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 with related applications This disclosure is an international application claiming priority to U.S. Patent Application No. 15 / 953108, filed on April 13, 2018, which is a U.S. Provisional Patent Application No. 15 / 953,108, filed on April 14, 2014. 61 / 979,351, which is a continuation-in-part of U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, which claims priority to U.S. Provisional Patent Application No. 61, filed April 14, 2014. 979,351 and is a continuation-in-part of U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, which claims priority to U.S. Provisional Patent Application No. 62 / 171,090, filed June 4, 2015. , all of which are incorporated herein by reference in their entirety.

[0002] Incorporation of references U.S. Patent Application No. 15 / 230,354 filed August 5, 2016 and 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; U.S. Patent Application No. 15 / 829,541 filed December 1, 2017; U.S. Patent Application No. 15 / 881,318 filed January 26, 2018; U.S. Patent Application No. 14 / 686,640 filed April 14, 2015 and published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application No. 2016 / 0058872, filed July 6, 2015. Published U.S. Patent Application No. 14 / 792,414; and U.S. Patent Application No. 14 / 371,956 filed July 11, 2014 and published as U.S. Patent Application Publication No. 2014 / 0356322; and March 18, 2016 U.S. Patent Application No. 15 / 074,820, filed on 2016 / 0272639; Incorporated herein in its entirety. Additionally, all references cited herein are incorporated by reference in their entirety.

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

[0004] Most small molecule drugs bind to enzymes or receptors within tight and well-characterized pockets. On the other hand, protein-protein interactions are notoriously difficult to target using small molecules because their contact surfaces are large and the grooves involved are shallow or the interfaces are flat. is difficult. E3 ubiquitin ligases (of which several hundred are known in humans) provide substrate specificity to ubiquitination and are therefore more attractive than common proteasome inhibitors that are specific for some protein substrates. It is a therapeutic target. The development of ligands for E3 ligases has proven to be 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, nutlins, additional compounds targeting E3 ligases have been reported, but the field remains and remains undeveloped.

[0005] One E3 ligase with therapeutic potential is von Hippel-Lindau (VHL) tumor suppressor. VHL contains the substrate recognition subunit / E3 ligase complex VCB, which includes elongin B and C and a complex containing Cullin-2 and Rbx1. A major substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), which, in response to low oxygen levels, stimulates genes such as VEGF, a proangiogenic growth factor, and erythropoietin, an erythroid-inducing cytokine. is a transcription factor that upregulates We first generated and obtained the crystal structure of a small molecule von Hippel-Lindau (VHL) ligand for the substrate recognition subunit of the E3 ligase VCB, an important target in cancer, chronic anemia, and ischemia. We confirmed that this compound mimics the binding mode of the transcription factor HIF-1α, which is 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 their physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulatory factor of cullins1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not completely understood, cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates numerous developmental processes such as limb and otocyst formation. The bottom line is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage binding protein.

[0007] Thalidomide is approved for the treatment of a number of immune indications and is also approved for the treatment of certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and some of its analogs are also currently under consideration for use in the treatment of various other types of cancer. The exact mechanism of thalidomide's antitumor activity is still being elucidated, and it is known to inhibit angiogenesis. Recent publications discussing the biology of this imide include Lu et al Science 343, 305 (2014) and Kronke et al Science 343, 301 (2014). In particular, thalidomide and its analogs, such as pomolinamiod and lenarinomide, are known to bind cereblon. These agents bind cereblon, altering the specificity of the complex and inducing ubiquitination and degradation of Icarus (IKZF1) and Aeolus (IKZF3), transcription factors essential for the growth of multiple myeloma. Indeed, high expression of cereblon has been linked to increased efficacy of imide 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 to solve the problem]

[0009] There is a continuing need in the art for effective treatment of diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, nonspecific effects and the inability to fully target and modulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer drugs. Therefore, it can be tailored to exploit or enhance cereblon's substrate specificity while targeting a wide range of protein classes and modulating specificity. Small molecule therapeutic agents that are highly effective as therapeutic modalities would be very useful.

[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 proteolytically targeted chimeric (PROTAC) compounds that have utility as modulators of targeted ubiquitination of various polypeptides or other proteins. The polypeptide or other protein produced is 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 activities are possible, consistent with degrading / inhibiting target polypeptides from almost any protein class or family. Additionally, the present description provides methods of using effective amounts of the compounds described herein for the treatment or amelioration of disease conditions such as cancer, eg, multiple myeloma.

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

[0012] In an additional aspect, 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 placing the target protein / polypeptide in close proximity to 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 (or "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 will be understood by those skilled in the art, 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 the protein / polypeptide targeting moiety, L is the linker, and CLM is the cerebron 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, moiety derived from a thioimide. In additional embodiments, the CLM includes 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 yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0016] In certain embodiments, compounds as described herein include multiple CLMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

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

[0018] In an additional aspect, the present description provides therapeutic compositions comprising an effective amount of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic compositions can be used to modulate proteolysis in a patient or subject, e.g., an animal such as a human, and to treat or ameliorate a disease state or condition that is modulated through the degradation of proteins. In certain embodiments, therapeutic compositions as described herein can be used to cause the degradation of proteins of interest for the treatment or amelioration of a disease, such as cancer. In yet another aspect, the disclosure provides a method of ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises a bifunctional compound as described herein comprising a CLM and a PTM, preferably linked via a linker moiety as otherwise described herein. wherein the CLM is linked to a PTM, the CLM recognizes a ubiquitin pathway protein (e.g. a ubiquitin ligase, preferably an E3 ubiquitin ligase, such as e.g. cereblon), and the PTM recognizes a target protein and the When a target protein is placed in the vicinity of a ubiquitin ligase, degradation of the target protein occurs, thus resulting in degradation / inhibition of the action of the target protein and suppression of protein levels. Suppression of this protein level provided by the present disclosure provides treatment for pathologies or conditions modulated through the target protein by reducing the level of the protein in the patient's cells.

[0019] In additional aspects, the present description provides methods for assessing (ie, determining and / or measuring) the binding affinity of a CLM. In certain embodiments, the method includes a test agent or test compound of interest, e.g., an agent having an imide moiety, e.g., a phthalimide group, a phthalimido-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 test compound relative to agents or compounds known to bind to cereblon and / or inhibit its activity. including.

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

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

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

[0023] The accompanying drawings are incorporated in and form a part of this specification, and together with the description serve to illustrate some embodiments of the disclosure and to explain the principles of the 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 invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings that illustrate illustrative embodiments of the invention. [Brief explanation of the drawing]

[0024] [Figure 1A] FIG. 2 is a diagram illustrating the general principle for PROTAC functionality. 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). [Figure 1B] FIG. 2 is a diagram illustrating the general principle for PROTAC functionality. FIG. 2 illustrates the functional use of PROTAC as described herein. Briefly, ULMs recognize and bind to specific E3 ubiquitin ligases, and PTMs bind and recruit target proteins and bring them into close proximity to the E3 ubiquitin ligases. Typically, E3 ubiquitin ligases form complexes with E2 ubiquitin-conjugated proteins, either alone or via E2 proteins, in which ubiquitin (dark circles) is attached to target proteins via isopeptide bonds. catalyzes the adhesion of lysine to lysine. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome machinery. [Details for carrying out the invention]

[0025] The following is a detailed description set forth to assist 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 disclosure. All publications, patent applications, patents, figures, and other references mentioned herein are expressly incorporated by reference in their entirety.

[0026] Described herein is that when an E3 ubiquitin ligase protein, such as cereblon, and a target protein are placed in close proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein, the E3 Compositions and methods related to the surprising and unexpected discovery that ubiquitin ligase proteins ubiquitinate target proteins. Accordingly, the present disclosure includes an E3 ubiquintin ligase binding moiety ("ULM") linked to a protein target binding moiety ("PTM"), resulting in ubiquitination of the selected target protein, thereby (See Figures 1A and 1B). The disclosure also provides libraries of compositions and uses thereof.

[0027] In certain embodiments, the present disclosure provides a ligand capable of binding to a ubiquitin ligase such as IAP, VHL, MDM2, or cereblon, such as a small molecule ligand (i.e., less than 2,000 Daltons, less than 1,000 Daltons, less than 500 Daltons, or less than 200 Daltons). (having a molecular weight of 100%). The compounds also include a moiety capable of binding to a target protein such that the target protein is placed in close proximity to the ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. Small molecule may mean, in addition to the above, that the molecule is non-peptidyl, ie, not generally considered to be a peptide, and includes, for example, fewer than 4, 3, or 2 amino acids. According to this description, PTM, ULM, or PROTAC molecules can be small molecules.

[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 specific embodiments only and is not intended as a limitation of the invention.

[0029] If a range of values ​​is given, between the upper and lower limits of the range and unless the context clearly states otherwise (for groups containing a number of carbon atoms, each number of carbon atoms being given in the range) etc.) It is understood that each intervening value up to one-tenth of the unit of the lower limit, and any other stated value or intervening value within its stated range, is encompassed within the invention. . The upper and lower limits of these smaller ranges, which may independently be included in the smaller ranges, are also included in the invention, subject to any specific excluded limit of the stated range. Where 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 invention. Unless specifically defined herein, a term is given its art-recognized meaning by those skilled in the art, who will understand the meaning in the context when writing this specification. He is the one who applies the term to its use.

[0031] As used in this specification and the appended claims, the articles "a" and "an" refer to one or more than one (i.e., at least one) grammatical Used herein to refer to the object of the article. For example, "an element( "Element)" means one element or more than one element.

[0032] The phrase "and / or," as used herein in the body of the specification and in the claims, refers to "either or both" of the elements joined thereby, whether or not they occur conjunctively. should be understood to mean elements that may exist disjunctively. Multiple elements listed with "and / or" should be construed in the same manner, ie, as "one or more" of the elements joined thereby. Other elements than those 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, reference to "A and / or B" when used in conjunction with an open-ended word such as "comprising" may refer to only A (optional) in one embodiment. in other embodiments only B (optionally including elements other than A); in still other embodiments both A and B (optionally including other elements ); and so on.

[0033] As used herein in the specification and claims, "or" is to be understood to have the same meaning as "and / or" as defined above. For example, in separating items of a enumeration, "or" or "and / or" is inclusive, i.e., out of a number of or enumerated elements and optionally additional non-enumerated items, shall be construed to include not only at least one, but also more than one. Only terms clearly marked to the contrary, such as "only one of" or "exactly one of" or, when used in a claim, "consisting of" refer to a number or series of It refers to the inclusion of exactly one of the listed elements. Generally, as used herein, the term "or" is preceded by an exclusionary phrase such as "either," "one of," "only one of," or "exactly one of." shall only be construed as indicating an excluded alternative (i.e., "one or the other, but not both").

[0034] In the claims, the words "comprising," "including," "carrying," "having," and "containing" are used as in the main text of the specification. , “involving,” “holding,” “consisting of,” etc. All transitional phrases in are open-ended, ie, shall be construed to mean including, but not limited to. Only the transitional phrases ``consisting of'' and ``consisting of'' United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, each of which is a closed or semi-closed transition clause. It is said that

[0035] As used herein in the specification and claims, the phrase "at least one" in a reference to a listing of one or more elements refers to any one or more of the listings of elements. means at least one element selected from Elements, but does not necessarily include at least one of each and every element specifically listed in the enumeration of elements, and any element in the enumeration of elements. It should be understood that this does not exclude combinations. This definition also means that any element other than the element specifically identified within the enumeration of elements indicated by the phrase "at least one", whether related or unrelated to the specifically identified element, Allow for selective existence. Thus, by way of non-limiting example, "at least one of A and B" (or, in an equal sense, "at least one of A or B", or, in an equal sense, "at least one of A and / or B") '') in one embodiment includes at least one and optionally more than one A and no B (and optionally includes elements other than B); in another embodiment , at least one and optionally more than one B and no A (and optionally containing elements other than A); in yet another embodiment, at least one and optionally containing more than one A, and containing at least one and optionally more than one B (and optionally containing other elements); and so on. .

[0036] Also, for certain methods described herein that include more than one step or act, the order of the method steps or acts is the same as the description of the method steps or acts, unless the context dictates otherwise. should not necessarily be construed as being limited to the order in which they are performed.

[0037] The terms "co-administration" and "co-administering" or "combined therapy" mean simultaneous administration (two or more treatments at the same time) as long as the therapeutic agents are simultaneously present in some degree, preferably in effective amounts, in the patient. (administration of one or more therapeutic agents at a different time than the administration of additional therapeutic agents or agents). In certain preferred embodiments, one or more of the compounds described herein are co-administered in combination with at least one additional bioactive agent, particularly anti-cancer agents. Examples include agents. In particularly preferred embodiments, co-administration of 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, tautomers, Positional isomers, geometric isomers, and stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, where applicable, and pharmaceutically acceptable salts thereof. , including their prodrugs and / or deuterated versions where applicable. Examples include derivatives. Contemplated deuterated small molecules are those in which one or more hydrogen atoms contained in a drug molecule are replaced with deuterium.

[0039] As used depending on the context, the term compound generally refers to a single compound, but may include other compounds of the disclosed compound, such as stereoisomers, positional isomers, and / or optical isomers (including racemic mixtures). ), as well as specific enantiomers or enantiomeric enriched mixtures. The term also refers, depending on the context, to prodrug forms of a compound that 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 invention, among other things, a large number of substituents and variants related thereto 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 shown, both double and single bonds are represented or understood within the context of the compounds shown and the well-known rules of valence interactions.

[0040] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins and target the substrate proteins for degradation. For example, cereblon, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the addition of ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome. It is an E3 ubiquitin ligase protein. Therefore, E3 ubiquitin ligase alone or in complex with E2 ubiquitin conjugate enzymes is involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, so that a second ubiquitin is added to a first; a third is added to a second, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are several ubiquitination events that limit monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead their location or function in the cell is altered, for example through binding to other proteins that have domains capable of binding ubiquitin. Sometimes. 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. This is the lysine used to generate polyubiquitin, which is recognized by the proteasome.

[0041] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, is provided with compositions according to the present disclosure. For the 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 domestic animals such as dogs or cats. or domesticated animals such as horses, cows, and sheep. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise stated or implied by the context of use of the term.

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

[0043] Compounds and compositions In one aspect, the present description provides compounds that include an E3 ubiquitin ligase binding moiety ("ULM") that is a cereblon E3 ubiquitin ligase binding moiety ("CLM"). In one embodiment, the CLM is attached to a chemical linker (L) with the following structure: (I) L-CLM where L is a chemical linker group and CLM is a cereblon E3 ubiquitin ligase binding moiety. The number and / or relative position of moieties in the compounds described herein are given by way of example only. As will be understood by those skilled in the art, the compounds described herein can be synthesized with any desired number and / or relative position of each functional moiety.

[0044] The terms ULM and CLM are used in an inclusive sense unless the context dictates otherwise. For example, the term ULM encompasses all ULMs, including those that combine cereblon (ie, CLM). Additionally, 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 degradation of a target protein. In certain embodiments, the compound comprises a CLM that is directly or indirectly attached, eg, covalently linked, to a moiety that binds a target protein (ie, a protein targeting moiety or "PTM"). In certain embodiments, the CLM and PTM are joined or linked via a chemical linker (L). CLM recognizes Cerebron E3 ubiquitin ligase, PTM recognizes target protein, and the interaction of each moiety with their target is determined by placing the target protein in the vicinity of the ubiquitin ligase protein. Promotes decomposition. 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, a bifunctional compound can be illustrated as follows: (III) PTM-L-CLM Where PTM is the protein / polypeptide targeting moiety, L is the linker, and CLM is the cerebron E3 ligase binding moiety.

[0047] In certain embodiments, the compounds described herein target multiple PTMs (targeting the same or different protein targets), multiple CLMs, one or more ULMs (i.e., another E3 ubiquitin ligase, for example, a portion that specifically binds to VHL), or a combination thereof. In any aspect of the embodiments described herein, the PTM, CLM, and ULM can be attached directly or through one or more chemical linkers or combinations thereof. In additional embodiments, when the compound has multiple ULMs, the ULMs can be for 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 through a chemical linker moiety (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 includes multiple CLMs, the CLMs are the same. In additional embodiments, the compound containing multiple CLMs is directly or linked to a chemical linker (L). further comprising at least one PTM coupled to the CLM via or both. In certain additional embodiments, compounds that include multiple CLMs further include multiple PTMs. In yet additional embodiments, the PTMs are the same or optionally different. In yet another embodiment, if the PTMs are different, each PTM may bind the same protein target or may specifically bind different protein targets.

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

[0051] In a preferred embodiment, the CLM includes a moiety that is a ligand for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM includes species from the "imide" class of molecules. In certain additional embodiments, the CLM includes 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 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 description provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutical properties. Includes acceptable salt forms, such as acid and base salt forms.

[0053] Exemplary cereblon binding and / or inhibiting compounds

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

[0055] neoimide compound

[0056] In one aspect, the present description provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of the following chemical structures: [ka] [ka] During the ceremony, W in formulas (a) to (e) is independently CH 2 ,CHR,C=O,SO 2 , NH, cyclopropyl, cyclobutyl, and N-alkyl; W 3 is selected from C or N; each X in formulas (a) to (e) is absent or independently selected from the group O and S; Y in formulas (a) to (e) is independently CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; each Z in formulas (a) to (e) is absent or independently selected from the group O and S, except that X and Z cannot both be absent; G and G' in formulas (a) to (e) are independently H, alkyl (straight chain, branched, optionally substituted), OH, R'OCOOR, R'OCONRR'', optionally CH substituted by R' 2 -heterocyclyl, and benzyl optionally substituted by R'; Q1-Q4 in formulas (a) to (e) represent a carbon C substituted by a group independently selected from R', N or N-oxide; A in formulas (a) to (e) is independently selected from the group of H, alkyl (straight chain, branched, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) to (e) may include, but is not limited to: -CONR’R”, -OR’, -NR’R”, -SR’, -SO 2 R’, -SO 2 NR’R”, -CR’R”-, -CR’NR’R”-, (-CR’O) n’ R”, ​​-aryl, -hetaryl, -alkyl (straight chain, 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, -CF 3 , -CN, -NR’SO 2 NR'R", -NR'CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR' C(=N-CN)R", -NR'C(=C-NO 2 )NR’R”, -SO 2 NR’COR”, -NO 2 ,-CO 2 R’, -C(C=N-OR’)R”, -CR’=CR’R”, -CCR’, -S(C=O)(C=N-R’)R”, -SF 5 , and -OCF 3 including; R' and R'' in formulas (a) to (e) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, -C(=O)R, heterocyclyl; each of which is optionally replaced; n' in formulas (a) to (e) is an integer from 1 to 10 (for example, 1 to 4); [ka] The above formulas (a) to (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 can be one to four independent functional groups, optionally substituted straight or branched alkyl (e.g. C1-C6 straight or branched, optionally substituted with one or more halogens) branched alkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), 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 combinations thereof) aryl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl represents one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl ( optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), replaced by [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), or an atom including; and Each of x, y, and z is independently 0, 1, 2, 3, 4, 5, or 6.

[0057] Exemplary CLM

[0058] For any compound described herein, the CLM includes a chemical structure selected from the following groups: [ka] [ka] During the ceremony: W in formulas (a) to (f) is independently CH 2 ,CHR,C=O,SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl; W 3 is selected from C or N; each X in formulas (a) to (f) is absent or independently selected from the group O and S; Y in formulas (a) to (f) is independently CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and selected from the group of S; each Z in formulas (a) to (f) is absent or independently selected from O and S groups, except that X and Z cannot both be absent; G and G' in formulas (a) to (f) are independently substituted with H, alkyl (straight chain, branched), OH, R'OCOOR, R'OCONRR'', optionally R' CH 2 -heterocyclyl, and benzyl optionally substituted by R'; Q1 to Q4 in formulas (a) to (f) represent a carbon C substituted by a group independently selected from R', N or N-oxide; A in formulas (a) to (f) is independently selected from the group of H, alkyl (straight chain, branched, optionally substituted), cycloalkyl, Cl, and F; R in formulas (a) to (f) includes, but is not limited to: -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR 'R”-, -CR'NR'R”-, (-CR'O) n’ R”, ​​-aryl, -hetaryl, -alkyl (straight chain, 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'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N -CN)R", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR' =CR'R", -CCR', -S(C=O)(C=N-R')R", -SF5, and -OCF3; R' and R'' in formulas (a) to (f) are independently selected from a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, -C(=O)R, heterocyclyl; each of which is optionally replaced; n' in formulas (a) to (f) is an integer from 1 to 10 (for example, 1 to 4); [ka] represents a single or double bond; [ka] The above formulas of formulas (a) to (f) represent bonds that can be stereospecific ((R) or (S)) or non-stereospecific; Rn can be one to four independent functional groups, optionally substituted straight or branched alkyl (e.g. C1-C6 straight or branched, optionally substituted with one or more halogens) branched alkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), 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 combinations thereof) aryl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl represents one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl ( optionally substituted [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), replaced by [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), or an atom including; 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 syloalkyl or monocyclic heterocycloalkyl of CLM is each independently absent or O or S, except that both X and Z cannot be absent. In any aspect or embodiment described herein, X on the intermediate ring is selected from O and S, and X and Z of the 6-membered monocyclic cyloalkyl or monocyclic heterocycloalkyl of CLM each independently is absent, O or S, except that both X and Z cannot be absent.

[0060] In certain embodiments described herein, the CLM or ULM comprises a chemical structure selected from the following group: [ka] Formula (g) During the ceremony: W in formula (g) is independently CH 2 , C=O, NH, and N-alkyl; R in formula (g) is independently H, methyl, alkyl (e.g. a or C1-C6 alkyl (straight chain, branched, optionally substituted)); of formula (g) [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific; and Rn can be one to four independent functional groups, optionally substituted straight or branched alkyl (e.g. C1-C6 straight or branched, optionally substituted with one or more halogens) branched alkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), 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 combinations thereof) aryl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl is one or more optionally substituted with multiple halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl) [ka] (e.g., optionally substituted with one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), replaced by [ka] (e.g., optionally substituted by one or more halogen, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g. C3-C6 cycloalkyl), or aryl (e.g. C5-C7 aryl)), or an atom include.

[0061] In any embodiment described herein, W, X, Y, Z, g, G', R, R', R'', Q1-Q4, A of formulas (a) to (g), and Rn can be independently 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 those "hybrid" molecules that arise from a 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 differ independently between applications.

[0064] The term "alkyl", depending on its context, refers to a straight, branched, or cyclic fully saturated hydrocarbon radical, or an alkyl group, preferably C 1 -C 10 , more preferably C 1 -C 6 , or optionally substituted C 1 -C 3 Refers to an alkyl group. Examples of alkyl groups are, among others, 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. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes. These compounds are generally contains a side chain (often linked via a polyethylene glycol group) terminating in an alkyl side chain with a halogen substituent (often chlorine or bromine) at its distal end; Halogen substituents covalently bind compounds containing such moieties to the protein.

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

[0066] The term "alkenyl" means a straight, branched, or cyclic C=C bond containing at least one C=C bond. 2 -C 10 (preferably C 2 -C 6 ) Refers to hydrocarbon radicals.

[0067] The term "alkynyl" refers to a straight, branched, or cyclic C 2 -C 10 (preferably C 2 -C 6 ) Refers to hydrocarbons.

[0068] The term "alkylene" as used means -(CH 2 ) n - refers to a group (n is generally an integer derived from 0 to 6) that can be optionally substituted. When substituted, the alkylene group preferably has C on one or more methylene groups. 1 -C 6 Substituted with alkyl groups (including cyclopropyl or t-butyl groups), but with one or more halo groups, preferably 1 to 3 halo groups, or as otherwise disclosed herein. 1 or 2 hydroxyl groups, O-(C 1 -C 6 (alkyl) groups or amino acid side chains. In certain embodiments, the alkylene group may be substituted with a urethane group or an alkoxy group (or other group), and such group is further substituted with a polyethylene glycol chain (from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units), and this chain is substituted by an alkyl chain (preferably, but not exclusively) substituted by a single halogen group, preferably a chlorine group. (but not exclusively, at the distal end of the polyethylene glycol chain). In still other embodiments, alkylene (often methylene) groups may be substituted with amino acid side groups, such as those of natural or non-natural amino acids, such as, for example, 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. C 0 A range of carbon atoms containing means that carbon is absent and replaced by H. Therefore, C 0 -C 6 The range of carbon atoms that is includes 1, 2, 3, 4, 5, and 6 carbon atoms, and C 0 For, H is in the carbon place.

[0070] The term "substituted" or "optionally substituted" means independently (i.e., when multiple substituents occur, each substituent is independent of another substituent) , one or more substituents at any carbon (or nitrogen) position anywhere on the molecule in the context of up to 5 substituents, preferably up to 3 independently on a portion of a compound according to the present disclosure (often one or two substituents, which may themselves contain further substituted substituents), and the substituents hydroxyl, thiol, carboxyl, cyano ( C≡N), nitro (NO 2 ), halogen (preferably 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group, such as trifluoromethyl), an alkyl group (preferably C 1 -C 10 , more preferably C 1 -C 6 ), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy groups (preferably C 1 -C 6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 acyl), ester or thioester (preferably C 1 -C 6 alkyl or aryl) and an alkylene ester (where the addition is on the alkylene group rather than on the ester function, this group is preferably C 1 -C 6 (substituted by an alkyl group or an aryl group), preferably C 1 -C 6 C 1 -C 6 Alkylamine or C 1 -C 6 dialkylamines) or optionally substituted -N(C 0 -C 6 alkyl)C(O)(O-C 1 -C 6 hydrazine, Amide, preferably 1 or 2 C 1 -C 6 substituted by an alkyl group (optionally 1 or 2 C 1 -C 6 (including carboxamides substituted with alkyl groups), alkanols (preferably C 1 -C 6 alkyl or aryl), or alkanoic acid (preferably C 1 -C 6 (alkyl or aryl). Substituents according to the present disclosure include, for example, -SiR 1sub R 2sub R 3sub In the formula, R 1sub and R 2sub each of which is as otherwise described herein, and R 3sub is H or C 1 -C 6 an alkyl group, preferably R in this context 1sub ,R 2sub ,R 3sub is C 1 -C 3 It is an alkyl group (including isopropyl group or t-butyl group). Each of the above groups may be linked directly to a substituent moiety, or the substituent may be substituted with one or more of the above substituents, optionally substituted - (CH 2 ) m -, also or optionally substituted -(OCH 2 ) m -,-(OCH 2 CH 2 ) m - or -(CH 2 CH 2 O) m It may be linked to the substituent moiety (preferably in the case of an aryl or heteroaryl moiety) via a - group. Alkylene group -(CH 2 ) m - group or -(CH 2 ) n The - group or other chains specified above, such as the ethylene glycol chain, may be substituted anywhere on the chain. Suitable substituents on the alkylene group include halogen or C 1 -C 6 (preferably C 1 -C 3 ) alkyl groups, such groups optionally containing one or two hydroxyl groups, one or two ether groups (O-C 1 -C 6groups), up to three halo groups (preferably F), or side chains of amino acids as otherwise described herein, and optionally substituted amides (preferably substituted as above) carboxamide) or urethane groups (often one or two C 0 -C 6 (with alkyl substituents, which groups may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) has one or two optionally substituted C 1 -C 6 Alkyl group, preferably C 1 -C 4 Substituted with an alkyl group, most often a methyl or O-methyl group, or a side chain of an amino acid as otherwise described herein. In this disclosure, a portion of the molecule may be optionally substituted with up to 5 substituents, preferably with up to 3 substituents. In most cases, in this disclosure, substituted moieties are substituted with one or two substituents.

[0071] The term "substituted" (with each substituent being independent of any other substituents) also means, within the context of its use, that C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C 1 -C 6 Esters (oxyesters or carbonyl esters), C 1 -C 6 Keto, urethane-O-C(O)-NR 1sub R 2sub or -N(R 1sub )-C(O)-O-R 1sub , nitro, cyano, and amines (especially C 1 -C 6 Alkylene-NR 1sub R 2sub , mono- or di-C substituted by an amine, which may be optionally substituted by one or two hydroxyl groups. 1 -C 6 alkyl). Each of these groups, unless otherwise indicated, within the context contains between 1 and 6 carbon atoms. In certain embodiments, suitable substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m -( where m and n are 1, 2, 3, 4, 5, or 6 depending on the context), -S-, -S(O)-, SO 2 -or-NH-C(O)-NH-, -(CH 2 ) n OH, -(CH 2 ) n SH, -(CH 2 ) n COOH,C 1 -C 6 Alkyl, -(CH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n OC(O)-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)O-(C 1 -C 6 alkyl), -(CH 2 ) n NHC(O)-R 1sub ,-(CH 2 ) n C(O)-NR 1sub R 2sub ,-(OCH 2 ) n OH, -(CH 2 O) n COOH,C 1 -C 6 Alkyl, -(OCH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 O) n C(O)-(C 1 -C 6 alkyl), -(OCH 2 ) n NHC(O)-R 1sub ,-(CH 2 O) n C(O)-NR 1sub R 2sub , -S(O) 2 -R S , -S(O)-R S (R S is C 1 -C 6 Alkyl or -(CH 2 ) m -NR 1sub R 2sub base), NO 2 , CN or halogen (F, Cl, Br, I, preferably F or Cl). R 1sub and R 2sub are respectively H or C in the context 1 -C 6 It is an alkyl group (optionally substituted by one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The term "substituted", within the chemical context of the compound defined and the substituents used, also refers to optionally substituted aryl or heteroaryl groups as otherwise described herein; or an optionally substituted heterocyclic group. Alkylene groups are also preferably optionally substituted C 1 -C 6 an alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thus providing a chiral center), a side chain of an amino acid group as otherwise described herein; Amide group or urethane group O-C(O)-NR 1sub R 2sub A group in which R 1sub and R 2sub may be substituted by groups as otherwise described herein, although numerous other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably with 1 or 2 substituents. If a substitution is required in a compound at a particular position in the molecule (primarily due to valency), but the substitution is not indicated, the substituent is H unless the context of the substitution suggests otherwise. Please note that this may be interpreted or understood as

[0072] The term "aryl" or "aromatic" in the context refers to a substituted compound (as otherwise described herein) having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.). ) or an unsubstituted monovalent aromatic radical that may be attached to compounds according to the present disclosure at any available stable position on the ring or as otherwise indicated in the chemical structure presented. can. Other examples of aryl groups include, in this context, "heteroaryl" groups having, inter alia, heterocyclic aromatic ring systems, i.e. one or more nitrogen, oxygen or sulfur atoms in the ring (single ring), such as imidazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., which are optionally May be substituted as above. Among the heteroaryl groups that may be mentioned, 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, quinolidine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, Carbazole, carbazolin, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine, etc.; sulfur-containing aromatic heterocycles, e.g. such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran; and aromatics containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen. Group heterocycles, such as thiazole, thiazizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazane, phenoxazine, pyrazolooxazole, imidazothiazole, thienofuran, furopyrole, 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 consisting of multiple fused rings, at least one of which is aromatic, where the rings is substituted with a substituent. For example, an aryl group can include substituents selected from: -(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 )alkyl, -(CH 2 ) n -O-(CH 2 ) n -(C 1 -C 6 )alkyl, -(CH 2 ) n -C(O)(C 0 -C 6 )alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 )alkyl, -(CH 2 ) n -OC(O)(C 0 -C 6 )alkyl, amine, mono- or di-(C 1 -C 6 OH, COOH, in which the alkyl group on the amine is optionally substituted by one or two hydroxyl groups or up to three halo (preferably F, Cl) groups; ,C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , or a CN group (which may be substituted in the ortho, meta and / or para positions, respectively, of the phenyl ring, preferably in the para position), an optionally substituted phenyl group (the phenyl group itself preferably contains a ULM group) (substituted by a linker group attached to the PTM group) and / or F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , or at least one of the CN groups (in the ortho, meta and / or para positions of the phenyl ring, preferably in the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl , optionally substituted isoxazoles including preferably methyl-substituted isoxazoles, optionally substituted oxazoles including methyl-substituted oxazoles, optionally substituted including methyl-substituted thiazoles. optionally substituted isothiazoles, including methyl-substituted isothiazoles; optionally substituted pyrroles, including methyl-substituted pyrrole; optionally substituted pyrroles, including methyl-substituted pyrrole; optionally substituted benzimidazoles, including substituted imidazoles, methoxybenzylimidazole, or optionally substituted oximidazole or methyloxyimidazole, optionally substituted diazoles, including methyldiazole groups. optionally substituted triazole groups, including methyl-substituted triazole groups, halo-(preferably F)-substituted or methyl-substituted pyridine or oxapyridine groups, where the pyridine group is replaced by a phenyl group with oxygen. optionally substituted pyridine groups, optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted 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; A specific substituent has a meaning consistent with the definition of the corresponding group as defined herein.

[0075] The term "heteroaryl" or "hetaryl" refers to an optionally substituted quinoline (which may be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring); optionally substituted indoles (including dihydroindole), optionally substituted indolizines, optionally substituted azaindolizines (2, 3, or 4-azaindolizines), optionally substituted benzimidazoles, benzodiazoles, benzoxofurans , optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted 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 groups, triisopropylsilyl groups, optionally substituted -(CH 2 ) m -O-C 1 -C 6 an alkyl group, or an optionally substituted -(CH 2 ) m -C(O)-O-C 1 -C 6 1,2,3-triazole substituted by an alkyl group), an optionally substituted pyridine (2-, 3, or 4-pyridine), or a group according to the following chemical structure, but none of these Without limitation: [ka] During the ceremony, S c is CHR SS ,NR URE , or O; R HET H,CN,NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably 1 or 2 hydroxyl groups or up to 3 halo groups (e.g. CF 3 ) and optionally substituted O(C 1 -C 6 alkyl) (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylene group -C≡C-R a , in which R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 alkyl); R SS H,CN,NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups), optionally substituted O-(C 1 -C 6 alkyl) (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups) or optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups); R URE H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl) or -C(O)(C 1 -C 6 alkyl), each group of which is optionally substituted by one or two hydroxyl groups or up to three halogens, preferably fluorine groups, or an optionally substituted heterocycle , such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperidine, etc. perazine, each of which is an optionally substituted heterocycle, and Y C is N or C-R YC , in which R YC are H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups (e.g. CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted by 1 or 2 hydroxyl groups or up to 3 halo groups) or an optionally substituted acetylene group -C≡C-R a , in which R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 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. As such, heteroaryl moieties are incorporated 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, iso oxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, Mention may be made, among others, of pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolane, thiane.

[0078] Heterocyclic groups optionally include alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, Heterocycle, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2- Can be substituted with a member selected from the group consisting of aryl, oxo (=O), and -SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple fused 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, quinolidine, 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 or cyclohexane ring or to another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0079] The term "cycloalkyl" refers to a monocyclic or polycyclic alkyl group or a monovalent group derived from a cycloalkane as defined herein, e.g., having from 3 to 20 carbon atoms in the ring. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "substituted cycloalkyl" refers to a monocyclic ring substituted with one or more substituents, such as amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo. This may refer to, but is in no way limited to, polycyclic alkyl groups, while these general substituents have meanings consistent with the definitions of the corresponding groups as defined in this legend.

[0080] The term "hydrocarbyl" means a compound containing carbon and hydrogen, which can be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups. shall be taken as a thing.

[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 a combination of one or more characteristics of the following compounds: [ka] [ka] [ka] During the ceremony: W independently, CH 2 ,CHR,C=O,SO 2 , 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, substituted alkoxy; R 4 is methyl or ethyl; R 5 is H or halo; R 6 is H or halo; R of CLM is H; R’ is H or a point of attachment for PTM, PTM’, chemical linker group (L), ULM, CLM, CLM’; Q1 and Q2 are each independently C or N substituted with groups independently selected from H or C1-C3 alkyl; [ka] is a single or double bond; and Rn includes a functional group or an atom.

[0084] In any embodiment described herein, W, R 1 ,R 2 ,Q 1 ,Q 2 ,Q 3 ,Q 4 , and R 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. can.

[0085] In any embodiment described herein, R 1 ,R 2 ,Q 1 ,Q 2 ,Q 3 ,Q 4 , and R 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. can.

[0086] In any embodiment described herein, Q 1 ,Q 2 ,Q 3 ,Q 4 , and R 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. can.

[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 plurality or combination thereof. be done.

[0088] example linker

[0089] In certain embodiments, the compounds described herein are provided with a chemical linker ( comprises one or more CLMs chemically linked or bonded via L). In certain embodiments, the linker group L includes one or more covalently attached structural units (e.g., -A L 1 …(A L ) q -or-(A L ) q -), in the formula, A 1is a group attached to PTM and Aq is a group attached to at least one of ULM, ULM', CLM, CLM', or combinations thereof. In certain embodiments, A L 1 connects a CLM or CLM' directly to another ULM, PTM, or a combination thereof. In other embodiments, A L 1 A CLM or CLM’ indirectly into another ULM, PTM, or a combination thereof. q Connect through.

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

[0091] In certain embodiments, the linker group is -(A L ) q -, and in the formula, -(A L ) q - is a group connected to at least one of a ULM moiety, a PTM moiety, or a combination thereof; The linker's q is an integer greater than or equal to 1; Each A L are independently, combined, CR L1 R L2 ,O,S,SO,SO 2 ,NR L3 ,S.O. 2 NR L3 ,SONR L3 ,CONR L3 ,NR L3 CONR L4 ,NR L3 S.O. 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 ,P(O)R L1 ,P(O)OR L1 ,NR L3 C(=NCN)NR L4 ,NR L3 C(=NCN),NR L3 C(=CNO 2 )NR L4 , 0~6 R L1 group and / or R L2 optionally by group replaced C 3-11 cycloalkyl, 0-9 R L1 group and / or R L2 C optionally substituted with groups 5-13 Spirocycloalkyl, 0-6 R L1 group and / or R L2 C optionally substituted with groups 3-11 heterocyclyl, 0-8 R L1 group and / or R L2 C optionally substituted with groups 5-13 spiroheterocycloalkyl, 0 to 6 R L1 group and / or R L2 Aryl optionally substituted with groups, 0 to 6 R L1 group and / or R L2 selected from the group consisting of heteroaryl optionally substituted with a group, in which R L1 or R L2 each independently form a cycloalkyl moiety and / or a heterocyclyl moiety optionally linked to other groups, which moieties optionally contain 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, 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, NH 2 , S.H., S.O. 2 C 1-8 Alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 Alkyl, CO 2 H, halogen, CN, CF 3 ,CHF 2 ,C.H. 2 F, NO 2 ,SCIENCE FICTION 5 ,S.O. 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 alkyl) 2 ,CONHC 1-8 Alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 ,NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 ,NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 ,NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 ,NHSO 2 N.H. 2 It is.

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

[0093] In certain embodiments, for example, if q is greater than 2, then A L q is a group attached to the ULM or ULM’ part (such as CLM or CLM’), and A L 1 and A L q are connected through the structural unit of the linker (L).

[0094] In certain embodiments, for example, if q of the linker is 2, then A L q is A L 1 and a ULM moiety or ULM' moiety (such as CLM or CLM').

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

[0096] In certain embodiments, the linker (L) comprises a group represented by the general structure selected from the group consisting of: -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxyl)-, -NR(CH 2 ) n -(Lower alkoxyl)-OCH 2 -, -NR(CH 2 ) n -(Lower alkoxyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(cycloalkyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 )n -(heterocycloal kill)-, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heterocycloalkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(lower alkyl)-NH-aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-aryl-CH 2 , -NR(CH 2 CH 2 O) n -cycloalkyl-O-aryl-, -NR(CH 2 CH 2 O) n -cycloalkyl-O-(heteroaryl)l-, -NR(CH 2 CH 2 ) n -(cycloalkyl)-O-(heterocycle)-CH 2 , -NR(CH 2 CH 2 ) n -(heterocycle)-(heterocycle)-CH 2 , -N(R1R2)-(heterocycle)-CH 2 ;In the formula, Linker n can be from 0 to 10; R of the linker can be H, lower alkyl; R1 and R2 of the linker can form a ring 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 above linker are independently 0, 1, 2, 3, 4, 5, 6; 7, 8, 9, 10, 11, 12, 13, 14, is 15, 16, 17, 18, 19, or 20; If the number is zero, there is no N-O or O-O bond; R in the linker is H, methyl, and ethyl; X in the linker above is H and F, [ka] In the above formula, m of the linker can be 2, 3, 4, 5; [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] where each n and m of the linker can be independently 0, 1, 2, 3, 4, 5, 6.

[0098] In any aspect or embodiment described herein, A L The group is selected from the group consisting of: [ka] [ka] [ka] where 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: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] where each m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20;

[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, but not limited to, the structures shown below. These include, but are not limited to, structures where the dashed line indicates the point of attachment with the PTM or ULM moiety: [ka] During the ceremony: W L1 and W L2 are each independently absent or optionally R Q A 4- to 8-membered ring having 0 to 4 heteroatoms substituted by R Q but independently, H, halo, OH, CN, CF 3 ,C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), C 1 -C 6 is alkoxy (straight chain, branched, optionally substituted) or 2 R Q the groups together with their attached atoms form a 4- to 8-membered ring system containing 0 to 4 heteroatoms; Y L1 are each independently a combination or C 1 -C 6 is an alkyl (straight chain, branched, optionally substituted) in which one or more C atoms are optionally replaced by O; or 1 -C 6 alkoxy (straight chain, branched, optionally substituted); n is 0~10; and The dashed line indicates the addition point of the PTM or ULM portion.

[0102] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line marks the point of attachment with the PTM or ULM moiety. : [ka] and During the ceremony: W L1 and W L2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclic, C 1-6 alkyl optionally with one or more C atoms substituted by O, C 1-6 alkenes in which one or more C atoms are optionally replaced by O, C 1-6 an alkyne, bicyclic, biaryl, biheteroaryl, or biheterocycle in which one or more C atoms are optionally substituted with O, each optionally R Q and each R Q but, Independently H, halo, OH, CN, CF 3 , hydroxyl, nitro, C≡CH, C 2-6 alkenyl, C 2-6 Alkynyl, C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), C 1 -C 6 Alkoxy (straight chain, branched, optionally substituted), OC 1-3 Alkyl (optionally substituted with one or more -F), OH, NH 2 ,NR Y1 R Y2 , CN, or 2 R Q the groups together with their attached atoms form a 4- to 8-membered ring system containing 0 to 4 heteroatoms; Y L1 are each independently combined, NR YL1 ,O,S,NR YL2 ,CR YL1 R YL2 , C=O, C=S, SO, SO 2 ,C 1 -C 6 alkyl (straight chain, branched, optionally substituted) with one or more C atoms optionally replaced by O; C 1 -C 6 alkoxy (straight chain, branched, optionally substituted); Q L is a 3-6 membered cycloaliphatic or aromatic ring having 0-4 heteroatoms, optionally bridged, optionally containing 0-6 R Q and each R Q But independently H, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 (substituted by alkoxyl) or 2 R Q the groups together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); R YL1 ,R YL2 are independently H, OH, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 alkoxyl) or R 1 ,R 2 together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); n is 0~10; and The dashed line indicates the addition point of the PTM or ULM portion.

[0103] In additional embodiments, the linker group is an optionally substituted (poly)ethylene glycol, comprising between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units. ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, and between 1 and 6 ethylene glycol units optionally substituted ethylene glycol units, between 2 and 4 ethylene glycol units, or interspersed with optionally substituted O, N, S, P, or Si atoms It has an alkyl group. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, linkers can 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 comprising about 1 to about 12 ethylene glycol units, about 1 to about 10 ethylene glycol units, about 2 to about Ranging in size from 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.

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

[0106] In certain embodiments, the linker group L is a group comprising one or more covalently connected structural units independently selected from the group consisting of: [ka] X is O, N, S, S(O), and SO 2 selected from the group consisting of;n is an integer from 1 to 5;R L1 is hydrogen or alkyl, [ka] is a mono- or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; [ka] is mono- or bicyclic cycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; phenyl ring The 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 that is appropriate and appropriate to the chemistry of the linker, in preferred embodiments of the present disclosure, the linker independently , covalently bonded to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of the above groups being bonded on the ULM and PTM groups. may be inserted somewhere in the ubiquitin ligase to provide maximum binding of the ULM group to the ubiquitin ligase and of the PTM group to the target protein to be degraded. (Note that in certain embodiments where the PTM group is a ULM group, the target protein for degradation may be the ubiquitin ligase itself). In certain preferred embodiments, the linker may be attached to an optionally substituted alkyl, alkylene, alkene or alkyne group, aryl group or heterocyclic group on the ULM and / or PTM groups.

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

[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, comprising between 1 and about 100 ethylene glycol units, between about 1 and about 50 ethylene glycol units. ethylene glycol units, between 1 and about 25 ethylene glycol units, between about 1 and 10 ethylene glycol units, between 1 and about 8 ethylene glycol units, and between 1 and 6 ethylene glycol units optionally substituted ethylene glycol units, between 2 and 4 ethylene glycol units, or interspersed with optionally substituted O, N, S, P, or Si atoms It has an alkyl group. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, linkers can 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 comprising about 1 to about 12 ethylene glycol units, about 1 to about 10 ethylene glycol units, about 2 to about Ranging in size from 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.

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

[0113] In certain embodiments, "L" is a linear chain having from 4 to 24 linear atoms. and carbon atoms within the straight chain can be replaced by oxygen, nitrogen, amides, fluorocarbons, etc., as follows: [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" are: These 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, and the 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 PTM

[0116] In preferred aspects of the present disclosure, the PTM group is a group that binds to a target protein. Targets for PTM groups are highly diverse and are selected from proteins expressed in cells such that at least a portion of the sequence is found in cells and capable of binding to PTM groups. The term "protein" includes oligopeptide and polypeptide sequences of sufficient length that can be attached to a PTM group according to the present disclosure. Any protein of eukaryotic or microbial systems, 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 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). 1 -C 10 the haloalkane can be covalently linked 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, target protein moieties of small molecules. :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 hormones Receptor compounds, immunosuppressive compounds, and compounds that target 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 targeting 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. Also included. These binding moieties are linked to the ubiquitin ligase binding moiety, preferably via a linker, in order to present the target protein (which binds the protein target moiety) in close proximity to the ubiquitin ligase for ubiquitination and degradation.

[0118] Any protein that binds to a protein targeting moiety or PTM group and can be acted upon by a ubiquitin ligase or degraded is a target protein according to the present disclosure. In general, target proteins include, for example, structural proteins; receptors; enzymes; cell surface proteins; catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolic and catabolic), antioxidant activity, proteolysis, biosynthesis. , protein 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 (protein, lipid carbohydrate), receptor proteins involved in the integrated functions of the cell, including proteins involved in body activity, cell motility, membrane fusion, cell-to-cell communication, regulation of biological processes, development, cell differentiation, and response to stimuli; behavioral proteins; cell adhesion proteins; proteins involved in cell death; transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity; Proteins involved in pathogenesis; chaperone regulator activity; nucleic acid binding activity; transcription regulator activity; extracellular organization and biosynthetic activity; translation regulator activity may be mentioned. It can include proteins derived from living organisms, including, among others, humans as targets for drug therapy, other animals, including domestic animals, and microorganisms for determining the targets of antibiotics. , and other antimicrobials and botanicals, and even viruses.

[0119] In still other embodiments, the PTM group is a haloalkyl group, wherein the alkyl group generally ranges in size from about 1 or 2 carbons to about 12 carbons in length, and often about 2 to 10 carbons long, often about 3 carbons to about 8 carbons long, and more often about 4 carbons to about 6 carbons long. It is the length of carbon. haloal Kill groups are generally straight chain alkyl groups (although branched alkyl groups may also be used), terminated by at least one halogen group, preferably a single halogen group, often a single chloride group. It is capped. Haloalkyl PT groups for use in this disclosure preferably have the chemical structure -(CH 2 ) v -halo, where v is any integer from 2 to about 12, often from about 3 to about 8, more often from about 4 to about 6. Halo may be any halogen, but is preferably Cl or Br, more often Cl.

[0120] In another embodiment, the present disclosure provides a library of compounds. The library comprises more than one compound in which each composition has a formula A to B, where A is a ubiquitin pathway protein binding moiety (preferably as otherwise disclosed herein). (E3 ubiquitin ligase moiety such as , recognizes ubiquitin pathway proteins, specifically E3 ubiquitin ligases such as cereblon. In one specific embodiment, the library contains specific cerebron E3 ubiquitin ligase binding moieties linked to random target protein binding elements (eg, a chemical compound library). Therefore, the target protein is not determined in advance, and methods can be used to determine the activity of a putative protein binding element and its pharmacological value as a target for degradation by ubiquitin ligase.

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

[0122] In additional aspects, the description provides an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally additional A bioactive agent is provided. The therapeutic compositions can be used to modulate proteolysis in a patient or subject, e.g., an animal such as a human, and to treat or ameliorate a disease state or condition that is modulated through the degradation of proteins. In certain embodiments, therapeutic compositions as described herein result in the degradation of proteins of interest for the treatment or amelioration of diseases, such as cancer (such as prostate cancer) and Kennedy's disease. It is sometimes used as such. In certain additional embodiments, the disease is prostate cancer.

[0123] In an alternative aspect, the present disclosure provides a method for treating a medical condition or ameliorating symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide that modulates the medical condition or condition. In this regard, the method comprises administering to said patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described herein above, in a pharmaceutically acceptable carrier, additive, or excipient, and, optionally, selectively with additional bioactive agents, optionally in combination, wherein the composition is effective to treat or ameliorate the disease or disorder or symptoms thereof in the subject. . Methods according to the present disclosure may be used to treat numerous disease states or conditions, including cancer, by administering an effective amount of at least one compound described herein. The disease state or condition may be a disease caused by microbial agents or other exogenous agents, such as viruses, bacteria, fungi, protozoa, or other microorganisms; It may also be a medical condition caused by overexpression of proteins that lead to.

[0124] In another aspect, this description provides methods for determining the effects 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 conjugation to compounds according to the present disclosure and the ubiquitin ligators described below. used to describe a protein or polypeptide that is a target for degradation by enzymes. Such small molecule targeting 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. Also included. These binding moieties are connected to the CLM or ULM groups via linker groups L.

[0126] A target protein that can be bound to a protein target moiety and degraded by a ligase bound by a ubiquitin ligase binding moiety includes any protein or peptide, including fragments thereof, analogs thereof, and / or homologs thereof. It will be done. Target proteins include proteins and peptides that have any biological function or activity, such as structure, regulation, hormones, enzymes, genes, immunity, contraction, storage, transport, Examples include signal transduction. In certain embodiments, target proteins include, for example, structural proteins; receptors; enzymes; cell surface proteins; catalytic activity, aromatase activity, motor 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 (protein, lipids and carbohydrates), receptor activity, cell motility, membrane fusion, cell-to-cell communication, regulation of biological processes, and proteins involved in development, cell differentiation, and response to stimuli. Related proteins; behavioral proteins; cell adhesion proteins; proteins involved in cell death; transport (protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transport proteins involved in physical activity; pathogenesis; chaperone regulator activity; nucleic acid binding activity; transcription regulator activity; extracellular organization and biosynthetic activity; translation regulator activity. It can contain proteins derived from nuclear and prokaryotic organisms, including microorganisms, viruses, fungi, and parasites, among which humans, microorganisms, and viruses as targets for drug therapy. , fungi, and parasites, and other animals, including domestic animals, microorganisms for determining the target of antibiotics, and other antimicrobials and plants, and even viruses.

[0127] More specifically, many drug targets used in human therapeutics represent protein targets to which protein targeting moieties can be attached and incorporated into compounds according to the present disclosure. These include proteins that can be used to restore function in a large number of polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and Other partners of the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, Cyclooxidase 1, cyclooxidase 2, 5HT receptor, dopamine receptor, G protein i.e. Gq, histamine receptor, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside nucleoside phosphorylase, trypanosome GAPDH, glycogen phosphorylase, carbonic acid Dehydrases, chemokine receptors, JAWSTAT, RXR and similar, HIV1 protease, HIV1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channels, multidrug resistance (MDR), protein P-glycoprotein (and MRP ), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alphaR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspases, HCV , NS3 protease, HCVNS3RNA 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 11, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y and receptors, estrogen receptor, androgen receptor (AR), adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase , TrkA, the receptor for NGF, beta amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21neu, telomerase inhibition, cytosolic phospholipase A2 and EGF receptor tyrosine kinase. Additional protein targets include, for example, ecdysone 20-monooxygenase, GABAergic chloride channel ion channels, acetylcholinesterase, voltage sensitive sodium channel proteins, calcium release channels, and chloride channels. Additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate phosphate synthase.

[0128] Haloalkane dehalogenase enzymes are another target for specific compounds according to the present disclosure. Chloroalkane peptide binding moiety (C 1 -C 12 an alkylhalo group, often about C 2 -C 10 PCT / US2012 / 063401 filed on December 6, 2011 and published on June 14, 2012, the contents of which are incorporated herein by reference. Haloalkane dehalogenase enzymes used in fusion proteins or related diagnostic proteins may be inhibited and / or degraded as described in US Pat.

[0129] These various protein targets may be used in screens to identify compound moieties that bind to the protein, and by incorporating that moiety into compounds according to the present disclosure, the level of activity of the protein may be influenced by the end result of therapy. It can change.

[0130] The term "protein targeting moiety" or PTM refers to the term "protein targeting moiety" or PTM that binds to a target protein or other protein or polypeptide of interest and brings the protein or polypeptide into proximity to a ubiquitin ligase such that degradation of the protein or polypeptide by the ubiquitin ligase occurs. Used to describe the arrangement / presentation of small molecules. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase, among others. These include inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds that target aryl hydrocarbon receptors (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 methyltransferases. These include inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds that target aryl hydrocarbon receptors (AHR).

[0132] The compositions described below incorporate several of these types of small molecule target protein binding moieties. Here are some members. Such small molecule targeting 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. Also included. The references cited herein below are incorporated herein 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. Vallee, et al., "Tricyclic", including YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide) 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 hindrance Harmful agent:

[0136] [ka] where the linker group L or -(L-CLM) group is derivatized such that it is added, for example via a terminal amide group;

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

[0138] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is added, for example 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) with the following structure: Brough, et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J.MED.CHEM. vol: 51, pag: HSP90 inhibitors (modified) identified in 196 (2008):

[0140] [ka] where the linker group L or -(L-CLM) group is derivatized, for example, so that it is added via an amide group (at the amine or at the alkyl group on the amine);

[0141] 4. 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 with the following structure. Identified HSP90 inhibitors (modified type):

[0142] [ka] where the linker group L or -(L-CLM) is derivatized, such that it is added, for example via a butyl group; and

[0143] 5.HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetra Methyl-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. derivatized as described above).

[0144] II. Kinase and phosphatase inhibitors:

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

[0146] 1.Erlotinib derivative tyrosine kinase inhibitor: [ka] where 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] where R is derivatized, such as being a linker group L or a -(L-CLM) group attached to the pyrrole moiety;

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

[0150] [ka] where R is derivatized, such as being 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 a pyrimidine. to be derivatized;

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

[0153] [ka] where the linker group L or -(L-CLM) group is derivatized such that it is added via the terminal methyl of the sulfonylmethyl group, for example;

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

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

[0156] 7. Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the 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, In the formula, the linker group L or a-(L-CLM) group is for example i derivatized, such that it is added through 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 where the linker group L or -(L-CLM) group is derivatized, for example, so that it is attached, preferably via either an i-propyl group or a t-butyl group;

[0158] 8. Schenkel, including compounds 6TP and 0TP (derivatized) with 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-carboxamidethienopyridine 19 where the linker group L or -(L-CLM) group is derivatized such that it is added, for example 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-carboxamidethienopyridine 8 where the linker group L or -(L-CLM) group is derivatized such that it is added, for example via a terminal methyl group attached to the amide moiety;

[0159] 9. Van Eis, et al., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein, including the kinase inhibitor 07U, which has the following structure: Kinase inhibitors identified in “kinase C isozymes”, Biorg. Med. Chem. Lett.2011 Dec 15;21(24):7367-72: [ka] 2-Methyl-N-1-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine where the linker group L or -(L-CLM) group is derivatized such that it is added, for example via a secondary amine or a terminal amino group;

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

[0161] [ka] In the formula, either the linker group L or the -(L-CLM) group is, for example, a terminal hydroxyl group. derivatized, so as to be added via;

[0162] 11.Identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011) is a kinase inhibitor; Contains the kinase inhibitors XK9 and NXP (derivatized) with 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 where the linker group L or -(L-CLM) group is derivatized such that it is added, for example via a terminal hydroxyl group (XK9) or a hydrazone group (NXP);

[0164] 12. Kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazoline yl]-4(dimethylamino)-2-butenamide) (wherein the linker group L or -(L-CLM) group is derivatized such that it is attached, for example via an aliphatic amine group);

[0165] 13. 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 - derivatized, such that the (L-CLM) group is added, 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] In the formula, the linker group L or -(L-CLM) group is, for example, a methoxy group or an ether group. derivatized, as added through;

[0168] 15. 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 added, for example via a cyclopropyl group);

[0169] 16. Kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine)( derivatized, such that the linker group L or -(L-CLM) group is attached, for example via a methoxy group or a hydroxyl group);

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

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

[0172] [ka] where the linker group L or R as the -(L-CLM) group is derivatized, such that it is added, for example, via an amide group or via an aniline amine group;

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

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

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

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

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

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

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

[0180] [ka] where R is derivatized such that it is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety or an aniline amine group;

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

[0182] [ka] where R is derivatized such that it is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety or a diazole group;

[0183] 24. Kinase inhibitor crizotinib derivatized Alk inhibitor

[0184] [ka] where R is derivatized such that it is, for example, a linker group L or a -(L-CLM) group attached to a phenyl moiety or a diazole group;

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

[0186] [ka] derivatized, such that R is, for example, a linker group L or a -(L-CLM) group attached to the phenyl moiety;

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

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

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

[0190] [ka] where the linker group L or the -(L-CLM) group is derivatized, such that it is attached, for example at the indicated R;

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

[0192] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

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

[0194] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

[0195] 30. Inhibitor of tyrosine kinase ABL (derivatization)

[0196] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

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

[0198] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

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

[0200] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

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

[0202] [ka] where the linker group L or -(L-CLM) group is derivatized, such that it is attached, for example at R;

[0203] In any of the embodiments described in Sections I-XVII, where "R" refers to a 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. Vassilev, including (or in addition) the compounds Nutlin-3, Nutlin-2, and Nutlin-1 (derivatized), and all derivatives and analogues thereof, described below. 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 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 such that it is added, for example with a methoxy group or as a hydroxyl group); [ka] (wherein the linker group L or -(L-CLM) group is derivatized such that it is attached, for example with methoxy or with a hydroxyl group); [ka] (wherein the linker group L or -(L-CLM) group is derivatized such that it is added, for example, via a methoxy group or as a hydroxyl group); and

[0207] 2.trans-4-iodo4'-boranyl-chalcone [ka]

[0208] (wherein 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 that target human BET bromodomain-containing proteins:

[0210] In certain embodiments, a "PTM" can be a ligand that binds to the bromo- and extra-end (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 described below, where "R" or "linker" is, for example, a linker group L or refers to the site for addition of the -(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. Compound 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 (US Patent Application Publication No. 2015 / 0256700)

[0216] [ka]

[0217] 6. Pyrrolopyridone type (US 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] (wherein R or L or linker in each case refers to a site for the addition of, for example, a linker group L or -(L-CLM) group).

[0230] In any aspect or embodiment described herein, the claimed structural PTM may consist of a tricyclic diazepine or a tricyclic azepine as the BET / BRD4 targeting moiety (PTM-a) and has the formula Inside, the dashed line indicates the activation of the linker connection, and three possible attachment sites for the linker are defined: [ka] During the ceremony: A and B are independently an aromatic ring, a heteroaromatic ring, a 5-membered carbocycle, a 6-membered carbocycle, a 5-membered heterocycle, a 6-membered heterocycle, thiophene, pyrrole, pyrazole, pyridine, pyrimidine, pyrazine; , optionally substituted by alkyl, alkoxy, halogen, nitrile, or another aromatic or heteroaromatic ring, where A is a central azepine (Y1=C) or diazepine (Y1=N) moiety. fused; Y1, Y2, and Y3, and Y4 can be carbon, nitrogen, or oxygen to form a fused five-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 the dashed line represents a possible linker. Mark connection points. In structures PTM-aa to 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 is between the BET / BRD4 targeting moiety and the linker. Mark the connection points: [ka] [ka] [ka]

[0234] V.HDAC inhibitors:

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

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

[0237] 2. According to formula (I) of PCT WO0222577 (“DEACETYLASE INHIBITORS”) a compound defined as in which the 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:

[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 so as to refer to a site for the addition of a linker group L or -(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 so as to refer to a potential site for the addition of a linker group L or -(L-CLM) group);

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

[0245] 4.Decitarabine (derivatized) (4-amino-1-(2-deoxy-b-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (wherein the linker group L or derivatized such that a -(L-CLM) group is added, for example via either a hydroxy group or at an 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 analogues thereof having the structure and attachment to a linker as described in Dec;2(12):1350-8;

[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 can be attached to a linker group L or -(L-CLM) group (derivatized);

[0250] 3. Including, but not limited to, DHT and its derivatives and analogs, 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. Estradiol, testosterone (derivatized), and related derivatives having a structure generally as described and bonding with a linker group L or -(L-CLM) group; and

[0251] 4.Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA.2001 Jul 17;98(15):8554-9 and United States Patent No. 7,208,157. Ovarisin, fumagillin (derivatized), and derivatives and analogs thereof, having a bond with or -(L-CLM) group.

[0252] VIII. Immunosuppressive compounds:

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

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

[0255] 2. Glucocorticoids (e.g. hydrocortisone, prednisone, prednisolone, and methylprednisolone) (where the linker group L or -(L-CLM) group is derivatized such that it is attached to any hydroxyl, for example) and beclomethasone dipropionate (wherein the linker group or -(L-CLM) is derivatized, for example, so that it is attached to a propionate ester);

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

[0257] 4. Cyclosporine (wherein the linker group or the -(L-CLM) group is derivatized such that it can be attached, for example with either a butyl group);

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

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

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

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

[0262] 1. Apigenin (as outlined in Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007) derivatized in such a way that it attaches 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 such that the linker group L or -(L-CLM) is attached).

[0264] Compounds that target X.RAF receptors (kinases): [ka]

[0265] PLX4032

[0266] (derivatized, where "R" is, for example, a linker group L or -(L-CLM ) refers to the site for addition of groups).

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

[0268] In any aspect or embodiment described herein, the PTM targets and / or binds RAF (ie, a targeting 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 a combination of: 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, CH, C, N, N; C, N, C, CH, N; C, N, C, N, C; and C, N , N, N, C; X PTM35 ,X PTM36 ,X PTM37 , and X PTM38 are independently selected from CH and N; R PTM1 is covalently conjugated to a ULM, a chemical linker group (L), CLM, ILM, VLM, MLM, ULM', CLM', ILM', VLM', MLM', or a combination thereof; R PTM2 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM3 is absent or hydrogen, aryl, methyl, ethyl, other alkyl, cyclic alkyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM4 is hydrogen, halogen, aryl, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 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 include 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; RPTM5 is selected from the group consisting of: [ka] R PTM6a and R PTM6b are each independently hydrogen, halogen, or optionally substituted C 1 -C 6 selected from alkyl (straight chain, branched, optionally substituted); R PTM6 is absent or hydrogen, halogen, aryl, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM7 is absent or hydrogen, halogen, aryl, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM8 ,R PTM9 , or R PTM10 are independently absent or hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM11 is absent or hydrogen, halogen, methyl, ethyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM8 ,R PTM9 , or R PTM10 at least one of the above is covalently conjugated 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. It is modified as follows.

[0270] In certain embodiments, the PTM has 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 When is the position joined by a covalent bond, R PTM7 and R PTM8 is R PTM7 and R PTM8 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0272] In other embodiments, R PTM8 is the position joined by a covalent bond, then R PTM9 and R PTM10 is R PTM9 and R PTM10 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0273] In yet another embodiment, R PTM10 When is the position joined by a covalent bond, R PTM8 and R PTM9 is R PTM8 and R PTM9 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0274] In any aspect or embodiment described herein, the PTM may include 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 are independently absent or hydrogen, halogen, aryl, heteroaryl, cycloalkyl, heterocycle, methyl, ethyl, other alkyl, OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; R PTM20 is a small group containing less than 4 non-hydrogen atoms; R PTM21 is trifluoromethyl, chloro, bromo, fluoro, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, OCH 3 ,NHCH 3 , dimethylamino, or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, or NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl, or heterocycle; and R PTM12 ,R PTM13 , or R PTM16 at least one of the above is covalently conjugated 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. It is modified as follows.

[0275] In some embodiments, R PTM12 When is the position joined by a covalent bond, R PTM13 and R PTM14 is R PTM13 and R PTM14 and can be connected together via a covalent bond to form a bicyclic group containing a ring to which R PTM15 and R PTM16 is R PTM15 and R PTM16 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0276] In some embodiments, R PTM13 When is the position joined by a covalent bond, R PTM12 and R PTM16 is R PTM12 and R PTM16 and can be connected together via a covalent bond to form a bicyclic group containing a ring to which R PTM15 and R PTM16 is R PTM15 and R PTM16 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0277] In yet another embodiment, R PTM16 When is the position joined by a covalent bond, R PTM12 and R PTM13 is R PTM12 and R PTM13 contains a ring to which and / or R PTM13 and R PTM14 is R PTM13 and R PTM14 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0278] In any aspect or embodiment described herein, the PTM may include 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 hydrogen, halogen, or C 1 -C 6 selected from alkyl (straight chain, branched, optionally substituted); R PTM23 ,R PTM24 ,R PTM28 ,R PTM29 ,R PTM30 ,R PTM31 ,R PTM32 is, independently, absent or a bond, hydrogen, halogen, aryl (optionally substituted), heteroaryl (optionally substituted), cycloalkyl (optionally substituted), heterocycle (optionally substituted), optionally substituted), methyl, ethyl (optionally substituted), other alkyl (straight chain, branched, optionally substituted), OCH 3 ,NHCH 3 , or M1-CH 2 -CH 2 -M2, where M1 is CH 2 , O, and NH, and M2 is hydrogen, alkyl (straight chain, branched, optionally substituted), cyclic alkyl (optionally substituted), aryl (optionally substituted), or heterocycle ( optionally replaced); and R PTM25 is absent or hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), OCH3, NHCH 3 , or SCH 3 And; R PTM26 is absent or hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), OCH3, NHCH 3 , or SCH 3 And; R PTM27 is absent or hydrogen, halogen, C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), OCH 3 ,NHCH 3 , or SCH 3 selected from the group consisting of; and R PTM24 ,R PTM29 , or R PTM32 at least one of the above is covalently conjugated 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. It is modified as follows.

[0279] In some embodiments, R PTM24 When is the position joined by a covalent bond, R PTM31 and R PTM32 is R PTM31 and R PTM32 and can be connected together via a covalent bond to form a bicyclic group containing a ring to which R PTM29 and R PTM30 is R PTM29 and R PTM30 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0280] In some embodiments, R PTM29 When is the position joined by a covalent bond, R PTM24 and R PTM32 is R PTM24 and R PTM32 and can be connected together via a covalent bond to form a bicyclic group containing a ring to which R PTM31 and R PTM32 is R PTM31 and R PTM32 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0281] In yet another embodiment, R PTM32 When is the position joined by a covalent bond, R PTM24 and R PTM29 is R PTM24 and R PTM29 and can be connected together via a covalent bond to form a bicyclic group containing a ring to which R PTM29 and R PTM30 is R PTM29 and R PTM30 and can be connected together via a covalent bond to form a bicyclic group containing the ring to which it is attached.

[0282] In any aspect or embodiment described herein, the PTMs have the following chemical structures PTM-1, PTM-2, PTM-3, PTM-4, PTM-5, PTM-6, PTM-7, and Selected from the group consisting of PTM-8: [ka] [ka]

[0283] Compounds targeting XI.FKBP:

[0284] [ka]

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

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

[0287] 1. RU59063 ligand of androgen receptor (derivatization)

[0288] [ka]

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

[0290] 2. SARM ligand of androgen receptor (derivatization)

[0291] [ka]

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

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

[0294] [ka]

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

[0296] 4.MDV3100 ligand (derivatization)

[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). A variety of 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 Mention may be made of steroidal compounds such as bicalutamide, enzalutamide, and the like, some of which are mentioned above. Those skilled in the art will recognize that these androgen receptor binding compounds may potentially be used as androgen binding moieties (ABMs) within PROTAC compounds. Such references include, but are not limited to, G. F. Allan et. al, Nuclear Receptor Signaling, 2003, 1, e009; R. H. Bradbury et. al, Bioorganic & Medicinal Chemistry Letters, 2011 5442-5445; C. Guo et. al, Bioorganic & Medicinal Chemistry Letters, 2012 2572-2578; P. K. Poutiainen et. al, J. Med. Chem. 2012, 55, 6316 - 6327 A. Pepe et. al, J. Med. Chem. 2013, 56, 8280 - 8297; M. E. 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 includes a structure selected from, but not limited to, the structures shown below, where the dashed line represents a linker moiety or a ULM, such as a CLM. Mark additional points: [ka] [ka] During the ceremony: W 1 is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently containing one or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (straight chain, branched, optionally substituted; e.g., optionally one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (straight chain, branched, optionally substituted; e.g., optionally substituted by one or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 replaced by; Y 1 ,Y 2 are each independently NR Y1 ,O,S; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, C=S, SO, SO 2 , heteroaryl, or aryl; Q is optionally 0 to 6 R Q is a 3- to 6-membered ring having 0 to 4 heteroatoms substituted by, each R Q But independently, H, C 1-6 Alkyl (straight chain, branched, optionally substituted, e.g., optionally halo, C 1-6 substituted by alkoxyl), halogen, C 1-6 Alkoxy or 2 R Q the groups together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); R 1 ,R 2 ,R a ,R b ,R Y1 ,R Y2 are independently H, C 1-6 Alkyl (straight chain, branched, optionally substituted; e.g., optionally one or more halo, C 1-6 substituted by alkoxyl), halogen, C 1-6 is alkoxy, cyclic, heterocyclic, or R 1 ,R 2 together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); W 2 is a combination, C 1-6 Alkyl, C 1-6 heteroalkyl, O, aryl, heteroaryl, cycloaliphatic, heterocycle, biheterocycle, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 replaced by; Each R W2 are independently H, halo, C 1-6 Alkyl (straight chain, 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), heterocycle (optionally substituted), aryl (optionally substituted) or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC 1-3 Alkyl (optionally substituted), OH, NH 2 ,NR Y1 R Y2 , CN; and R W2A H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (straight chain, branched), each optionally cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC 1-3 Substituted by alkyl.

[0306] In any aspect or embodiment described herein, W 2 is covalently conjugated 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, CF 3 , 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, where: [ka] indicates the linker or ULM attachment point: [ka] During the ceremony: R Q2 is H, halogen, CH 3 , or CF 3 And; R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (straight chain, branched, optionally substituted with one or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 And; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, heteroaryl, or aryl; R Y1 ,R Y2 are each independently H or C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 alkoxyl, cyclic or heterocyclic); and R Q are independently H, C 1 -C 6 Alkyl (straight chain, branched, optionally one or more halo, or C 1-6 (substituted by alkoxyl) or two RQ together with the atoms to which they are attached form a 3- to 8-membered ring system containing 0 to 2 heteroatoms.

[0310] In any aspect or embodiment described herein, each R Q are independently H or CH 3 It is. In another embodiment, R Q3 is CN.

[0311] In any aspect or embodiment described herein, the ABM includes the following structures set forth below: including a structure selected from the formula: [ka] indicates the linker or ULM attachment point: [ka] During the ceremony: R Q2 is H, halogen, CN, CH 3 , or CF 3 is; and R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (straight chain, branched, optionally substituted with one or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 And; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, heteroaryl, or aryl; and R Y1 ,R Y2 are each independently H or C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 alkoxyl, 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 linker moiety or point of attachment of the 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, C 1 -C 6 Alkyl (straight chain, branched, optionally substituted), C 1 -C 6 Alkoxy, or -CF 3 And; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C 1 -C 6 heteroaryl, or C 1 -C 6 is aryl; R 1 ,R 2 are each independently H or C 1 -C 6 Alkyl (straight chain or branched, optionally substituted; for example, optionally one or more halo, or C 1-6 substituted by alkoxyl); W 2 is a combination, C 1-6 Aryl, C 1 - 6 heteroaryl, C 1-6 Alicyclic, or C 1 - 6 heterocycle, biheterocycle, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 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 conjugated 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 marks the linker moiety or point of attachment of the ULM. death: [ka] During the ceremony: W 1 teeth, [ka] And; Each R 22 are independently H or -CN; Each R 23 is independently H, halo, or -CF 3 And; 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 combination, C 1-6 aryl, or heteroaryl, each optionally containing 1, 2, or 3 R W2 replaced by; and Each R W2 are independently H, halo, 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 2 is covalently conjugated 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] In any aspect or embodiment described herein, the ABM is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] .

[0322] In any aspect or embodiment described herein, the ABM includes the following structure: [ka] During the ceremony: W 1 is aryl or heteroaryl, each independently containing one or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (straight chain, branched, optionally substituted by one or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 replaced by; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, C=S, SO, SO 2 , heteroaryl, or aryl; Q is a 4-membered cycloaliphatic or aromatic ring with 0 to 2 heteroatoms, optionally 0 to 6 R Q and each R Q But independently H, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 (substituted by alkoxyl) or 2 R Q the groups together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); R Y1 ,R Y2 are independently H and C 1-6 Alkyl (straight chain, branched, optional one or more halos, C 1-6 substituted by alkoxyl); and W 2 is a combination, C 1-6 Alkyl, C 1-6 heteroalkyl, O, C 1-6 cycloaliphatic, heterocycle, aryl, biheterocycle, biaryl or biheteroaryl, or heteroaryl, each optionally containing 1, 2, or 3 R W2 ; and Each R W2 are independently H, halo, C 1-6 Alkyl (straight chain, branched, optionally substituted with one or more F), C 1-6 heteroalkyl (straight chain, 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), Heterocycle (optionally substituted), Aryl (optionally substituted), Heteroaryl (optionally substituted), Bicyclic Heteoaryl (optionally substituted) ), bicyclic aryl, OH, NH 2 ,NR Y1 R Y2 , or CN; and R W2A H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (straight chain, branched), each optionally 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 is aryl, heteroaryl, bicyclic, or biheterocyclic, each independently containing one or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 substituted by alkoxyl), C 1-6 Alkoxyl (straight chain, branched, optionally substituted by one or more halo), C 2-6 alkenyl, C 2-6 alkynyl, or CF 3 replaced by; Y 1 ,Y 2 are each independently NR Y1 , O, or S; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, C=S, SO, SO 2 , heteroaryl, or aryl; Q is a 3-6 membered cycloaliphatic or aromatic ring having 0-4 heteroatoms, optionally 0-6 R Q and each R Q But independently H, C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 (substituted by alkoxyl) or 2 R Q the groups together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); R 1 ,R 2 ,R a ,R b ,R Y1 ,R Y2 are independently H and C 1-6 Alkyl (straight chain, branched, optionally one or more halo, C 1-6 substituted by alkoxyl) or R 1 ,R 2 together with their attached atoms form a 3- to 8-membered ring system containing 0 to 2 heteroatoms); W 2 is a combination, C 1-6 Alkyl, C 1-6 heteroalkyl, O, C 1-6 cycloaliphatic, heterocycle, aryl, biheterocycle, biaryl or biheteroaryl, or heteroaryl, each optionally containing 1, 2, or 3 R W2 ; replaced by; Each R W2 are independently H, halo, C 1-6 Alkyl (straight chain, branched, optionally one or replaced by multiple F), C 1-6 heteroalkyl (straight chain, 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), heterocycle (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, N.H. 2 ,NR Y1 R Y2 , CN; and R W2A H, C 1-6 Alkyl (straight chain, branched), or C 1-6 heteroalkyl (straight chain, branched), each optionally cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC 1-3 Substituted by alkyl.

[0324] 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 is independently H, halo, or -CF 3 And; Y 3 is a bond or O; Q is optionally 0 to 4 R Q is a 4-membered ring substituted by 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, C1-6 aryl or heteroaryl, each optionally containing 1, 2, or 3 R W2 and each R W2 is independently H, halo, a 6-membered cycloaliphatic ring with 1 or 2 heteroatoms, or a 5-membered aromatic ring with 1 or 2 or 3 heteroatoms It is.

[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 conjugated 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] In any aspect or embodiment described herein, the androgen binding moiety has the following structure: [ka] During the ceremony: W 1 is aryl independently substituted by one or more halo, CN; Y 3 are each independently combined, NR Y2 ,CR Y1 R Y2 , C=O; Q is a 5-membered aromatic ring with 1 or 2 heteroatoms; R Y1 ,R Y2 are independently H, C 1-6 Alkyl (straight chain, branched); W 2 is a bond, aryl, or heteroaryl, each optionally containing 1, 2, or 3 R W2 replaced by; and Each R W2 are independently H, halo, 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 conjugated 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 is independently halo or CN; and Each R 23 is 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] It is.

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

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

[0335] In any aspect or embodiment described herein, the ABM includes a structure selected from, but not limited to, the structures shown below, where the dashed line represents a linker moiety or a ULM, such as a CLM. Mark additional points: [ka] During the ceremony: W 1 teeth, [ka] And; Each R 22 are independently H or -CN; Each R 23 is independently H, halo, or -CF 3 And; Y 1 ,Y 2 are each independently O or S; Y 3 ,Y 4 ,Y 5 are each independently combined, O, NR Y2 ,CR Y1 R Y2 , C=O, C=S, SO, or SO 2 And; R 1 ,R 2 are each independently H or a methyl group; W 2 is a combination, C 1-6 aryl, or heteroaryl, each optionally containing 1, 2, or 3 R W2 replaced by; and Each R W2 are independently H, halo, 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 conjugated 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 linker moiety or point of attachment of the ULM or CLM: [ka] During the ceremony: W 1 teeth, [ka] And; Each R 22 are independently H or -CN; Each R 23 is independently H, halo, or -CF 3 And; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C 1 -C 6 heteroaryl, or C 1 -C 6 is aryl; R 1 ,R 2 are each independently H or C 1 -C 6 Alkyl (straight or branched, optionally one or more halo, or C 1-6 substituted by alkoxyl); W 2 is a combination, C 1-6 Aryl, C 1 - 6 heteroaryl, C 1-6 Alicyclic, or C 1 - 6a heterocycle, each optionally containing 1 to 10 R W2 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 conjugated 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 ABM androgen receptor binding compound 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 that targets the estrogen receptor (ER)

[0346] 1. Estrogen receptor ligand

[0347] [ka]

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

[0349] In any embodiment or aspect described herein, 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 independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, where R PTM is an alkyl or aryl group in the above ester; at least one R PTM2 and each independently H, OH, halogen, CN, CF 3 ,S.O. 2 -alkyl, O-lower alkyl; at least one R PTM3 each independently selected from H, halogen; and The dashed line marks the site of addition of at least one linker, CLM, CLM', PTM, PTM', or combinations thereof.

[0350] In any embodiment or aspect described herein, 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 independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, where R PTM is an alkyl or aryl group in the above ester; Each R PTM2 are independently H, OH, halogen, CN, CF 3 ,S.O. 2 -alkyl, O-lower alkyl; Each R PTM3 are independently selected from H, halogen; PTM-I is at least R PTM2 , at least one R PTM3 , or a combination thereof in each ring; and The dashed line marks the site of addition of at least one linker, CLM, CLM', PTM, PTM', or combinations thereof.

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

[0352] In any embodiment or aspect described herein, 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 independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, where R PTM is an alkyl or aryl group in the above ester; R PTM2 and R PTM4 are independently H, OH, halogen, CN, CF 3 ,S.O. 2 -alkyl, O-lower alkyl; R PTM3 and R PTM5 are independently selected from H, halogen; and The dashed line marks the site of addition of at least one linker, CLM, CLM', PTM, PTM', or combinations 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, 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 formula (I PTM ) compounds or PTMs: [ka] Formula (I PMT ) During the ceremony: each X PTM are independently CH, N; [ka] indicates the site of addition of at least one of a linker, CLM, CLM', PTM, PTM', or combinations 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 aryl groups, and the substitution can be mono-, di-, or tri-substituted; Each R PTM2 are independently H, halogen, CN, CF 3 , alkoxy and the substitutions can be mono- or di-substituted; and Each R PTM3 are independently H, halogen, and the substitutions can be mono- or di-substituted.

[0356] In any aspect or embodiment described herein, the PTM is of formula (II PTM ) is represented by: [ka] Formula (II PMT ) During the ceremony: X PTM is CH,N; [ka] indicates the site of addition of at least one of a linker, CLM, CLM', PTM, PTM', ULM, ILM, VLM, MLM, ULM', ILM', VLM', MLM', or a combination thereof; Each R PTM1 are independently OH, halogen (e.g. F); Each R PTM2 are independently H, halogen (e.g. F), CF 3 and the substitutions can be mono- or di-substituted; and Each R PTM3 are independently halogen (eg F) and the substitutions can be mono- or di-substituted.

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

[0358] XIV. Compounds that target thyroid hormone receptors (TR)

[0359] 1.Thyroid hormone receptor ligand (derivatization)

[0360] [ka]

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

[0362] XV. Compounds that target HIV protease

[0363] 1. Inhibitor of HIV protease (derivatization)

[0364] [ka]

[0365] (derivatized, where "R" refers to the site for the addition 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 the addition 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. Inhibitor of HIV integrase (derivatization)

[0371] [ka]

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

[0373] 2. Inhibitor of HIV integrase (derivatization)

[0374] [ka]

[0375] 3. HIV integrase inhibitor Icentres (derivatization)

[0376] [ka]

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

[0378] XVII.Compounds that target HCV protease

[0379] 1.HCV protease inhibitor (derivatization)

[0380] [ka]

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

[0382] XVIII. Compounds targeting acyl-protein thioesterases-1 and -2 (APT1 and APT2)

[0383] 1. Inhibitors of APT1 and APT2 (derivatization)

[0384] [ka]

[0385] (derivatized, where "R" refers to the site for the addition of a linker group L or -(L-CLM) group). See Angew. Chem. Int. Ed. 2011, 50, 9838 -9842 In this document, L is a linker group, as otherwise described herein, and the CLM group is defined as -(L-CLM), which links the CLM group to PTM, as otherwise described herein. such as attached to a group as otherwise described herein.

[0386] Compounds that target VIV.Tau protein

[0387] In any aspect or embodiment described herein, the PTM may include a Tau protein binding moiety. For example, a PTM can 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 an optionally substituted 5- or 6-membered aryl or heteroaryl ring, an optionally substituted 4- or 7-membered selected from cycloalkyl or heterocycloalkyl, where contacts between the circles indicate fusion of the rings; 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 -O -, -S-, -NR 1 PTM -(In the formula, R 1 PTM is selected from H or alkyl), -N=N-, -S(O)-, -SO 2 -, -C(O)-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -NHC(O)NH-, -NHC(O)O-, or -OC(O)NH-, wherein the functional group is optionally nirin 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 the PTM are optionally substituted with 1 to 3 substituents. and each substituent is independently selected from alkyl, alkenyl, haloalkyl, halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, where said alkyl Groups 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 an optionally substituted 5- or 6-membered aryl ring. or a heteroaryl ring;

[0390] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula I, where: Ring A, Ring B, and Ring 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 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 the chemical structure of Formula I, where: A and C are phenyl or a 6-membered heteroaryl ring; B is a 5-membered heteroaryl ring; L PTM is a combination; and D is a 6-membered heteroaryl ring or a 6-membered heterocycloalkyl ring; wherein each of A, B, C, and D is optionally and independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano; , B, C, and D rings are not directly connected to a heteroatom or a carbon atom to which another heteroatom is directly attached.

[0392] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula III or IV, where A, B, and C are a 5- or 6-membered fused aryl ring or a hetero is an aryl ring, and L PTM is selected from a bond or alkyl, and D and E are a 5- or 6-membered fused aryl or heteroaryl ring, where A, B, C, D, and E are optionally Substituted by 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 are independently selected from H, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trifluoroethyl; R 4 and R 5 are independently selected from H, methyl, ethyl, and halogen; and R 6 are 1 to 2 substituents independently selected from H, methyl, ethyl, and halogen; where PTM is coupled to ULM via L.

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

[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 are 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 is 1 to 8 substituents, independently from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, aceylamino, trifluoromethyl, or cyano selected, where the PTM is connected 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 a dotted line: [ka]

[0398] therapeutic compounds

[0399] A combination of an effective amount of at least one bifunctional compound described herein and one or more other compounds described herein, all in an effective amount, a pharmaceutically effective amount of a carrier, an excipient, or in combination with excipients represent yet another aspect of the disclosure.

[0400] The present disclosure includes compositions that, where available, include pharmaceutically acceptable salts, particularly acid addition salts or base addition salts of the compounds described herein. The acids used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned base compounds useful according to this embodiment include non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions. Such salts include, among others, hydrochlorides, hydroiodides, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, acetates, lactates, Citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate gluconate, saccharinate, benzoate, methanesulfonate, ethanesulfonate, benzene sulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salt].

[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. The claimed compound is acidic in nature Chemical bases that can be used as reagents to prepare pharmaceutically acceptable basic salts of are those that form non-toxic basic salts with such compounds. Such non-toxic basic salts include, but are not limited to, those derived from such pharmaceutically acceptable cations, such as, for example, 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 alkanol ammonium and pharmaceutically acceptable Other basic salts of organic amines.

[0402] The compounds described herein can be administered by oral, parenteral, or topical routes in single or divided doses in accordance with the present disclosure. Administration of the active compound can range from continuous administration (intravenous infusion) to multiple oral administrations per day (e.g. Q.I.D.), including oral, topical, parenteral, intramuscular administration, among other routes of administration. Administration may include intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, sublingual, and suppository administration. Enteric-coated oral tablets may also be used to enhance the bioavailability of compounds from the oral route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent chosen as well as the severity of the patient's disease. Administration of compounds according to the present disclosure as a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration may also be used. As such, 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 excipient. Compounds according to the present disclosure may be administered in immediate release, intermediate release, or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but also in suppositories and transdermally or other topical forms. Intramuscular injection in liposomal form may also be used to control or sustain the release of the compound at the site of injection.

[0403] The compositions described herein may be formulated in conventional manner using one or more pharmaceutically acceptable carriers and may be administered in a controlled release formulation. Pharmaceutically acceptable carriers that may 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, buffers such as phosphate, etc. substances, 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, etc. , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0404] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. can be administered. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or Includes injection techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

[0405] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing 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 employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-irritating non-volatile oils may be utilized including synthetic mono- 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 may also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[0406] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, etc. Examples include suspensions and solutions. In the case of 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 suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring, or coloring agents may also be added, if desired.

[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, which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum. and release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

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

[0409] For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component 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 compound, emulsifying wax, and water. In certain preferred embodiments of the invention, the compound is coated onto a stent that is surgically implanted within a patient to inhibit or reduce the potential for occlusion of the stent within the patient. Good too.

[0410] Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

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

[0412] Pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, etc. It may be prepared as a solution in saline employing Bone and / or other conventional solubilizing or dispersing agents.

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

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

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

[0416] These compounds can be administered by any suitable route, e.g., orally, parenterally, intravenously, intradermally, subcutaneously, or topically, e.g., transdermally, as a liquid, cream, gel, or It can be administered in solid form or by aerosol form.

[0417] The active compound is present in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the indication without causing serious toxic effects in the patient being treated. included. Suitable doses of active compound for all conditions described herein are about 10 ng / kg to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, and more generally the weight of the recipient / patient per day. It ranges from 0.5 to about 25 mg per kilogram. 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, less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. Examples include those containing. Oral dosages of about 25 to 250 mg are convenient in many cases.

[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 aqueous media, or the active ingredient may be administered as a bolus. Oral administration is also suitable to produce effective plasma concentrations of the active agent.

[0420] The concentration of active compound in the drug composition will depend on the absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It is noted that dosage values ​​will also vary depending on the severity of the condition being alleviated. For any particular subject, the specific dosing 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. It should be noted that the concentration ranges and concentration ranges set forth herein are exemplary only and do not exceed the scope of the claimed compositions. It will be further understood that they are not intended to limit scope or practice. The active ingredient may be administered immediately or may be divided into a number of smaller doses and administered at various time intervals.

[0421] Oral compositions will 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 prodrug derivative thereof, can be incorporated into tablets, troches, or capsules with excipients. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition.

[0422] Tablets, pills, capsules, troches and the like may contain any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; Dispersants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate or Stelotes; lubricants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or fragrances. agents, such as peppermint, methyl salicylate, or orange scent. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Additionally, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as coatings with sugar, shellac, or enteric agents.

[0423] The active compound or its pharmaceutically acceptable salt can be administered as a component of elixirs, suspensions, syrups, wafers, chewing gums, and the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[0424] The active compound or a pharmaceutically acceptable salt thereof may also be combined with other active agents that do not impair the desired action or with materials that supplement the desired action, such as erythropoietin stimulators, including EPO and darbapoietin alfa, among others. It can also be mixed with other agents. In certain preferred embodiments of the invention, one or more compounds according to the present disclosure are combined with another bioactive agent, such as an erythropoietin stimulant or an antibiotic, as otherwise described herein. It is co-administered with trauma healing agents.

[0425] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: sterile diluents such as water for injection, saline solutions, non-volatile such as oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibiotics, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers agents, such as acetate, citrate, or phosphate, 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] When administered intravenously, a suitable carrier is physiological saline or phosphate buffered saline (PBS).

[0427] In one embodiment, the active compound is prepared with a carrier that will protect the compound against rapid elimination from the body, such as, for example, controlled release formulations, including implants and microencapsulated delivery systems. be. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters Tel, 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 may be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811, incorporated herein by reference in its entirety. For example, liposomal formulations can be dissolved in suitable lipids (such as stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, aracadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, and the lipids are then evaporated to form a dry lipid on the surface of the container. may be prepared by leaving a thin film of Then, an aqueous solution of the active compound is introduced into the container. The container is then manually swirled to peel the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0429] Method of treatment

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

[0431] As used herein, the terms "treat," "treating," "treatment," and the like refer to any action that benefits a patient to whom a Compound can be administered, Includes treatment of any disease state or condition that is modulated through proteins. Disease conditions or conditions, including cancer, that can be treated using compounds according to the present disclosure are described herein above.

[0432] The present description provides therapeutic compositions as described herein for causing the degradation of proteins of interest for the treatment or amelioration of diseases, such as cancer. In certain additional embodiments, the disease is multiple myeloma. Thus, in yet another aspect, the present description provides a method for ubiquitination / degradation of a target protein in a cell. In certain embodiments, the method comprises bifunctional as described herein, e.g., comprising a CLM and a PTM, preferably linked via a linker moiety as otherwise described herein. wherein the CLM is linked to a 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. , thereby causing degradation of the target protein to occur when the target protein is placed in the vicinity of the ubiquitin ligase, thus resulting in degradation / inhibition of the action of the target protein and suppression of protein levels. Suppression of this protein level provided by the present disclosure reduces the level of the target protein in a cell, such as a patient's cells, thereby providing treatment for a disease state or condition modulated through the protein. In certain embodiments, the method comprises an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof. of the compound.

[0433] In an additional aspect, the present description provides a method for treating or ameliorating a disease, disorder, or symptoms thereof in a subject or patient, e.g., an animal such as a human, the method comprising administering an effective amount, e.g. A composition comprising an 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 symptoms thereof in the subject. be.

[0434] In another aspect, this description provides methods for determining the effects 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 modulating a disease state or condition via a protein, where degradation of the protein is what provides a therapeutic effect in the patient. , the method comprises administering to a patient in need thereof 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 microbial agents or other exogenous agents, such as viruses, bacteria, fungi, protozoa, or other microorganisms; It may also be a medical condition caused by overexpression of proteins that lead to.

[0436] The term "medical condition or condition" is defined as a disease in which protein dysregulation (i.e., the amount of protein expressed in the patient is elevated) occurs and the degradation of one or more proteins in the patient requires it. Used to describe any medical condition or condition that may result in beneficial therapy or symptom relief. In certain cases, a medical condition or condition may be cured.

[0437] Conditions that may be treated with compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathy, cleft palate, diabetes, heart disease, hypertension, inflammatory diseases, etc. Bowel disease, mental retardation, mood disorders, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia , Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease (PKD1) or 4 (PKD2), Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, and Turner syndrome. .

[0438] Additional medical conditions or conditions that may be treated by compounds according to the present disclosure include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, Deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, diabetes type 1, diabetes type 2, epilepsy, Guillain-Barre 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, occlusive thrombotic blood vessels inflammation, Tourette's syndrome, and vasculitis.

[0439] Additional disease states or conditions that can be treated by compounds according to the present disclosure include aceruloplasminemia, achondroplasia type 2, achondroplasia, acanthosis, Gaucher disease type 2, acute intermittent porphyria, canavan. disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric tissue brown discoloration, alpha-1-antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, hereditary enamel hypoplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, diffuse truncal angular angiomatous anemia, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnidactyly (Marfan syndrome), Stickler syndrome, congenital multiplex joint laxity (Ehlers-Danlos syndrome joint laxity type), ataxia telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson circular scalp syndrome, family Mediterranean fever, Benjamin syndrome, Beta thalassemia, bilateral acoustic neuroma (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (dyschromatosis), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bonneville disease (tuberous sclerosis), prion disease, Bert-Hogg-Dubé syndrome, brittle bone disease (osteogenesis imperfecta), broad big toe syndrome (Rubinstein-Taibi syndrome), bronze color diabetes / bronze liver cirrhosis (hemochromatosis), spinal and bulbar muscular atrophy (Kennedy's disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disorder, flexural limb dysplasia, biotinase deficiency, Cardiomyopathy (Noonan syndrome), cat noise disorder, CAVD (congenital vas deferens defect), Keiler cardiofacial syndrome (CBAVD), CEP (congenital hematopoietic porphyria), cystic fibrosis, congenital hypothyroidism, cartilage Dysplastic syndrome (achondroplasia), autosomal dominant otospinal macroepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, fatal osteodysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (familial adenomatous polyposis), congenital hematopoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease , conus arteriosus abnormal facial syndrome, Cooley anemia (beta thalassemia), copper storage disease (Wilson disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormality (Crouzon syndrome) , Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson circumvertebral scalp syndrome, primary hyperoxaluria, vertebral epiphyses Neurodegenerative diseases, developmental disorders, and distal spinal muscular atrophy, including metaphyseal dysplasia (Strudwick type), Duchenne and Becker type muscular dystrophy (DBMD), Usher syndrome, de Grouchy syndrome and Dejerin-Sottas syndrome type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protosyndrome Porphyria, erythroid 5-aminolevulin synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, late onset porphyria cutanea, familial pressure-fragile neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, genetic brain disorder, giant cell hepatitis (neonatal hemochromatosis), Glenblatt ·Strandberg syndrome (pseudoxanthoma elasticum), Gunter's disease (congenital hematopoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatomyeloid porphyria (HEP), Hippel ·Immunology including Lindow syndrome (von Hippel-Lindau disease), Huntington's disease, Hutchison-Gilford premature aging syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, and X-linked severe combined immunodeficiency system disorders, Inslee-Astley syndrome, Kennedy syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney disease including hyperoxaluria, Klinefelter syndrome, Kniest osteodysplasia, Metabolic disorders including lacunar infarct dementia, Langer-Sardino chondroplasia, ataxia telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, Kniest osteodysplasia, Marfan syndrome , movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Munke syndrome, multiple neurofibromatosis, Nance-Inslee syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Landue disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous osteodysplasia (McKeown-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 premature aging syndrome), chronic hereditary (Huntington's) progression Sexual chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PXE (elastic fibrous pseudoyellow) tumor), Rb (retinoblastoma), Klinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinopathy, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Levy syndrome, developmental delay and melanoma severe achondroplasia with acanthosis (SADDAN), Li-Fraumeni syndrome and its associated breast sarcoma, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, congenital SED (congenital Strudwick type SED (spondyloepiphyseal dysplasia congenital), Strudwick type SED (spondyloepiphyseal dysplasia congenital), Strudwick type SEMD (spondyloepiphyseal dysplasia congenital), Strudwick type), Sprinzen syndrome, skin pigment disorder, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (atypical porphyria), infantile-onset ascending hereditary spastic paralysis, speech communication disorder, sphingolipidosis, T.I. Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta thalassemia, thyroid disease, sausage-like neuropathy (hereditary pressure-fragile neuropathy), Torcher-Collins syndrome, triplo-X syndrome ( triple These include Fredelius syndrome, Weisenbacher-Zweimuller syndrome, Wolff-Hirschhorn syndrome, Wolff periodic disease, Weisenbacher-Zweimuller syndrome, and xeroderma pigmentosum.

[0440] The term "neoplasty" or "cancer" refers to the formation and growth of cancerous or malignant new tissue, i.e. cells that grow faster than normal, often due to cell proliferation, and when the stimulus that started the new growth has ceased. Used throughout this specification to refer to a pathological process that results in abnormal tissue that continues to grow. Malignant neotissue formations exhibit a partial or complete loss of structural organization and functional coordination with normal tissue, often invade surrounding tissues, metastasize to multiple sites, and attempt removal. It is likely to recur later and cause death of the patient unless properly treated. As used herein, the term neoplasia is used to describe all cancerous pathologies, including pathological conditions associated with malignant hematopoietic tumors, ascites tumors, and solid tumors. involves or involves a process. Exemplary cancers that may be treated by the compounds, 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. , cancers of the bladder, large intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphoma, specifically Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, stellate Cytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pinealocytoma, meningioma, meningosarcoma, Sarcomas, including neurofibromas and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, Includes esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colorectal cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms tumor, and teroblastoma. Additional cancers that can be treated with 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 These include 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 agent is used to effect the therapy, inhibition and / or prevention / prophylaxis for which the present compound is used. It is used in combination with the compounds of the present application as a biologically active agent to aid in the development of biologically active agents. Bioactive agents suitable for use herein include the compounds used or Agents that have the same pharmacological activity when administered include, for example, anticancer agents, antiviral agents, especially anti-HIV and anti-HCV agents, antimicrobial agents, antifungal agents, and the like.

[0442] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that can be combined with a compound according to the present disclosure to treat cancer. These agents include, for example, 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 inhibitor, VEGFR inhibitor, EGFR TK inhibitor, Aurora Kinase inhibitor agent, PIK-1 modulator, Bcl-2 inhibitor, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, EGFR TK inhibitor, IGFR-TK inhibitor, anti-HGF antibody, PI3 kinase inhibitor , 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, nolatrexide, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmirifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM- 601, ALT-110, BIO140, CC8490, Cilengitide, Jaimatecan, IL13-PE38QQR, INO1001, IPdR 1 , KRX-0402, KRX-0402, KRX-0402, Luconon, Ly317615, Neiladiab, Vites, RTA744, SDX102, Taran panel, Attra Center, XR311, Lomi Depsine, ADS-100380, Snichinib, 5-Fluorowlasil, Volinostat, Genushita, Genushita Bin, Doxorbicin, Liposome Doxorbicin, 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, retro 3-[5-(methylsulfonylpiperazinemethyl)-indolyl]-quinolone, vatalanib, AG- 013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelinpamate, 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, Suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, Rafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone , cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, Mechlorethamine, melphala 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, deoxycohol Mycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, lazoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, Angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimibe, paclitaxel, paclitaxel without cremophor, docetaxel, epithilon B, BMS-247550, BMS-310705, Droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584 , VX-745, PD184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Waltman Nin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a , pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megest role, 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 antagonist, Palonosetron, Aprepitant, Diphenhydramine, Hydroxyzine, Metoclopramide, Lorazepam, Alprazolam, Haloperidol, Droperidol, Dronabinol, Dexamethasone, Methylprednisolone, Prochlorperazine, Included are 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, and fusion inhibitors; exemplary compounds thereof include, among others, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine). , abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (stavudine), lacivir, L-FddC, L-FD4C, NVP (nevirapine), DLV (delavirdine), EFV (efavirenz) ), fusion inhibition of SQVM (saquinavir mesinate), RTV (ritonavir), IDV (indinavir), SQV (saquinavir), NFV (nelfinavir), APV (amprenavir), LPV (lopinavir), T20, etc. 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 nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothamide), 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 (alkenyldiarylmethane 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)methylsulfonylamide]-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-indoyli)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-546), 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), Inophyllum P, L-737, 126, Michelamine A (NSC650898), Michelamine B (NSC649324) ), Michelamine 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-dithiol-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-fluorophenethyl) Furanyl)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(pipridine-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 (Robiride), 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, tibirapine (R86183), UC-38 and UC-84.

[0445] The term "pharmaceutically acceptable salt" is used to increase the solubility of the compound in the gastric fluids of the gastrointestinal tract of the patient, where applicable, to promote dissolution and bioavailability of the compound. is used throughout this specification to describe one or more salt forms of the compounds described herein that exist in. 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 neutralizing salts of phosphoric acid according to the present disclosure.

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

[0447] General synthesis approach

[0448] Synthetic realization and optimization of the bifunctional molecules described herein can be approached stepwise or modularly. For example, identification of compounds that bind to a target molecule may involve high-throughput or moderate-throughput screening operations when suitable ligands are not readily available. Starting ligands require iterative design and optimization cycles to improve sub-optimal aspects as identified by appropriate in vitro pharmacological and / or ADMET assay data. is not uncommon. Part of the optimization / SAR action will be probing ligand positions, which are amenable to substitution and may be suitable places to add linker chemistries already mentioned herein. If crystallographic or NMR structural data are available, these can be used to focus such synthetic efforts.

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

[0450] With PTMs and ULMs (eg, CLMs) at their disposal, those skilled 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 flexibilities and can be functionalized such that PTM and ULM groups can be sequentially added to the distal end of the linker. I can do it. Therefore, libraries of bifunctional molecules can be used both in vitro and in vitro. Can be implemented and profiled in vivo pharmacological and ADMET / PK studies. The final bifunctional molecule, as well as the 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 Boc 2 O, di-tert-butyl decarbonate BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BPO:benzoyl peroxide Cbz:carbonylbenzyloxy CDCl 3 , deuterated chloroform CD3OD, deuterated methanol CH 3 CN, acetonitrile CH 3 OH, methanol CsF, cesium fluoride Cs 2 C.O. 3 , cesium carbonate Cu(OAc) 2 , copper(II) acetate Cy 2 NMe, dicyclohexylmethylamine DAST: Diethylamino sulfur trifluoride DBE:1,2-dibromoethane DCM: dichloromethane DEAD:Diethyl azodicarboxylate DIAD: Diisopropylazodicarboxylate DIBAL: dithiobutylaluminum hydride DIEA or DIPEA: diisopropylethylamine DMA:N,N-dimethylacetamide DMAP, N,N-dimethylaminopyridine DMF:N,N-dimethylformamide DMP:Des Martin Periodinan DMSO, dimethyl sulfoxide DMSO-d 6 , hexadeuterated dimethyl sulfoxide EA: Ethyl acetate EDCI:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et 2 NH, diethylamine EtOAc or EA, ethyl acetate HCl, hydrochloric acid H 2 O, water HBTU:N,N,N’N’-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HMDS:Bis9trimethylsilyl)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 M.W: Microwave N 2 ,nitrogen NaH, sodium hydride NaBH 3 CN, sodium cyanoborohydride NaBH(OAc) 3 , sodium triacetate borohydride NaCl, sodium chloride NaHCO 3 , sodium bicarbonate NaI, sodium iodide Na 2 S.O. 4 , sodium sulfate NBS:N-bromosuccinimide n-BuLi, n-butyllithium N.H. 3 ,ammonia N.H. 4 Cl, ammonium chloride N.H. 2 OH . HCl, hydroxylamine hydrochloride NMP, N-methylpyrrolidone NMR, nuclear magnetic resonance O 2 ,oxygen PCC: Pyridinium chlorochromate Pd-118 or Pd(dtpf)Cl 2 :1,1’-bis(di-tert-butylphosphino)ferrocene dichloropalladium Pd(aMPhos)Cl 2 , bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd 2 (dba) 3 :Tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl 2 :1,1’-bis(diphenylphosphino)ferrocene dichloropalladium Pd(dba) 2 :Bis(dibenzylideneacetone)palladium Pd(OH) 2 , palladium hydroxide Pd(PPh 3 ) 4 , tetrakis(triphenylphosphine)palladium(0) PE, petroleum ether Ph 3 P, 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 liquid chromatography TBAF, tetra-n-butylammonium fluoride TBDPSCl, tert-butyldiphenylsilyl chloride TBS, tert-butyldimethylsilyl tBuOK, potassium tert-butoxide [tBu 3 PH]BF 4 , 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, trimethylsilyltrifluoromethanesulfonate 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(pentamethylcyclopentadienyl rhodium 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 describe routes used to prepare CRBN ligands and CRBN ligands with attached 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- depicting routes used to prepare representative chimeric compounds claimed herein. 13, A-14, A-15, A-16, and A-17.

[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-tetrahydronaphthalene) -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 eq.) in dichloromethane (50 mL) was added a solution of dimethyl sulfoxide (5.61 g, 72 mmol, 4.00 eq.) in dichloromethane (10 mL) at -70 °C over 30 min, and then , 5-bromopentan-1-ol (3.00g, 18mmol, 1.00eq) was added below -60°C. The resulting mixture was stirred at -70°C for 1 hour. Thin layer chromatography (petroleum ether:ethyl acetate=10:1) showed the reaction was complete. Triethylamine (14.54g, 144mmol, 20mL, 8.00eq) 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 x 3). The combined organic phases were 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. Five -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] A solution of 5-bromopentanal (2.80 g, 16.97 mmol, 1.00 eq.) in methanol (50 mL) contains trimethoxymethane (9.00 g, 85 mmol, 9 mL, 5.00 eq.) and 4-methylbenzenesulfonic acid hydrate (161 mg, 0.85 mmol, 0.05 eq) was added at 25°C. The resulting mixture was stirred at 25°C for 16 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 10:1) showed a predominant new spot. The mixture was poured into water (40 mL) and stirred for 1 minute. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 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=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, CDCl 3 ) 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] A solution of 4-[(1R,2S)-6-benzyloxy-2-phenyl-tetralin-1-yl]phenol (500 mg, 1.23 mmol, 1.00 equivalents) in dimethylformamide (5 mL) was added with cesium carbonate (1.2 g, 3.69 mmol, 3.00 eq.) and 5-bromo-1,1-dimethoxy-pentane (390 mg, 1.84 mmol, 1.50 eq.) were added. 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 phases were 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) was obtained as a white solid. LC / MS (ESI) m / z: 559.2 [M+23] + , 1 H NMR (400MHz, CDCl 3 ) 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] (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 ( Palladium on carbon (200 mg, 10% purity) was added to the solution (20 mL) under nitrogen atmosphere. The suspension was degassed with hydrogen three times. The mixture was stirred at 25° C. under hydrogen (15 psi) 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 ) was obtained 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] Sulfuric acid (2M in water, 18 mL, 40.00 eq.) was added. The mixture was stirred at 70°C for 0.5 hour. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) showed that the reaction was complete and a new spot was formed. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium bicarbonate (15 mL) and saturated brine (2 x 20 mL), 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) was obtained 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] 1-Methyl of 5-fluoro-7-methoxy-3H-isobenzofuran-1-one (1 g, 5.49 mmol, 1 eq.) and tert-butylpiperazine-1-carboxylate (2.05 g, 10.98 mmol, 2 eq.) To the mixture in pyrrolidin-2-one (6 mL) was added N-ethyl-N-isopropylpropan-2-amine (2.84 g, 21.96 mmol, 3.83 mL, 4 eq.) 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 that a new spot had formed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 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, CDCl 3 ) 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] tert-Butyl 4-(7-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (1 g, 2.87 mmol, 1 eq.) in methyl alcohol (10 mL) and tetrahydrofuran (10 mL) To the mixture was added a solution of sodium hydroxide (459 mg, 11.48 mmol, 4 eq.) 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 that a new spot had formed. 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 x 2). The aqueous phase was adjusted to a pH value of 4-5 with hydrochloric acid (1.5N) and then filtered to collect the solids. 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) as a white solid. Obtained. 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] Dioxide Manganese (1.54 g, 17.74 mmol, 10 eq.) was added in one portion at 20° C. under nitrogen. The mixture was stirred at 50°C for 12 hours. LC / MS showed the reaction was complete and the desired product was formed. The reaction mixture was filtered and the solution was concentrated under vacuum. 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] 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-6-methoxy-benzoic acid (600 mg, 1.65 mmol, 1 eq.) and 3-aminopiperidine-2,6-dione (407 mg, 2.47 mmol, 1.5 eq. Added. LC / MS showed the reaction was complete and the desired product was formed. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase flash silica gel chromatography (120 g SepaFlash silica gel column, elution 0-60% acetonitrile in water with 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] 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-6-methoxy-benzoic acid (300 mg, 0.63 mmol, 1 eq. ) in dichloromethane (10 mL), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (181 mg, 0.94 mmol, 1.5 eq.), N-hydroxybenzotrizole (128 mg, 0.94 mmol, 1.5 eq.), and triethylamine (191 mg, 1.89 mmol, 3 eq.) were added. The mixture was stirred at 20°C for 1 hour. LC / MS showed the reaction was complete and the desired product was formed. The reaction mixture was quenched by the addition of water (15 mL) and then extracted with dichloromethane (40 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to preparative TLC (dichloromethane:methyl alcohol = 10:1, R f =0.60). tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-7-methoxy-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate (260 mg, 0.57 mmol, yield 90 %) was obtained 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] 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 eq.) To a mixture of dioxane (10 mL) was added hydrogen chloride / dioxane (4M, 17 mL, 105.81 eq.) 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 dissolved in white Obtained as a 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-isoy Preparation of Ndol-2-yl}piperidine-2,6-dione (Exemplary Compound 2) [ka]

[0496] 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 ( Sodium acetate (102 mg, 1.25 mmol, 5 eq.) was added in one portion at 20 °C. The mixture was stirred at 20 °C for 1 h, then 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (100 mg, 0.25 mmol, 1 eq.) Added to reaction mixture and stirred for 1 hour. Sodium cyanoborohydride (31 mg, 0.50 mmol, 2 eq.) 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 showed the reaction was complete and the desired product was formed. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: 35% to 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 (50g, 234.71mmol, 1 To a solution of 1-iodopyrrolidine-2,5-dione (55.45 g, 246.45 mmol, 1.05 eq.) in trifluoromethanesulfonic acid (680 g, 4.53 mol, 400 mL, 19.30 eq.) at 0 °C was added all at once at 0 °C. did. The mixture was allowed to warm to 15°C and held for 16 hours. TLC (petroleum ether: ethyl acetate = 5:1) shows that no starting material remains and two new spots (R f =0.4, 0.5) was formed. The reaction mixture was poured into ice water (1 L) and a yellow solid precipitated. 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 x 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, CDCl 3 ) 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] 5-bromo-4-iodo-3H-isobenzofuran-1-one (40 g, 118.02 mmol, 1 eq.), sodium hydroxide (23.60 g, 590.10 mmol, 5 eq.) in water (400 mL) and N,N-dimethyl To the mixture in acetamide (200 mL) was added cuprous oxide (3.38 g, 23.60 mmol, 2.4 mL, 0.2 eq.). The reaction mixture was heated to 80°C and maintained for 16 hours. TLC (petroleum ether: ethyl acetate = 1:1, R f=0.3) indicated that 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), 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. 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (14.5 g, 60.15 mmol, 50% yield, 95% purity) was obtained 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] A mixture of 5-bromo-4-hydroxy-3H-isobenzofuran-1-one (3 g, 13.10 mmol, 1 eq.) in acetone (20 mL) was added with iodomethane (17.5 g, 123.29 mmol, 7.7 mL, 9.41 eq.) and Potassium carbonate (5.43g, 39.30mmol, 3eq) was added. The mixture was stirred at 20°C for 15 hours. TLC (Ethyl acetate:petroleum ether=1:3, R f =0.37) indicated that the reaction was complete. The reaction mixture was quenched by the addition of water (10 mL) and then extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated sodium bicarbonate (10 mL x 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, CDCl 3 ) 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] In a vial, 5-bromo-4-methoxy-3H-isobenzofuran-1-one (500 mg, 2.06 mmol, 1 eq.), tert-butylpiperazine-1-carboxylate (383 mg, 2.06 mmol, 1 eq.), Tris( Loaded with dibenzylideneacetone)dipalladium(0) (188 mg, 0.20 mmol, 0.1 eq.), XantPhos (119 mg, 0.20 mmol, 0.1 eq.), potassium phosphate (873 mg, 4.11 mmol, 2 eq.), and dioxane (5 mL). I entered. The mixture was degassed with nitrogen and heated at 100° C. for 16 hours. TLC (ethyl acetate:petroleum ether=1:3) showed 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 x 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] tert-Butyl 4-(4-methoxy-1-oxo-3H-isobenzofuran-5-yl)piperazine-1-carboxylate (700 mg, 2.01 mmol, 1 eq.) in tetrahydrofuran (4 mL) and water (4 mL). To the solution was added sodium hydroxide (401 mg, 10.05 mmol, 5 eq.). The mixture was stirred at 20°C for 16 hours. TLC (ethyl acetate:petroleum ether=1:2) showed the reaction was complete. The mixture was adjusted to pH=4 with aqueous hydrochloric acid (1M) and extracted with ethyl acetate (10mL x 3). I put it out. The organic layer was washed with brine (20 mL) and dried over sodium sulfate. The crude material was not purified further. 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] A solution of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(hydroxymethyl)-3-methoxy-benzoic acid (700 mg, 1.91 mmol, 1 eq.) in dichloromethane (10 mL) was added with manganese dioxide. (2.49g, 28.66mmol, 15eq) was added. The mixture was stirred at 20°C for 1 hour. TLC (dichloromethane:methanol=20:1) showed 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 eq., HCl salt) in methanol (2 mL) and dichloromethane (4 mL) was added sodium acetate (270 mg, 3.29 mmol, 4 eq.). did. The mixture was stirred at 20 °C for 10 min, then 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formyl-3-methoxy-benzoic acid (300 mg, 0.82 mmol, 1 eq.) was added. , the mixture was stirred for 10 minutes. Sodium cyanoborohydride (103 mg, 1.65 mmol, 2 eq.) was added and the mixture was stirred for a further 40 minutes. LCMS showed the reaction was complete. The mixture was adjusted to pH=4~5 with aqueous hydrochloric acid solution (1M) and extracted with ethyl acetate (10mL x 3). The organic layer was dried over sodium sulfate. The crude product was not purified further. 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic acid (400 mg, crude) in white Obtained as a 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] 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[[(2,6-dioxo-3-piperidyl)amino]methyl]-3-methoxy-benzoic acid (400 mg, 0.84 mmol, 1 eq. ) in dimethylformamide (5 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (383 mg, 1.01 mmol , 1.2 equivalents) were added. The solution was stirred for 10 minutes, then N,N-diisopropylethylamine (325 mg, 2.52 mmol, 3 eq.) was added. The solution was stirred at 20°C for 20 minutes. LCMS showed the reaction was complete. The solution was diluted with ethyl acetate (40 mL) and washed with water (30 mL x 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) in light yellow Obtained as a 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] 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 eq.) To a mixture of dioxane (2 mL) was added hydrochloric acid in dioxane (4M, 4 mL, 18.34 eq.). 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: 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] 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 to a mixture in methanol (1 mL) was added sodium acetate (83 mg, 1.01 mmol, 4 eq.). The mixture was stirred at 20°C for 10 minutes. 5-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1-yl]phenoxy]pentanal (101 mg, 0.25 mmol, 1.00 eq.) was then added and the mixture was stirred for 10 min. . 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] + ; 1 H-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 synthesis scheme B-1 [ka]

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

[0521] Exemplary synthetic 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, add 4-bromo-2-methoxy-6-methylbenzonitrile (800 mg, 3.54 mmol, 1.00 eq.), water (10 mL), sodium hydroxide (708 mg, 17.70 mmol, 5.00 eq.), KMnO. 4 (1.12g, 7.09mmol, 2.00eq) was placed. The resulting solution was stirred at 100°C in an oil bath for 16 hours. The solids were filtered off. The pH value of the solution was adjusted to 3 with hydrogen chloride (2 mol / L). The resulting solution was extracted with dichloromethane (15 mL x 3) and the aqueous layers were combined. The resulting solution was extracted with ethyl acetate / methanol=10:1 (15 mL x 3) and the organic layers were combined, dried under reduced pressure in an oven, and concentrated under vacuum. This yielded 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 were placed 5-bromo-3-methoxybenzene-1,2-dicarboxylic acid (330 mg, 1.20 mmol, 1.00 equivalent), methanol (20 mL), and sulfuric acid (5 mL). The resulting solution was stirred at 70°C in an oil bath for 16 hours. The resulting solution was diluted with water (40 mL). The pH value of the solution was adjusted to 8 with sodium carbonate. The resulting solution was extracted with ethyl acetate (3x30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:10). This gave 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 minutes (2.0 minute run).

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

[0528] In a 100 mL round bottom flask, add 1,2-dimethyl 5-bromo-3-methoxybenzene-1,2-dicarboxylate (300 mg, 0.99 mmol, 1.00 eq.), tert-butylpiperazine-1-carboxylate (277 mg, 1.49mmol, 1.50equiv), RuphosPd (39mg, 0.05mmol, 0.05eq), Cs 2 C.O. 3 (978 mg, 3.00 mmol, 3.00 equivalents) and toluene (15 mL) were added. The resulting solution was stirred at 100° C. for 12 hours in an oil bath. The resulting solution was diluted with water (30 mL). The resulting solution was extracted with ethyl acetate (3x30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane / ethyl acetate (10:1). This produced 340 mg (84%) of 1,2-dimethyl 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate in a pale yellow color. Appeared as an oil.

[0529] LC-MS (ES+): m / z 409.05 [MH+], t R= 0.963 minutes (2.0 minute 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, add 1,2-dimethyl 5-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]-3-methoxybenzene-1,2-dicarboxylate (340 mg, 0.83 mmol, 1.00 eq), methanol / H 2 O / THF (8 mL), sodium ol (100 mg, 2.50 mmol, 3.00 eq.) were arranged. The resulting solution was stirred at 25°C for 12 hours. The resulting solution was diluted with water (30 mL). The pH value of the solution was adjusted to 8 with hydrogen chloride (2 mol / L). The pH was adjusted to 3 using citric acid monohydrate. The resulting solution was extracted with ethyl acetate (3x30 mL) and the organic layers were combined, 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 minutes (2.0 minute run).

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

[0534] In a 100 mL round bottom flask, add 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 (equivalent), 3-aminopiperidine-2,6-dione hydrochloride (153.6 mg, 0.93 mmol, 1.30 eq), and pyridine (10 mL). 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 (3x30 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column using dichloromethane / methanol (100:1). This resulted in 280 mg (83%) of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-iso Indol-5-yl]piperazine-1-carboxylate was obtained as a yellow solid.

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

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

[0537] In a 50 mL round bottom flask, add tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-7-methoxy-1,3-dioxo-2,3-dihydro-1H-isoindole- 5-yl]piperazine-1-carboxylate (270 mg, 0.57 mmol, 1 eq.), dichloromethane (6 mL, 0.07 mmol, 0.124 eq.), TFA (2 mL, 0.02 mmol, 0.031 eq.) were arranged. 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 Obtained as an oil.

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

[0539] 7.6-[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 synthesis

[0540] In a 100 mL round bottom flask, add 2,2,2-trifluoroacetaldehyde;2-(2,6-dioxopiperidin-3-yl)-4-methoxy-6-(piperazin-1-yl)-2,3 -dihydro-1H-isoindole-1,3-dione (130mg, 0.28mmol, 1.078eq), dichloromethane (10mL, 0.12mmol), 6-(4-formylpiperidin-1-yl)-N-[(1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide (120 mg, 0.26 mmol, 1 eq.), NaBH(OAc) 3 (163.4mg, 0.77mmol, 3.006eq) was distributed. The resulting solution was stirred at 25°C for 2 hours. The resulting solution was diluted with dichloromethane (30 mL). The resulting mixture was heated with H 2 Washed with O (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 using dichloromethane / ethyl acetate (3:1). The crude product was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 5um, 19*150mm; mobile phase, water (10mmol / L NH 4 HCO 3 ) and acetonitrile (43% B phase up to 65% in 8 min); detector, UV. This resulted in 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- The 3-carboxamide resulted 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 ClN 9 O 7 [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 eq.) in chloroform (90 mL) was added thionyl chloride (59 g, 499.56 mmol, 36 mL, 2.2 eq.). The mixture was stirred at 70°C for 1 hour. Liquid bromine (36.29 g, 227.07 mmol, 1 eq.) was added dropwise into the mixture. The mixture was stirred at 70°C for 12 hours. The mixture was cooled to 0°C and methanol (58g, 1.82mol, 73mL, 8 eq.) was added dropwise into the mixture at 0°C. LCMS detected the desired product. The mixture was extracted with ethyl acetate (150 mL x 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 (4g+20g (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:C 7 H 11 BrO 4 , molecular weight: 239.06

[0550] 1 H NMR: (400 MHz, DCCl 3 ) 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-fluoro-benzoate (10 g, 55.82 mmol, 1 eq.), tert-butylpiperazine-1-carboxylate (12.48 g, 66.98 mmol, 1.2 eq.) in dimethyl sulfoxide (100 mL), Diisopropylethylamine (28.86g, 223.28mmol, 4eq) was added. The reaction mixture was stirred at 120°C for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) showed that the methyl 2-cyano-4-fluoro-benzoate was consumed and the desired product was 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 H 23 N 3 O 4 , 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 eq.) in tetrahydrofuran (200 mL) was added tetraisopropyl titanate (17.77 g, 62.54 mmol). , 1.2 eq.) and a solution of ethylmagnesium bromide in tetrahydrofuran (2M, 52.11 mL, 2 eq.) were added at 0.degree. The mixture was stirred at 25°C for 1 hour. Thin layer chromatography (petroleum ether:ethyl acetate = 1:1) shows that tert-butyl 4-(3-cyano-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate is consumed and the desired product is detected. It showed that it was done. The mixture was poured into saturated aqueous ammonium chloride (150 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and filtered. 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. obtained as.

[0557] Chemical formula:C 19 H 25 O 3 N 3 , molecular weight: 343.42

[0558] 1 H NMR: (400 MHz, CDCl 3 ) 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: Dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindoline]-2'-yl]pentanedio Synthesis of ate [ka]

[0561] 20 batches in parallel:

[0562] tert-Butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate (100 mg, 0.29 mmol, 1 eq.) and dimethyl 2-bromopentanedio To a solution of the ate (104 mg, 0.44 mmol, 1.5 eq.) in dimethylformamide (2 mL) was added sodium hydride (35 mg, 0.88 mmol, 60% in mineral oil, 3 eq.). The mixture was stirred at 30°C for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 1: 1) showed that 30% of tert-butyl 4-(1'-oxospiro[cyclopropane-1,3'-isoindolin]-5'-yl)piperazine-1-carboxylate was consumed. The 20 reaction mixtures were poured into 50 mL of brine, extracted with ethyl acetate (30 mL x 2), and 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 collected on recovered starting material) as a yellow oil. Also, 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 N 3 O 7 , molecular weight: 501.57

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

[0565] Dimethyl 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-2'-yl]pentanedioate (800 mg , 1.59 mmol, 1 eq.) in tetrahydrofuran (5 mL) and methanol (5 mL) was added a solution of sodium hydroxide (255 mg, 6.38 mmol, 4 eq.) in water (3 mL). The mixture was stirred at 25°C for 2 hours. LCMS showed the reaction was complete and the desired MS was detected. The mixture and other batches 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 (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-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 N 3 O 7 , molecular weight: 473.52

[0568] Step 6: 5-Amino-4-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-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' Synthesis of -isoindoline]-5'-yl]piperazine-1-carboxylate [ka]

[0569] 2-[6'-(4-tert-butoxycarbonylpiperazin-1-yl)-3'-oxo-spiro[cyclopropane-1,1'-isoindolin]-2'-yl]pentanedioic acid (400 mg, A mixture of urea (253 mg, 4.22 mmol, 5 eq) in 1-methyl-2-pyrrolidinone (4 mL) was heated to 160°C and stirred at 160°C for 2 hours. LCMS showed two peaks with the desired MS signals. The mixture was combined with another batch and filtered. The filtrate was further purified by semi-preparative reverse phase HPLC (column: Boston Green ODS 150*305um; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 35%~45%, 10 min) did. The 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 '-isoindolin]-2'-yl]-5-oxo-pentanoic acid was obtained (170 mg, 0.36 mmol, 42% yield and 90 mg, 0.19 mmol, 22% yield, respectively. Which of the two isomers was (We were not ultimately sure which structure it corresponds to.) Also, tert-butyl4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane- 1,3'-isoindolin]-5'-yl]piperazine-1-carboxylate (90 mg, 0.20 mmol, 23% yield) was isolated 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] Chemical formula of monoamide product 1: C 24 H 32 N 4 O 6 , molecular weight: 472.53.

[0572] Chemical formula of monoamide product 2: C 24 H 32 N 4 O 6 , molecular weight: 472.53.

[0573] Chemical formula of imide product: C 24 H 30 N 4 O 5 , molecular weight: 454.52.

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

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

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

[0577] Chemical formula:C 19 H 22 N 4 O 3 , molecular weight: 354.40.

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

[0579] tert-Butyl 4-[2'-(2,6-dioxo-3-piperidyl)-1'-oxo-spiro[cyclopropane-1,3'-isoindolin]-5'-yl]piperazine-1-carboxy To a mixture of Rate (90 mg, 0.20 mmol, 1 eq.) in dichloromethane (5 mL) was added hydrochloric acid (4M in dioxane, 2.5 mL, 50 eq.) in one portion at 25°C. The mixture was stirred at 25°C for 1 hour. LCMS showed the product was the main peak. The mixture was concentrated in vacuo. The crude solid product 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane-1,1'-isoindoline]-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 N 4 O 3 , molecular weight: 354.40.

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

[0583] 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 A solution of triethylamine (38 mg, 0.38 mmol, 3 eq.) in 1,2-dichloroethane (3 mL) and 3-(3'-oxo-6'-piperazin-1-yl-spiro[cyclopropane- 1,1'-isoindolin]-2'-yl)piperidine-2,6-dione (50 mg, 0.12 mmol, 1 eq., hydrochloride) was added. The mixture was stirred at 30°C for 30 minutes. Sodium triacetic acid borohydride (54 mg, 0.25 mmol, 2 eq.) 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 solution. The residue was purified by semi-preparative reverse phase HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 40% to 70%, 10 min). , 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, yield 16%, purity 98%) was obtained as a white solid.

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

[0585] 1 H NMR: (400MHz, DMSO-d 6 ) 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 ClN 7 O 5 , molecular weight: 832.43.

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

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

[0589] General synthesis scheme C-1

[0590] 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] Dissolve 6-chloronicotinic acid (1.6 g, 10.0 mmol) in N,N-dimethylacetamide (15 mL), add tert-butylpiperazine-1-carboxylate (1.9 g, 10.0 mmol) and ethyldiisopropylamine (2.6 g, 20 mmol) was added thereto, and then stirred at 130°C overnight. The reaction mixture was concentrated under reduced pressure and 1M aqueous NaOH solution (10 mL) was added to the resulting residue followed by CHCl 3 (50 mL). The pH of the aqueous layer was adjusted to approximately 6 to 7 by the addition of 1M hydrochloric acid, followed by CHCl 3 (50 mL x 3). The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (CH 2 Cl 2 / MeOH=10 / 1) to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 65% yield) 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: 2.0mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 0.7 min). Purity is 83.17%, Rt=1.312 min; MS calculated value: 307.15; MS observed value: 308.2 [M+H] + .

[0595] Chemical formula:C 15 H 21 N 3 O 4 , molecular weight: 307.34.

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

[0597] 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (614 mg, 2.0 mmol), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclo butoxy)-2-chlorobenzonitrile hydrochloride (630 mg, 2.0 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate ( A mixture of 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 extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate. Concentration of the solvent gave 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, yield 86%) as a white solid. I got it as a thing.

[0598] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 0.7 min). Purity is 88.26%, Rt=2.161 min; MS calculated value: 567.26; MS observed value: 568.3 [M+H] + .

[0599] 1 H NMR (400 MHz, DMSO-d 6) 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 ClN 5 O 4 , molecular weight: 568.11.

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

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

[0603] tert-Butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine- A mixture of 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-(piperazine- 1-yl) Nicotinamide hydrochloride (353 mg, 100% yield) was obtained as a white solid.

[0604] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 0.7 min). Rt=1.791 min;MS calculated value:467.21;MS observed value:468.3[M+H] + .

[0605] Chemical formula:C 25 H 31 Cl 2 N 5 O 2 , molecular weight: 504.45

[0606] General synthesis 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. under nitrogen overnight. After cooling to room temperature, water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by CC (PE / EA=10:1) to yield the compound tert-butyl 4-(4-(hydroxymethyl)piperidine- 1-yl)benzoate (31 g, 91.2%) was obtained as a white solid.

[0611] LCMS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50mm x 4.6mm x 3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 90% [(total 10mM AcONH 4 )Water / CCH 3 CN=900 / 100(v / v)] and 10%[(total 10mM AcONH 4 ) Water / CH 3 CN=100 / 900(v / v)] to 10%[(total 10mM AcONH 4 )Water / CH 3 CN=900 / 100(v / v)] and 90%[(total 10mM AcONH 4 )Water / CH 3 CN=100 / 900(v / v)] within 1.6 minutes, then under these conditions for 2.4 minutes, finally 90% [(total 10mM AcONH 4 )Water / CH 3 CN=900 / 100(v / v)] and 10%[(total 10mM AcONH 4 )Water / CH 3 CN=100 / 900(v / v)] for 0.1 min and 0.7 min under these conditions). Purity is 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 (150mm x 4.6mm x 3.5μm); Column temperature: 40℃; Flow rate: 1.0mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 10 min, then 5 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 5 min). Purity is 93.27%, Rt=9.542 min.

[0613] 1 H NMR (400 MHz, CDCl 3 ) 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 NO. 3 , 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) at 0 °C. was added slowly. The reaction mixture was stirred at room temperature for 1 hour. It was then filtered and concentrated in vacuo to give 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. for 16 hours under nitrogen gas and concentrated under reduced pressure. After cooling to room temperature, sodium bicarbonate (2.0M) was added to adjust PH=8. This was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (30 mL). The combined organic phases were 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 4 )Water / CCH 3 CN=900 / 100(v / v)] and 10%[(total 10mM AcONH 4 )Water / CH 3 CN=100 / 900(v / v)] to 10%[(total 10mM AcONH 4 )Water / CH 3 CN=900 / 100(v / v)] and 90%[(total 10mM AcONH 4 )Water / CH 3 CN=100 / 900(v / v)] within 1.6 minutes, then under these conditions for 2.4 minutes, finally 90% [(total 10mM AcONH 4 )Water / CH 3 CN=900 / 100(v / v)] and 10%[(total 10mM AcONH 4 )Water / CH 3 CN=100 / 900(v / v)] for 0.1 min, and under this condition for 0.7 min. Purity is 98 .94%, Rt=2.609 min; MS calculated value: 243.97; MS observed value: 245.0 [M+H] + .

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

[0624] Methyl 2-bromo-4-methoxybenzoate (3.0g, 12.3mmol), cesium carbonate (12.0g, 36.9mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( To a solution of 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 nitrogen atmosphere. The reaction mixture was heated to 100°C and stirred for 4 hours. The resulting reaction was concentrated under reduced pressure, then water (10 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were 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 %[CH 3 CN+0.05%TFA] to 0%[water+0.05%TFA] and 100%[CH 3 CN + 0.05% TFA] within 1.5 min, then 0.5 min under these conditions, finally 95% [water + 0.05% TFA] and 5% [CH 3 CN+0.05%TFA] for 0.1 min and 0.5 min under these conditions. Purity is 96.85%, Rt=1.293 min; MS calculated value: 206.09; MS observed value: 207.3 [M+H] + .

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

[0627] Periodic acid was added 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=10mL:10mL:10mL). Sodium (4.99g, 23.3mmol) 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 x 3 mL). The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Separate the residue Purification by commercial TLC (petroleum ether / ethyl acetate=4:1) gave 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 (50mm x 4.6mm x 3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.05% TFA] and 5% [CH 3 CN+0.05%TFA] to 0%[Water+0.05%TFA] and 100%[CH 3 CN + 0.05% TFA] within 1.5 min, then 0.5 min under these conditions, finally 95% [water + 0.05% TFA] and 5% [CH 3 CN+0.05%TFA] for 0.1 min and 0.5 min under these conditions). Purity is 96.26%, Rt=1.007 min; MS calculated value: 208.1; MS observed value: 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] A solution of methyl 4-methoxy-2-(2-oxoethyl)benzoate (420 mg, 2.02 mmol) in methanol (6 mL) was added with 3-aminopiperidine-2,6-dione hydrochloride (397 mg, 2.42 mmol) and triethylamine ( A solution of 245 mg, 2.24 mmol) in methanol (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (254 mg, 4.04 mmol) was added at 0°C. The reaction was stirred at room temperature overnight, water (10 mL) was added, extracted with ethyl acetate (20 mL x 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%) was obtained as a pale yellow solid.

[0631] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm x 3mm x 2.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN+10mM NH 4 HCO 3 ] to 5% [water + 10mM NH 4 HCO 3 ] and 95%[CH 3 CN+10mM NH 4 HCO 3 ] within 1.5 min, then 0.5 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN+10mM NH 4 HCO 3 ] within 0.1 min and under these conditions for 0.5 min). Purity is 80.84%, Rt=0.924 min; MS calculated value: 288.1; MS observed value: 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] 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 A solution of boronate (0.5 mL) in dichloromethane (2 mL) was added 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 x 5). The organic layer was washed with brine (10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane / methanol = 10:1) to yield the compound 3-(6-hydroxy-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-2, 6-dione (80 mg, 38%) was obtained as a yellow solid.

[0634] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm x 3mm x 2.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN+10mM NH 4 HCO 3 ] to 5% [water + 10mM NH 4 HCO 3 ] and 95%[CH 3 CN+10mM NH 4 HCO 3 ] within 1.5 min, then 0.5 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN+10mM NH 4 HCO 3 ] within 0.1 min and under these conditions for 0.5 min). Purity is 96.22%, Rt=0.736 min; MS calculated value: 274.1; MS observed value: 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] 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) To a solution of 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 x 3). The organic layer was washed with brine (10 mL x 3). The combined organic phases were 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 (25mg, 23%) was obtained 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 mMNH 4 HCO 3 ] and 5% [CH 3 CN + 10mM NH 4 HCO 3 ] to 5% [water + 10 mM NH 4 HCO 3 ] and 95% [CH 3 CN + 10mM NH 4 HCO 3 ] within 1.5 min, then 0.5 min under these conditions, and finally 95% [water + 10 mM NH 4 HCO 3 ] and 5% [CH 3 CN+ 10mM NH 4 HCO 3 ] within 0.1 min and under these conditions for 0.5 min). Purity is 93.68%, Rt=1.263 min; MS calculated value: 378.1; MS observed value: 379.1 [M+H] + .

[0638] Step 7: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2- Synthesis of (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 added to acetonitrile (2 mL). ), 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), potassium iodide (2 mg) were added to the solution. The mixture was heated to 100° C. for 16 hours under a closed tube. After cooling to room temperature, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and then purified by preparative HPLC to yield 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%) was obtained as a white solid.

[0640] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50mm x 4.6mm x 3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 3.0 min, then 1.0 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 0.7 min). Purity is 87.84%, Rt=2.923 min; MS calculated value: 809.4; MS observed value: 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 NH 4 HCO 3 ] and 5%[CH 3 CN] to 0% [water + 10mM NH 4 HCO 3 ] and 100%[CH 3 CN] within 10 min, then 5 min under these conditions, and finally 95% [water + 10mM NH 4 HCO 3 ] and 5%[CH 3 CN] within 0.1 min and under these conditions for 5 min). Purity is 84.56%, Rt=10.161 min.

[0642] 1 H NMR (400 MHz, DMSO-d 6 ) 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 ClN 7 O 6 , 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. It was added at -78°C. The mixture was kept stirring at that temperature for 1 hour, then dimethyl carbonate (2.98g, 33.1mmol) was added. The reaction mixture was kept stirring overnight. Water (200 mL) and ethyl acetate (100 mL) were added. The aqueous layer was separated, extracted with ethyl acetate (50 mL x 2), and neutralized with hydrochloric acid (1N) until pH<4. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (50.0 mL x 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 (1N) was added until pH<4. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated brine (50.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(carboxymethyl)-4-methoxybenzoic acid ( 4.6 g, 73% over 2 steps) was obtained as a yellow solid.

[0650] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.1% TFA] and 5% [CH 3 CN+0.1%TFA] to 0%[Water+0.1%TFA] and 100%[CH 3 CN + 0.1% TFA] within 0.5 min, then 1.5 min under these conditions, finally 95% [water + 0.1% TFA] and 5% [CH 3 CN+0.1%TFA] for 0.1 min and 0.5 min under these conditions). Purity is 94.6%, Rt=0.774 min; MS calculated value: 210.1; MS observed value: 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 stirred for 2 hours. The mixture was cooled to room temperature and the solvent was then removed in vacuo to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether=1:1) and 4-Methoxy-2-(2-methoxy-2-oxoethyl)benzoate (900 mg, 66%) was obtained 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 in an ice-water bath. It was added by 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. Solvent was removed. The residue was dissolved in water (30 mL). Hydrochloric acid (1N) was added until pH<4. The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (20.0 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 2-(carboxymethyl)-4-hydroxybenzoic acid ( 0.45 g, 61% over 2 steps) was obtained as a yellow solid.

[0655] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 1.5mL / min; Mobile phase: 95% [water + 0.1% TFA] and 5% [CH 3 CN+0.1%TFA] to 0%[Water+0.1%TFA] and 100%[CH 3 CN + 0.1% TFA] within 0.5 min, then 1.5 min under these conditions, finally 95% [water + 0.1% TFA] and 5% [CH 3 CN+0.1%TFA] for 0.1 min and 0.5 min under these conditions). Purity is 95.2%, Rt=0.570 min; MS calculated value: 196.0; MS observed value: 197.2 [M+H] + .

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

[0657] 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) The mixture 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 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 lithium hydroxide hydrate (128 mg, 3.05 mmol) was added. The mixture was stirred at room temperature overnight. Solvent was removed. The residue was dissolved in water (30 mL). Hydrochloric acid (1N) was added until pH<4. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 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 2 steps) was obtained as a yellow oil.

[0658] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 90% [water + 10mM NH 4 HCO 3 ] and 10%[CH 3 CN] to 5% [water + 10mM NH 4 HCO 3 ] and 95%[CH 3 CN] within 0.5 min, then 1.5 min under these conditions, and finally 90% [water + 10mM NH 4 HCO 3 ] and 10%[CH 3CN] within 0.1 min and under these conditions for 0.5 min). Purity is 69.9%, Rt=0.829 min; MS calculated value: 314.1; MS observed value: 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 dropwise thionyl chloride (48.3 mg, 0.41 mmol). Added. The mixture was refluxed for 2 hours. The mixture was cooled to room temperature and the solvent was then removed in vacuo to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether = 1:1) to give methyl 4-(5- Obtained 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 (30mm*4.6mm*3.5μm); Column temperature: 40℃; Flow rate: 2.0mL / min; Mobile phase: 90% [water + 10mM NH 4 HCO 3 ] and 10%[CH 3 CN] to 5% [water + 10mM NH 4 HCO 3 ] and 95%[CH 3 CN] within 0.5 min, then 1.5 min under these conditions, and finally 90% [water + 10mM NH 4 HCO 3 ] and 10%[CH 3 CN] within 0.1 min and under these conditions for 0.5 min). Purity is 72.9%, Rt=1.208 min; MS calculated value: 328.1; MS observed value: 329.2 [M+H] + .

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

[0663] Methyl 4-(5-chloropentyloxy)-2-(2-methoxy-2-oxoethyl)benzoate (55mg, 0.17mmol), ethyldiisopropylamine (65.8mg, 0.51mmol), potassium iodide (28.2mg, 0.17mmol) ), and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide A mixture of (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 x 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). 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%) was obtained as a white solid. .

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

[0665] Methyl 4-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridine-2- A mixture of 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) was dissolved in methanol (2 mL). , 0.35 mmol) was added. The mixture was stirred at room temperature for 3 hours. Solvent was removed. The residue was dissolved in water (15 mL). Hydrochloric acid (1N) was added until pH<4. The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with saturated brine (10 mL x 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%) was obtained as a white solid.

[0666] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge...

Claims

【Request 1】 【Chemical 367】 or a pharma- ceutically acceptable salt thereof.

2. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, further comprising at least one additional bioactive agent.

4. The pharmaceutical composition of claim 3, wherein the additional bioactive agent is an anti-cancer agent, an anti-neurodegenerative agent, an anti-microbial agent, an anti-viral agent, an anti-HIV agent, or an anti-fungal agent.

5. A pharmaceutical composition for use in treating a disease or disorder in a subject, comprising an effective amount of a compound described in claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, additive, and / or excipient.

6. A pharmaceutical composition for use as described in claim 5, wherein the disease or disorder is associated with accumulation and / or aggregation of BRD4 protein.

7. The pharmaceutical composition for use according to claim 5 or 6, wherein the disease or disorder is selected from the group consisting of 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.

8. The pharmaceutical composition for use according to claim 5 or 6, wherein the disease or disorder is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, 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.

9. The disease or disorder is selected from the group consisting of 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 histopathology, alpha-1-antitrypsin deficiency, alpha-1 proteinase inhibitors, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Allergy-related pulmonary hypertension, and pulmonary hypertension. Kissander 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 joint laxity (Ehlers-Danlos syndrome joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome, 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 syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis of the liver (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein Lipase deficiency), CGD chronic granulomatous disorder, ankle dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cricketing syndrome, CAVD (congenital absence of the vas deferens), Cuyler cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia), autosomal dominant otospondylomegalyepiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia, Ehlers-Danlos syndrome, lethal osteodysplasia, 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 dysfacies syndrome, Cooley anemia (beta thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Steve syndrome Neurodegenerative disorders including Johns Hopkins syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Grouchy syndrome and Degelin-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 protoporphyria, erythropoietinopathy, androgen hypersensitivity syndrome. 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 palsies, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, genetic brain disorders, giant cell hepatitis (neonatal hemochromatosis), Grenblatt-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Harg Renn's syndrome, sickle cell anemia, hemophilia, hepatoerythropoietic porphyria (HEP), Hippel-Lindau syndrome (von Hippel-Lindau disease), Huntington's disease, Hutchison-Gilford progeria syndrome, hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Inslee-Astley syndrome, Kennedy syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia,Lacunar infarct dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Inslee syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, Polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-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, PXE (elastic endothelial cell endothelial cell hypertension) fibrosis), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorder, 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, sarcoma, leukemia, and adrenal (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis complex), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia, strodewickian syndrome ... Ludwick type), SEDc (Spondyloepiphyseal dysplasia congenita), Strudwick type SEMD (Spondyloepiphyseal dysplasia, Strudwick type), Sprinzen syndrome, skin pigmentation disorder, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variant porphyria), infantile-onset ascending hereditary spastic paralysis, speech communication disorder, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta thalassemia, thyroid disease,7. The pharmaceutical composition for use according to claim 5 or 6, which is selected from the group consisting of 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.

10. The pharmaceutical composition for use according to any one of claims 5 to 9, wherein the pharmaceutical composition further comprises an additional bioactive agent.

11. The pharmaceutical composition for use according to claim 10, wherein the additional bioactive agent is an anti-cancer agent, an anti-neurodegenerative agent, an anti-microbial agent, an anti-viral agent, an anti-HIV agent, an anti-fungal agent, or a combination thereof.

12. The anticancer drug is 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, Le p-etu, nolatrexide, azd2171, butabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR 1 , KRX-0402, Lucanton, LY317615, Neurajiab, 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, acetate of [D-Ser(But) 6, Azgly 10 ] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH 2 acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X , where x = 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, Clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevac, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan,6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, Lysine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin dif Chitox, Gefitinib, Bortezimib, Paclitaxel, Cremophor-free Paclitaxel, Docetaxel, Epithilon B, BMS-247550, BMS-310705, Droloxifene, 4-Hydroxytamoxifen, Pipendoxifene, ERA-923, Arzoxifene, Fulvestrant, Acolbifene, Lasofoxifene, Idoxifene, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK222584, VX-745, PD184352, Rapamycin, 40-O-(2-Hydroxy-3-(2-hydroxy-1,4-diphenyl-2-propanediol), ethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon 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, immunoglobulins, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal da The pharmaceutical composition for use according to claim 11, selected from the group consisting of unorubicin, 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 alpha, darbepoetin alpha, and mixtures thereof.

13. A pharmaceutical composition for use in inducing degradation of BRD4 protein in a cell, comprising an effective amount of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

14. A pharmaceutical composition for use in treating cancer, comprising an effective amount of a compound of claim 1 or a pharma- ceutically acceptable salt thereof.

15. The cancer includes squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, colon, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; multiple myeloma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma.

15. The pharmaceutical composition of claim 14, wherein the cancer is selected from the group consisting of: colon 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 or teratoblastoma, 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.

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