at 0 °C. LCMS confirmed the desired product. The mixture was extracted with ethyl acetate (150 mL × 3) and washed with saturated aqueous sodium bicarbonate (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash C18 column chromatography (acetonitrile:water = 1:0 to 1:1). Dimethyl 2-bromopentanedioate (4 g + 20 g (crude), 16.73 mmol, 7% yield) was obtained as a yellow oil.

[0548] LCMS: MS (ESI) m / z: 241.0 [M+1] + .

[0549] Chemical formula:C7H 11 BrO4, molecular weight: 239.06

[0550] 1 H NMR: (400 MHz, DCCl3) δ: 4.39 - 4.36 (m, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.56 - 2.49 (m, 2H), 2.44 - 2.34 (m, 1H), 2.33 - 2.23 (m, 1H).

[0551] Total H number obtained from HNMR data: 11.

[0552] Step 2: Synthesis of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0553] To a solution of methyl 2-cyano-4-fluorobenzoate (10 g, 55.82 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (12.48 g, 66.98 mmol, 1.2 equiv.) in dimethyl sulfoxide (100 mL) was added diisopropylethylamine (28.86 g, 223.28 mmol, 4 equiv.). The reaction mixture was stirred at 120 °C for 12 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1) showed that methyl 2-cyano-4-fluorobenzoate had been consumed and the desired product had been detected. The mixture was poured into water (50 mL) and filtered. The filtrate was dried under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1). tert-Butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (18 g, 52.11 mmol, 93% yield) was obtained as a yellow solid.

[0554] Chemical formula:C 18 H23 N3O4, molecular weight: 345.39

[0555] Step 3: Synthesis of tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate [ka]

[0556] To a solution of tert-butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (18 g, 52.11 mmol, 1 equiv.) in tetrahydrofuran (200 mL) was added tetraisopropyl titanate (17.77 g, 62.54 mmol, 1.2 equiv.) and a solution of ethylmagnesium bromide in tetrahydrofuran (2 M, 52.11 mL, 2 equiv.) at 0°C. The mixture was stirred at 25°C for 1 hour. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) showed that tert-butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate had been consumed and the desired product had been detected. The mixture was added to saturated aqueous ammonium chloride (150 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and filtered to give tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate (6 g, 17.47 mmol, 33% yield) as a yellow solid.

[0557] Chemical formula:C 19 H 25 O3N3, molecular weight: 343.42

[0558] 1 H NMR: (400 MHz, CDCl3) δ: 7.75 - 7.73 (d, J=8.8 Hz, 1H), 6.97 - 6.95 (d, J=8.8 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.41 (s, 1H), 3.61 - 3.58 (t, J=4.8 Hz, 4H), 3.28 - 3.25 (t, J=4.8 Hz, 4H), 1.56 (s, 2H), 1.49 (s, 9H), 1.38 - 1.36 (m, 2H).

[0559] Total H number obtained from HNMR data: 25.

[0560] Step 4: Synthesis of dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioate [ka]

[0561] 20 batches in parallel:

[0562] To a solution of tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate (100 mg, 0.29 mmol, 1 equiv.) and dimethyl 2-bromopentanedioate (104 mg, 0.44 mmol, 1.5 equiv.) in dimethylformamide (2 mL) was added sodium hydride (35 mg, 0.88 mmol, 60% in mineral oil, 3 equiv.). The mixture was stirred at 30°C for 12 hours. Thin layer chromatography (petroleum ether:ethyl acetate=1: 1) showed that 30% of the tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate had been consumed. The reaction mixture was poured into 50 mL of brine and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1). Dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-2'-yl]pentanedioate (200 mg, 0.40 mmol, 10% yield relative to the recovered starting material) was obtained as a yellow oil. Additionally, tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate (675 mg) was isolated.

[0563] Chemical formula:C 26 H 35 N3O7, molecular weight: 501.57

[0564] Step 5: Synthesis of 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-2'-yl]pentanedioic acid [ka]

[0565] To a solution of dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioate (800 mg, 1.59 mmol, 1 equiv.) in tetrahydrofuran (5 mL) and methanol (5 mL) was added a solution of sodium hydroxide (255 mg, 6.38 mmol, 4 equiv.) in water (3 mL). The mixture was stirred at 25 °C for 2 hours. LCMS indicated the reaction was complete and the desired MS was detected. The mixture and another batch were poured into 20 mL of water, the pH was adjusted to 3.0 with 2.0 N hydrochloric acid, and then extracted with ethyl acetate (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioic acid (740 mg, 1.56 mmol, 97% yield) was obtained as an off-white solid, which was used directly in the next step without further purification.

[0566] LCMS: MS (ESI) m / z: 474.3[M+1] + .

[0567] Chemical formula:C 24 H 31 N3O7, molecular weight: 473.52

[0568] Step 6: Synthesis of 5-amino-4-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid; 5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid and tert-butyl 4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazine-1-carboxylate [ka]

[0569] A mixture of 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedioic acid (400 mg, 0.85 mmol, 1 equiv.) and urea (253 mg, 4.22 mmol, 5 equiv.) in 1-methyl-2-pyrrolidinone (4 mL) was heated to 160 °C and stirred at 160 °C for 2 h. LCMS showed two peaks with the desired MS signals. The mixture was combined with other batches and filtered. The filtrate was further purified by semi-preparative reverse-phase HPLC (column: Boston Green ODS 150*305 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 35%-45%, 10 min). Two isomeric monoamides, 5-amino-4-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid and 5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid, were obtained (17%). (0 mg, 0.36 mmol, 42% yield, and 90 mg, 0.19 mmol, 22% yield. It was not conclusively determined which of the two isomers corresponded to which structure.) Also isolated was tert-butyl 4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 23% yield) as an off-white solid.

[0570] LCMS: Monoamide product 1: MS (ESI) m / z: 473.1 [M+1] + , monoamide product 2 MS (ESI) m / z: 473.1 [M+1] + , imide product 3: MS (ESI) m / z: 455.1 [M+1]+ .

[0571] The chemical formula of monoamide product 1 is: C 24 H 32 N4O6, molecular weight: 472.53.

[0572] The formula of monoamide product 2 is: C 24 H 32 N4O6, molecular weight: 472.53.

[0573] The chemical formula of the imide product is: C 24 H 30 N4O5, molecular weight: 454.52.

[0574] Step 7a: Synthesis of 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)piperidine-2,6-dione from the monoamide product 1 of Step 6 [ka]

[0575] To a mixture of 5-amino-2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]-5-oxo-pentanoic acid (190 mg, 0.40 mmol, 1 equiv., the first-eluted monoamide product from above) in acetonitrile (15 mL) was added benzenesulfonic acid (114 mg, 0.72 mmol, 1.80 equiv.) in one portion at 25 °C under a nitrogen atmosphere. The mixture was stirred at 90 °C for 3 h. LCMS showed the product was the major peak. The mixture was concentrated in vacuo. The residue was purified by semi-preparative reverse-phase HPLC (column: Boston Green ODS 150*305 um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 1%-27%, 10 min). The product, 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindolin]-2'-yl)piperidine-2,6-dione (55 mg, 0.14 mmol, 34% yield, benzenesulfonate salt) was obtained as a brown solid.

[0576] LCMS: EW4875-628-P1B, MS (ESI) m / z: 355.1 [M+1] + .

[0577] Chemical formula:C 19 H 22 N4O3, molecular weight: 354.40.

[0578] Step 7b: Synthesis of 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)piperidine-2,6-dione from the imide product of Step 6 [ka]

[0579] To a mixture of tert-butyl 4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 1 equiv.) in dichloromethane (5 mL) was added hydrochloric acid (4 M in dioxane, 2.5 mL, 50 equiv.) in one portion at 25°C. The mixture was stirred at 25°C for 1 hour. LCMS showed the product was the major peak. The mixture was concentrated in vacuo. The crude solid product, 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindolin]-2'-yl)piperidine-2,6-dione (70 mg, 0.18 mmol, 90% yield, hydrochloride salt) was obtained as a brown solid and used directly in the next step without further purification.

[0580] LCMS: MS (ESI) m / z: 355.1 [M+1] + .

[0581] Chemical formula:C 19 H 22 N4O3, molecular weight: 354.40.

[0582] Step 8: Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-[[4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide [ka]

[0583] To a solution of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide (63 mg, 0.12 mmol, 1 equiv.) in 1,2-dichloroethane (3 mL), triethylamine (38 mg, 0.38 mmol, 3 equiv.) and 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-2'-yl)piperidine-2,6-dione (50 mg, 0.12 mmol, 1 equiv., hydrochloride salt) were added. The mixture was stirred at 30°C for 30 minutes. Sodium borohydride triacetate (54 mg, 0.25 mmol, 2 equiv.) was added, and the mixture was then stirred at 30°C for 12 hours. LCMS showed the reaction was complete and the desired MS could be detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by semi-preparative reverse-phase HPLC (column: Phenomenex Synergi C18 150*25*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 10 min) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-[[4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindoline]-5'-yl]piperazin-1-yl]methyl]-1-piperidyl]benzamide (17.8 mg, 0.02 mmol, 16% yield, 98% purity) as a white solid.

[0584] LCMS: MS (ESI) m / z: 932.3 [M+1] + .

[0585] 1 H NMR: (400MHz, DMSO-d6) δ: 10.88 (s, 1H), 8.22 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.53 - 7.45 (m, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.99 (dd, J=9.2, 17.6 Hz, 4H), 6.73 (s, 1H), 4.33 (s, 1H), 4.06 (d, J=9.2 Hz, 1H), 3.86 (d, J=12.4 Hz, 3H), 3.32 - 3.29 (m, 9H), 2.80 (t, J=12.0 Hz, 3H), 2.59 - 2.54 (m, 4H), 2.22 (d, J=6.8 Hz, 2H), 1.81 (d, J=10.3 Hz, 4H), 1.55 - 1.47 (m, 2H), 1.45 - 1.31 (m, 2H), 1.25 - 1.17 (s, 8H), 1.13 (s, 6H).

[0586] Chemical formula:C 47 H 54 ClN7O5, molecular weight: 832.43.

[0587] Total H number obtained from HNMR data: 54.

[0588] C. Exemplary Synthesis Scheme for Exemplary Androgen Receptor Binding Moiety-Based Compounds That Are Imide Isosteres

[0589] General synthetic scheme C-1

[0590] The building block N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl) Synthesis of Nicotinamide [ka]

[0591] Synthesis scheme [ka]

[0592] Step 1: Synthesis of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid [ka]

[0593] 6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and tert-butyl piperazine-1-carboxylate (1.9 g, 10.0 mmol) and ethyldiisopropylamine (2.6 g, 20 mmol) were added thereto, followed by stirring at 130 °C overnight. The reaction mixture was concentrated under reduced pressure, and 1 M aqueous NaOH solution (10 mL) was added to the resulting residue, followed by washing with CHCl (50 mL). The pH of the aqueous layer was adjusted to approximately 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CH2Cl2 / MeOH=10 / 1) to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, yield 65%) as a white solid.

[0594] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18(50mm*4.6mm*3.5μm); Column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under these conditions for 1.4 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, and under these conditions for 0.7 min. (Purity: 83.17%, Rt = 1.312 min; MS calculated: 307.15; MS observed: 308.2 [M+H]). + .

[0595] Chemical formula:C 15 H 21N3O4, molecular weight: 307.34.

[0596] Step 2: Synthesis of tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate [ka]

[0597] A mixture of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (614 mg, 2.0 mmol), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (630 mg, 2.0 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 g, 3.0 mmol), and ethyldiisopropylamine (516 mg, 4.0 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (50 mL × 2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=1 / 1) to give tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (977 mg, 86% yield) as a white solid.

[0598] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under these conditions for 1.4 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, and under these conditions for 0.7 min. Purity: 88.26%, Rt = 2.161 min; MS calculated: 567.26; MS observed: 568.3 [M+H] + .

[0599] 1 H NMR (400 MHz, DMSO-d6) δ1.12 (6H, s), 1.22 (6H, s), 1.43 (9H, s), 3.42-3.44 (4H, m), 3.60-3.63 (4H, m), 4.02-4.07 (1H, m), 4.31 ( 1H, s), 6.88 (1H, d, J = 8.8 Hz), 7.00 (1H, dd, J = 8.4, 2.4 Hz), 7.21 (1H, d, J = 2.4 Hz), 7.65 (1H, d, J = 9.2 Hz), 7.91 (1H, d, J = 8.8 Hz), 7.99 (1H, dd, J = 8.8, 2.4 Hz), 8.64 (1H, d, J = 2.4 Hz).

[0600] Chemical formula:C 30 H 38 ClN5O4, molecular weight: 568.11.

[0601] Total H number obtained from HNMR data: 38.

[0602] Step 3: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride [ka]

[0603] A mixture of tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (405 mg, 0.7 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuo to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (353 mg, 100% yield) as a white solid.

[0604] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then under these conditions for 1.4 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, and under these conditions for 0.7 min. Rt = 1.791 min; MS calculated: 467.21; MS observed: 468.3 [M+H] + .

[0605] Chemical formula:C 25 H 31 Cl2N5O2, molecular weight: 504.45

[0606] General synthetic scheme C-2

[0607] Synthesis of the building block tert-butyl 4-(4-formylpiperidin-1-yl)benzoate [ka]

[0608] Synthesis scheme: [ka]

[0609] Step 1: Synthesis of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate [ka]

[0610] To a solution of tert-butyl 4-fluorobenzoate (23 g, 0.12 mmol) in DMSO (100 mL) was added piperidin-4-ylmethanol (40.5 g, 0.35 mmol). The mixture was heated to 120 °C overnight under nitrogen. After cooling to room temperature, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine (15 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by CC (PE / EA = 10:1) to obtain the compound tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (31 g, 91.2%) as a white solid.

[0611] LCMS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: from 90% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)] and 10% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] to 10% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)] and 90% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] within 1.6 min, then maintained under this condition for 2.4 min, and finally 90% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)] and 10% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)]. (AcONH4) (water / CH3CN = 100 / 900 (v / v)) for 0.1 min, then under these conditions for 0.7 min. Purity: 99.57%, Rt = 2.035 min; MS calculated: 291.2; MS observed: 292.2 [M+H]+.

[0612] HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 1.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then under these conditions for 5 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, under these conditions for 5 min. Purity was 93.27%, Rt = 9.542 min.

[0613] 1H NMR (400 MHz, CDCl3) δ 1.29-1.40 (2H, m), 1.49 (1H, d, J = 5.4 Hz), 1.57 (9H, s), 1.70-1.75 (1H, m), 1.82 (2H, d, J = 12.8 Hz), 2.80-2.87 (2H, m), 3.53 (2H, t, J = 5.8 Hz), 3.87-3.90 (2H, m), 6.85 (2H, d, J = 9.2 Hz), 7.84 (2H, d, J = 9.2 Hz).

[0614] Chemical formula:C 17 H 25 NO3, molecular weight: 291.39.

[0615] Total H number obtained from HNMR data: 25.

[0616] Step 2: Synthesis of tert-butyl 4-(4-formylpiperidin-1-yl)benzoate [ka]

[0617] To a solution of tert-butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (300 mg, 1.03 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.31 g, 3.09 mmol) slowly at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. It was then filtered and concentrated in vacuo to give the compound tert-butyl 4-(4-formylpiperidin-1-yl)benzoate (240 mg, 81%) as a pale yellow solid.

[0618] Exemplary Synthesis of Exemplary Compound 46: [ka] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

[0619] Synthesis scheme [ka]

[0620] Step 1: Synthesis of methyl 2-bromo-4-methoxybenzoate [ka]

[0621] To a solution of 2-bromo-4-methoxybenzoic acid (5.0 g, 21.7 mmol) in methanol (50 mL) was added 98% sulfuric acid (0.5 mL). The reaction mixture was heated to 90° C. under nitrogen gas for 16 hours and concentrated under reduced pressure. After cooling to room temperature, sodium bicarbonate (2.0 M) was added to adjust the pH to 8. This was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with brine (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-bromo-4-methoxybenzoate (4.8 g, 91%) as a yellow oil.

[0622] Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: from 90% [(total 10 mM AcONH4) water / CCH3CN = 900 / 100 (v / v)] and 10% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] to 10% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)] and 90% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] within 1.6 min, then under this condition for 2.4 min, finally to 90% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] The mixture was then changed to 10% [(total 10 mM AcONH4) water / CH3CN = 900 / 100 (v / v)] for 0.1 min and then to 10% [(total 10 mM AcONH4) water / CH3CN = 100 / 900 (v / v)] for 0.7 min under these conditions. 0.94%, Rt=2.609 min; MS calculated: 243.97; MS observed: 245.0 [M+H] + .

[0623] Step 2: Synthesis of methyl 2-allyl-4-methoxybenzoate [ka]

[0624] To a solution of methyl 2-bromo-4-methoxybenzoate (3.0 g, 12.3 mmol), cesium carbonate (12.0 g, 36.9 mmol), and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.98 g, 18.5 mmol) in N,N-dimethylformamide / water (30.0 mL / 3.0 mL) was added tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 100 °C and stirred for 4 hours. The resulting mixture was concentrated under reduced pressure, and then water (10 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography column (petroleum ether / ethyl acetate=4:1) to give methyl 2-allyl-4-methoxybenzoate (2.6 g, 100%) as a yellow oil.

[0625] Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.5 min, then changed under these conditions for 0.5 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under these conditions for 0.5 min. Purity: 96.85%, Rt = 1.293 min; MS calculated: 206.09; MS observed: 207.3 [M+H] + .

[0626] Step 3: Synthesis of methyl 4-methoxy-2-(2-oxoethyl)benzoate [ka]

[0627] To a solution of methyl 2-allyl-4-methoxybenzoate (1.20 g, 5.83 mmol) and osmium tetroxide (5 mg) in acetonitrile, acetone, and water (v:v:v = 10 mL:10 mL:10 mL), sodium periodate (4.99 g, 23.3 mmol) was added at 0°C. The mixture was stirred at room temperature for 4 hours. The mixture was filtered through a pad of Celite and extracted with ethyl acetate (20 × 3 mL). The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was collected. The crude product was purified by TLC (petroleum ether / ethyl acetate=4:1) to give the compound methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg, 35%) as a yellow oil.

[0628] LC-MS (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.5 min, then changed under these conditions for 0.5 min, and finally changed to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min, and changed under these conditions for 0.5 min. Purity: 96.26%, Rt = 1.007 min; MS calculated: 208.1; MS observed: 209.3 [M+H] + .

[0629] Step 4: Synthesis of 3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione [ka]

[0630] To a solution of methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg, 2.02 mmol) in methanol (6 mL) was added a solution of 3-aminopiperidine-2,6-dione hydrochloride (397 mg, 2.42 mmol) and triethylamine (245 mg, 2.24 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (254 mg, 4.04 mmol) was added at 0° C. The reaction was stirred overnight at room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3), washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (dichloromethane / methanol=20:1) to give 3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (340 mg, 59%) as a pale yellow solid.

[0631] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 3 mm x 2.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] in 1.5 min, then under these conditions for 0.5 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] in 0.1 min, and under these conditions for 0.5 min. Purity: 80.84%, Rt = 0.924 min; MS calculated: 288.1; MS observed: 289.1 [M+H]. + .

[0632] Step 5: Synthesis of 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione [ka]

[0633] To a solution of 3-(6-methoxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (220 mg, 0.76 mmol) in dichloromethane (10 mL) was added boron tribromide (0.5 mL) in dichloromethane (2 mL) dropwise at −78° C. and stirred at room temperature overnight. The reaction mixture was added to water (10 mL) and sodium bicarbonate (20 mL) and then extracted with dichloromethane / methanol (30 mL×5). The organic layer was washed with brine (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane / methanol=10:1) to give compound 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (80 mg, 38%) as a yellow solid.

[0634] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 3 mm x 2.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] in 1.5 min, then changed under these conditions for 0.5 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] in 0.1 min, and changed under these conditions for 0.5 min. Purity: 96.22%, Rt = 0.736 min; MS calculated: 274.1; MS observed: 275.1 [M+H] + .

[0635] Step 6: Synthesis of 3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione [ka]

[0636] To a solution of 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (80 mg, 0.292 mmol) in N,N-dimethylformamide (5.0 mL) was added 5-chloropentyl 4-methylbenzenesulfonate (64.5 mg, 0.234 mmol) and potassium carbonate (121 mg, 0.876 mmol). The mixture was heated to 40° C. overnight. After cooling to room temperature, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane / methanol=10:1) to give 3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (25 mg, 23%) as a yellow solid.

[0637] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 3 mm x 2.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN + 10 mM NH4HCO3] within 1.5 min, then under this condition for 0.5 min, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN + 10 mM NH4HCO3] within 0.1 min and maintained under these conditions for 0.5 min. Purity: 93.68%, Rt = 1.263 min; MS calculated: 378.1; MS observed: 379.1 [M+H] + .

[0638] Step 7: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide [ka]

[0639] A solution of 3-(6-(5-chloropentyloxy)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2,6-dione (25 mg, 0.066 mmol) was dissolved in acetonitrile (2 mL), and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (31 mg, 0.066 mmol), ethyldiisopropylamine (17 mg, 0.132 mmol), and potassium iodide (2 mg) were added to the solution. The mixture was heated to 100° C. in a sealed tube for 16 hours. After cooling to room temperature, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then purified by preparative HPLC to give the compound N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide (4.1 mg, 8%) as a white solid.

[0640] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 3.0 min, then under these conditions for 1.0 min, and finally to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, and under these conditions for 0.7 min. Purity: 87.84%, Rt = 2.923 min; MS calculated: 809.4; MS observed: 810.3 [M+H]. + .

[0641] HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm × 4.6 mm × 3.5 μm); column temperature: 40 °C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] changed from 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] within 10 min, then changed under these conditions for 5 min, and finally changed to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] within 0.1 min, and changed under these conditions for 5 min). Purity was 84.56%, Rt = 10.161 min.

[0642] 1 H NMR (400 MHz, DMSO-d6) δ 1.12 (6H, s), 1.21 (6H, s), 1.43-1.54 (4H, m), 1.74-1.78 (2H, m), 1.88-1.91 (1H, m), 2.30-2.44 (8H, m), 2.90-2.97 (3H, m), 3.42-3.59 (7H, m), 4.03-4.07 (3H, m), 4.30 (1H, s), 6.86-6.91 (3H, m), 6.99-7.02 (1H, m), 7.22 (1H, d, J = 2.4 Hz), 7.64 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 8.8 Hz), 7.90-7.97 (2H, m), 8.62 (1H, d, J = 2.0 Hz), 10.90 (1H, s).

[0643] Chemical formula:C 44 H 52 ClN7O6, molecular weight: 810.38.

[0644] Total H number obtained from HNMR data: 52.

[0645] Exemplary Synthesis of Exemplary Compound 47: [ka]

[0646] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

[0647] Synthesis scheme [ka]

[0648] Step 1: Synthesis of 2-(carboxymethyl)-4-methoxybenzoic acid [ka]

[0649] To a solution of 4-methoxy-2-methylbenzoic acid (5.0 g, 30.1 mmol) in dry tetrahydrofuran (50 mL) was added a solution of lithium diisopropylamide in tetrahydrofuran (1.0 mol / L) (66.3 mL, 66.3 mmol) under nitrogen gas at −78° C. The mixture was stirred at that temperature for 1 hour, and then dimethyl carbonate (2.98 g, 33.1 mmol) was added. The reaction mixture was stirred overnight. Water (200 mL) and ethyl acetate (100 mL) were added. The aqueous layer was separated, extracted with ethyl acetate (50 mL × 2), and neutralized with hydrochloric acid (1 N) to pH < 4. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (40 mL), and lithium hydroxide hydrate (5.06 g, 120.4 mmol) was added. The mixture was stirred at 120° C. for 2 hours, cooled to room temperature, and poured into ice water (200 mL). Hydrochloric acid (1 N) was added until the pH was <4. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine (50.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(carboxymethyl)-4-methoxybenzoic acid (4.6 g, 73% over two steps) as a yellow solid.

[0650] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm x 4.6mm x 3.5µm); Column temperature: 40°C; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1% TFA] in 0.5 min, then changed under these conditions for 1.5 min, and finally changed to 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 min, and changed under these conditions for 0.5 min. Purity: 94.6%, Rt = 0.774 min; MS calculated: 210.1; MS observed: 233.1 [M+23] + .

[0651] Step 2: Synthesis of methyl 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate [ka]

[0652] To a solution of 2-(carboxymethyl)-4-methoxybenzoic acid (1.2 g, 5.7 mmol) in methanol (10.0 mL) was added thionyl chloride (1.7 g, 14.3 mmol) dropwise. The mixture was refluxed for 2 hours. The mixture was cooled to room temperature, and then the solvent was removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether=1:1) to give 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (900 mg, 66%) as a white solid.

[0653] Step 3: Synthesis of 2-(carboxymethyl)-4-hydroxybenzoic acid [ka]

[0654] To a solution of 4-methoxy-2-(2-methoxy-2-oxoethyl)benzoate (0.9 g, 3.78 mmol) in dichloromethane (30 mL) was added boron tribromide (4.7 g, 18.9 mmol) dropwise under an ice-water bath. The resulting mixture was allowed to warm to room temperature and stirred overnight. Water (100 mL) was added. The organic layer was separated, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a mixture. The mixture was dissolved in methanol (30 mL), and sodium hydroxide (0.76 g, 18.9 mmol) in water (4.0 mL) was added. The mixture was refluxed for 5 hours. The solvent was removed. The residue was dissolved in water (30 mL). Hydrochloric acid (1 N) was added until the pH was < 4. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(carboxymethyl)-4-hydroxybenzoic acid (0.45 g, 61% over two steps) as a yellow solid.

[0655] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm x 4.6mm x 3.5µm); Column temperature: 40°C; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1% TFA] in 0.5 min, then changed under these conditions for 1.5 min, and finally changed to 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 min, and changed under these conditions for 0.5 min. Purity: 95.2%, Rt = 0.570 min; MS calculated: 196.0; MS observed: 197.2 [M+H] + .

[0656] Step 4: Synthesis of 2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid [ka]

[0657] A mixture of 2-(carboxymethyl)-4-hydroxybenzoic acid (120 mg, 0.61 mmol), potassium carbonate (253 mg, 1.83 mmol), and 5-chloropentyl 4-methylbenzenesulfonate (506 mg, 1.83 mmol) in dimethyl sulfoxide (5 mL) was stirred at 70 °C overnight. The resulting mixture was allowed to cool to room temperature and stirred overnight. Water (20 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a mixture. The mixture was dissolved in methanol (30 mL), and lithium hydroxide hydrate (128 mg, 3.05 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was removed. The residue was dissolved in water (30 mL). Hydrochloric acid (1 N) was added until the pH was < 4. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85 mg, 44% over two steps) as a yellow oil.

[0658] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then under these conditions for 1.5 min, and finally to 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min, and under these conditions for 0.5 min. Purity: 69.9%, Rt = 0.829 min; MS calculated: 314.1; MS observed: 315.1 [M+H] + .

[0659] Step 5: Synthesis of methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate [ka]

[0660] To a solution of 2-(5-(5-chloropentyloxy)-2-(methoxycarbonyl)phenyl)acetic acid (85 mg, 0.27 mmol) in methanol (2 mL) was added thionyl chloride (48.3 mg, 0.41 mmol) dropwise. The mixture was refluxed for 2 hours. The mixture was cooled to room temperature, and then the solvent was removed in vacuo to give the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether=1:1) to give methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 62%) as a yellow oil.

[0661] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then under these conditions for 1.5 min, and finally to 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min, and under these conditions for 0.5 min. Purity: 72.9%, Rt = 1.208 min; MS calculated: 328.1; MS observed: 329.2 [M+H] + .

[0662] Step 6: Synthesis of methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate [ka]

[0663] A mixture of methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55 mg, 0.17 mmol), ethyldiisopropylamine (65.8 mg, 0.51 mmol), potassium iodide (28.2 mg, 0.17 mmol), and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (78.5 mg, 0.17 mmol) in dimethyl sulfoxide (2 mL) was stirred at 70° C. overnight. The resulting mixture was allowed to cool to room temperature and stirred overnight. Water (20 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by column and flash chromatography (ethyl acetate / petroleum ether = 1:1) to give methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (53 mg, 41%) as a white solid.

[0664] Step 7: 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanopropanol) Synthesis of (2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoic acid [ka]

[0665] A mixture of methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (53 mg, 0.07 mmol) was dissolved in methanol (2 mL), and lithium hydroxide hydrate (14.7 mg, 0.35 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solvent was removed. The residue was dissolved in water (15 mL). Hydrochloric acid (1 N) was added until the pH was <4. The mixture was extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-2-(2-methoxy-2-oxoethyl)benzoic acid (42 mg, 81%) as a white solid.

[0666] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then under these conditions for 1.5 min, and finally to 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min, and under these conditions for 0.5 min. Purity: 75.4%, Rt = 1.041 min; MS calculated: 745.3; MS observed: 746.2 [M+H] + .

[0667] Step 8: Synthesis of methyl 2-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-t...

Claims

[Claim 1] Multiple myeloma.

Images