Cereblon Ligands and Bifunctional Compounds Containing Cereblon Ligands

Abstract

To provide inhibitors of a variety of polypeptides and other proteins which work as modulators of targeted ubiquitination and are degraded and / or otherwise inhibited by bifunctional compounds.SOLUTION: A compound comprises on one end a ligand which binds to the cereblon E3 ligase, including a bifunctional compound comprising a cereblon E3 ligase binding compound, 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 the 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: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to U.S. Provisional Application No. 62 / 452,972, filed January 31, 2017. No. 60 / 699,999, filed on Oct. 1, 2007, which application is incorporated herein by reference in its entirety. Incorporation by Reference U.S. Provisional Patent Application No. 15 / 230,354, filed August 5, 2016, published as U.S. Patent Application Publication No. 2017 / 0065719, and U.S. Provisional Patent Application No. 15 / 801,243, filed November 1, 2017, and U.S. Provisional Patent Application No. 15 / 206,497, filed July 11, 2016, and U.S. Provisional Patent Application No. 15 / 209,648, filed July 13, 2016, and U.S. Provisional Patent Application No. 15 / 209,648, filed October 11, 2017 U.S. Provisional Patent Application No. 15 / 730,728, filed December 1, 2017; Provisional Patent Application No. 15 / 829,541, U.S. Provisional Patent Application No. 15 / 881,318, filed January 26, 2018, and U.S. Provisional Patent Application No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562, and U.S. Provisional Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872, and U.S. Provisional Patent Application No. 14 / 792,414, filed July 11, 2014, published as U.S. Patent Application Publication No. 2014 / 0356322. Application No. 14 / 371,956, and U.S. Provisional Patent Application No. 15 / 074,820, filed March 18, 2016, published as U.S. Patent Application Publication No. 2016 / 0272639, are incorporated by reference in their entireties. Additionally, all references cited herein are incorporated by reference in their entirety.

[0002] The present disclosure provides imide-based compounds, including bifunctional compounds comprising the same, and related methods of use, that 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 the bifunctional compounds of the present disclosure. [Background technology]

[0003] Most small molecule drugs bind closely and in well-defined pockets to enzymes or receptors, while other small molecule compounds can be used to target protein-protein interactions. Targeting E3 ligases is notoriously difficult due to the large protein contact surfaces and the shallow groove-like or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination. Therefore, their specificity for specific protein substrates makes them more attractive therapeutic targets than general proteasome inhibitors. Developing ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds targeting E3 ligases have been reported, but the field remains largely unexplored.

[0004] One E3 ligase with therapeutic potential is the von Hippel-Lindau (VHL) tumor suppressor. VHL contains the substrate-recognition subunit / E3 ligase complex VCB, which includes elongins B and C, and a complex containing Cullin-2 and Rbx1. The primary substrate of VHL is hypoxia-inducible factor 1α (HIF-1α), a transcription factor that upregulates genes such as the angiogenic growth factor VEGF and the erythroid-inducing cytokine erythropoietin in response to low levels of oxygen. The inventors have generated the first small molecule ligands for Von Hippel-Lindau (VHL) to VCB, the substrate recognition subunit of E3 ligase, an important target in cancer, chronic anemia, and ischemia. The crystal structure was obtained and confirmed that this compound mimics the binding mode of the transcription factor HIF-1α, a major substrate of VHL.

[0005] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon binds damaged DNA-binding protein 1 ( DDB1, Cullin-4A (CUL4A), and Regulator of Cullins1 (ROC1), form an E3 ubiquitin ligase complex that binds many other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates, for example, the formation of limbs and otic vesicles. It has been conclusively concluded that this ubiquitin ligase complex is important for limb outgrowth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0006] Thalidomide is approved for the treatment of many immunological indications and certain neoplastic diseases, including multiple myeloma. In addition to multiple myeloma, thalidomide and several of its analogs are currently under investigation for use in the treatment of various other types of cancer. While the exact mechanism of thalidomide's antitumor activity is still being elucidated, it is known to inhibit angiogenesis. Recent publications examining the biological properties of imides include Lu et al., Science 343, 305 (2014) and Kronke et al., Science 343, 301 (2014).

[0007] Significantly, thalidomide and its analogs, such as pomolinamiode and lenalinomide, are known to bind to cereblon. These agents bind to cereblon and alter the specificity of the complex, inducing ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for multiple myeloma growth. Indeed, high cereblon expression is associated with increased efficacy of imide-based drugs in the treatment of multiple myeloma.

[0008] BRD4 has also attracted considerable interest from academia and the pharmaceutical industry due to its potential as a novel target in multiple disease settings, particularly cancer. BRD4 belongs to the bromodomain and extra-terminal domain (BET) family of proteins, characterized by two N-terminal bromodomains (BD domains) and a C-terminal extra-terminal domain (ET domain) (J. Shi, et al., Molecular cell, 54 (2014) 728-736 and AC Belkina, et al., Nat. Rev. Cancer, 12 (2012) 465-477). The two BD domains recognize and interact with acetylated lysine residues in the N-terminal tails of histone proteins. The ET domain, while not fully characterized, is thought to play a scaffolding role in the recruitment of various transcription factors. Therefore, BRD4 plays an important role in regulating gene expression by recruiting related transcriptional regulators to specific genomic loci. Several studies have revealed that BRD4 is preferentially located in super-enhancer regions, which are often upstream of important oncogenes, such as c-MYC, Bcl-xL, and BCL-6, and play an important role in regulating their expression (J. Loven, et al., Cell, 153 (2013) 320-334 and B. Chapuy, et al., Cancer Cell, 24 (2013) 777-790). Due to its crucial role in regulating the expression of essential oncogenes, BRD4 has been implicated in midline carcinoma, AML, MM, BL, and other cancers. It has emerged as a promising therapeutic target in multiple cancer types, including breast and prostate cancer (J. Loven, et al., Cell, 153 (2013) 320-334; J. Zuber, et al., Nature, 478 (2011) 524-528; JE Delmore, et al., Cell, 146 (2011) 904-917; JA Mertz, et al.,PNAS, 108 (2011) 16669-16674; A. Wyce, et al., Oncotarget, 4 (2013) 2419-2429;IA Asangani, et al., Nature, 510 (2014) 278-282; and CA French, et al., Oncogene, 27 (2008) 2237-2242). The characteristically high occupancy of BRD4 at genomic loci proximal to specific oncogenes provides a promising therapeutic window that allows for specific targeting of tumor cells while sparing normal tissue. In particular, BRD4 may serve as an alternative strategy to targeting c-MYC. c-MYC contributes to the development and maintenance of most human cancers, but has not yet led to the development of new drugs. (JE Delmore, et al., Cell, 146 (2011) 904-917; JA Mertz, et al., PNAS, 108 (2011) 16669-16674; MG Baratta, et al., PNAS, 112 (2015) 232-237; and M. Gabay, et al., Cold Spring Harb Perspect Med. (2014) 4:a014241).

[0009] The development of small molecule BRD4 inhibitors, such as JQ1, iBET, and OTX15, has been driven by the development of BL (J. Loven, et al., Cell, 153 (2013) 320-334; B. Chapuy, et al., Cancer Cell, 24 (2013) 777-790; J.E. Delmore, et al., Cell, 146 (2011) 904-917; J.A. Mertz, et al., PNAS, 108 (2011) 16669-16674; I.A. Asangani, et al., Nature, 510 (2014) 278-282; M.G. Baratta, et al., PNAS, 112 (2015) 232-237; M.Boi, et al., Clin. Cancer Res., (2015) 21(7):1628-38; and A. Puissant, et al., Cancer discovery, 3 (2013) 308-323) Indeed, BRD4 inhibitors have shown promising therapeutic potential in various preclinical models of cancer, including those of leukemia, leukemia, and leukemia. BRD4 inhibitors have been well tolerated and have demonstrated diverse antitumor activity in various mouse tumor models, and not surprisingly, have demonstrated antitumor activity in various tumor types, including c-MYC-induced BL. High sensitivity to BRD4 inhibitors, such as JQ1, and high levels of either c-MYC or N-MYC Nearly all BL cases involve the super-enhancer located upstream of IgH. It involves a translocation of the c-myc gene that is placed under control, thus inducing abnormally high levels of c-MYC expression and tumor initiation and maintenance (K. Klapproth, et al., British journal of haematology, 149 (2010) 484-497).

[0010] Currently, four BET bromodomain inhibitors are in Phase I clinical trials, primarily focused on midline carcinoma and hematological malignancies (CPI-0610, NCT01949883; GSK525762, NCT01587703; OTX015, NCT01713582; TEN-010, NCT01987362). Preclinical studies with BRD4 inhibitors have demonstrated efficacy in suppressing c-MYC and proliferation in BL cell lines. However, IC 50 The value is In most cases, the concentration ranges from 100 nM to 1 μM (J.A. Mertz, et al., PNAS, 108 (2011) 16669-16674 and M. Ceribelli, et al., PNAS, 111 (2014) 11365-11370). Therefore, although BRD4 inhibitors are rapidly evolving and the effects of BRD4 inhibition are promising, they are not ideal in that they are mostly cell growth inhibitors and require relatively high concentrations of inhibitors.

[0011] There is a continuing need in the art for effective treatments for diseases, particularly hyperplasia and cancer, such as multiple myeloma. However, transcription factors, for example, have non-specific effects and are unable to completely target and regulate specific classes of proteins. This remains an obstacle to the development of effective anticancer drugs. Therefore, "tunable" small molecule therapeutics that exploit or enhance the substrate specificity of cereblon while simultaneously targeting and specifically regulating a wide range of protein species would be highly useful as therapeutic agents. Summary of the Invention

[0012] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of using the same. In particular, the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, and methods of using the same. Proteins are degraded and / or otherwise inhibited by the bifunctional compounds described herein. An advantage of the compounds provided herein is that they may have a broad range of pharmacological activity, consistent with the degradation / inhibition of target polypeptides from virtually any protein class or family. Further provided herein are methods of using an effective amount of the compounds described herein to treat or ameliorate a condition, such as cancer, e.g., multiple myeloma.

[0013] Thus, in one aspect, the present disclosure provides novel imide-based compounds as described herein.

[0014] In a further aspect, the present disclosure provides bifunctional compounds, or PROTAC compounds, which include an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase, or "ULM" group) and a moiety that binds to a target protein (i.e., a protein / polypeptide targeting ligand, or "PTM" group), thereby The target protein / polypeptide is brought into proximity with a ubiquitin ligase, which exerts its degradative (and inhibitory) effect on the protein. In a preferred embodiment, ULM is a Levron E3 ubiquitin ligase binding moiety (i.e., "CLM"). The structure of the functional compound can be shown as follows:

[0015] [ka]

[0016] The respective positions of the PTM and CLM moieties, as well as their numbers, exemplified herein are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by those skilled in the art, the bifunctional compounds described herein can be synthesized such that the number and positions of the respective functional moieties can be varied as desired.

[0017] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). In this example, the structure of the bifunctional compound can be shown as follows:

[0018] [ka]

[0019] where PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ubiquitin ligase binding moiety.

[0020] In a particularly preferred embodiment, the E3 ubiquitin ligase is cereblon. In certain additional embodiments, the CLM of the bifunctional compound comprises a chemical moiety, such as, for example, an imide, amide, thioamide, or thioimide-derived moiety. In additional embodiments, the CLM comprises a phthalimide group or an analog or derivative thereof. In yet additional embodiments, the CLM comprises a phthalimide-glutarimide group or an analog or derivative thereof. In still other embodiments, the CLM comprises one of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0021] In certain embodiments, the compounds described herein comprise multiple CLMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0022] In any aspect or embodiment described herein, the ULM (ubiquitination ligase modulator) binds to a von Hippel-Lindau E3 ubiquitin ligase (VHL) binding site. minute (VLM), or cereblon E3 ubiquitin ligase binding domain (CLM), or mouse double miniute 2 homolog (MDM2) E3 ubiquitin ligase binding domain (MLM), or IAP It may be an E3 ubiquitin ligase binding moiety (i.e., an "ILM"). In any aspect or embodiment described above, the bifunctional compound comprises at least one additional E3 ligase binding moiety selected from the group consisting of VLM, VLM', CLM, CLM', MLM, MLM', ILM, ILM', or a combination thereof, e.g., at least 1, 2, 3, 4, or 5 additional E3 ligase binding moieties.

[0023] In an additional aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to regulate protein degradation in a patient or subject, e.g., an animal such as a human, and to treat or ameliorate a disease state or condition regulated via the degraded protein. In certain embodiments, the therapeutic composition described herein can be used to cause degradation of a target protein for the treatment or amelioration of a disease, e.g., cancer. In yet another aspect, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound described herein comprising a CLM and a PTM, preferably linked via a linker moiety, wherein the CLM is linked to a PTM and the CLM is ubiquitinated via the ubiquitin pathway, as described elsewhere herein. The PTM recognizes a target protein, thereby allowing the target protein to bind to the target protein. When placed in proximity to a ubiquitin ligase, degradation of the target protein occurs, resulting in a concomitant reduction / inhibition of the target protein's action, resulting in control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition regulated via the target protein by reducing the level of that protein in the patient's cells.

[0024] In additional embodiments, the present disclosure provides methods for assessing (i.e., determining) the binding affinity of a CLM. In certain embodiments, the method includes providing a test agent or compound of interest, such as an agent or compound having an imide moiety, such as a phthalimide group, a phthalimide-glutarimide group, a derivatized thalidomide, a derivatized lenalidomide, or a derivatized pomalidomide, and comparing the cereblon-binding affinity and / or cereblon-inhibitory activity of the test agent or compound to agents or compounds known to bind to and / or inhibit the activity of cereblon.

[0025] In yet another aspect, the present specification provides a method of treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal, e.g., a human, the method comprising administering to a subject in need thereof a composition comprising an effective, e.g., a therapeutically effective amount, of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

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

[0027] The foregoing general description of utilities is presented for illustrative purposes only and is not intended to limit the scope of the disclosure and the appended claims. Additional objects and advantages associated with the process will be apparent to those skilled in the art in view of the claims, detailed description, and examples. For example, the various aspects and embodiments of the invention can be used in many combinations, all of which are expressly contemplated by this specification. These additional beneficial objects and embodiments are expressly included within the scope of this disclosure. Publications and other materials used to describe the background of the invention, and in particular cases to provide additional details regarding the practice, are incorporated by reference. [Brief explanation of the drawings]

[0028] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the invention. The drawings are for the purpose of illustrating embodiments of the invention only and are not to be construed as limiting the invention. Further objects, features, and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which set forth exemplary embodiments of the invention. [Figure 1A] Figure 1A is a diagram of the general principles of ROTAC function. An exemplary PROTAC includes a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that connects or joins the PTM and ULM. [Figure 1B]Figure IB is a schematic diagram of the general principles of PROTAC function, illustrating the functional applications of the PROTACs described herein. Briefly, ULM recognizes and binds a specific E3 ubiquitin ligase, and PTM binds to and recruits a target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes the attachment of ubiquitin to a lysine on the target protein via an isopeptide bond (dark circle). The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteosome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0029] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned herein are expressly incorporated by reference in their entirety.

[0030] Described herein are compositions and methods related to the surprising and unexpected discovery that an E3 ubiquitin ligase protein, such as cereblon, will ubiquitinate a target protein when the two proteins are brought into close proximity by a bifunctional or chimeric construct that binds the target protein. Accordingly, the present disclosure provides compositions and methods for ubiquitinating an E3 ubiquitin ligase protein, such as cereblon, linked to a protein target binding moiety (PTM). The present invention provides compounds and compositions comprising an ATP ligase binding moiety (ULM), results in ubiquitination of a selected target protein, leading to degradation of the target protein by the proteasome (see Figures 1A and 1B). The present disclosure also provides libraries of compositions and uses thereof.

[0031] In certain embodiments, the present disclosure provides ligands, e.g., small molecule ligands (i.e., 2,000 daltons, 1,000 daltons, 500 daltons, or 200 daltons) The present invention provides compounds comprising a small molecule, which can bind to a ubiquitin ligase, such as, for example, an IAP, VHL, MDM2, or cereblon. The compound also includes a moiety that can bind to a target protein in a manner that brings the target protein into proximity with the ubiquitin ligase, resulting in degradation (and / or inhibition) of the protein. This can mean that the molecule is non-peptidyl, i.e., has, for example, 4, 3, or 2 or more amino acids. In accordance with the present specification, a PTM, ULM, or PROTAC molecule may be a small molecule.

[0032] 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 herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0033] Where a range of values ​​is provided, unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated range, or between values ​​in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, as are any specifically excluded limits in the stated range. When the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0034] The following terms are used to describe the present invention: If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in connection with its use in describing the present invention.

[0035] As used herein, the articles "a" and "an" are used interchangeably with "a" and "an" unless the context clearly dictates otherwise. Unless otherwise indicated, the articles "a" and "b" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article in question. By way of example, "an element" means one element or more than one element.

[0036] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined. That is, in some instances, the elements are present conjunctivly and in other instances, they are present disjointly. Multiple elements listed with "and / or" should be construed in the same manner, that is, "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause can optionally be present, whether related or not to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" can, in one embodiment, refer only to A (optionally including elements other than B), in another embodiment to only B (optionally including elements other than A), and in yet another embodiment to both A and B (optionally including other elements).

[0037] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., including at least one of, but also including more than one of, a number or list of elements, and optionally including additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" will indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by terms of exclusion, such as "either," "one of," "only one of," or "exactly one of." should be interpreted as follows.

[0038] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrase "consisting essentially of" is definite or semi-definite, respectively. The term "patentable" is a transitional phrase, as set forth in Section 2111.03 of the United States Patent Examining Guidelines. It is being done.

[0039] As used herein, in the specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of all elements specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. Furthermore, this definition allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or not to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "A and In one embodiment, "at least one of A and / or B" refers to at least one A, optionally including multiple A, and no B (optionally including elements other than B). In the embodiment, it refers to at least one B, optionally including multiple Bs, and A is absent (optionally). In yet another embodiment, it refers to at least one A, optionally including multiple As, and at least one B, optionally including multiple Bs (optionally including other elements). ).

[0040] In certain methods described herein that include multiple steps or actions, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context indicates otherwise.

[0041] "Co-administration" and "co-administering" " or "combination therapy" refers to simultaneous administration (of two or more therapeutic agents) Co-administration refers to both simultaneous administration (simultaneous administration) and staggered administration (administration of one or more therapeutic agents at a time that differs from the administration of an additional therapeutic agent) while the therapeutic agents are simultaneously present in the patient's body in some, preferably effective, amount. In certain preferred embodiments, one or more of the present compounds described herein are co-administered in combination with at least one additional bioactive agent, including, particularly, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

[0042] As used herein, unless otherwise indicated, the term "compound" refers to any specific chemical compound disclosed herein, and includes tautomers, positional isomers, geometric isomers, and, where appropriate, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or deuterated forms, where appropriate in the context. Contemplated deuterated small molecules are small molecules in which one or more of the hydrogen atoms contained in the drug molecule have been replaced with deuterium.

[0043] Within its use in context, the term compound generally refers to a single compound, but may also refer to, for example, stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) of the disclosed compounds. and other compounds such as a specific enantiomer or a mixture enriched in a specific enantiomer. The term also refers, in context, to prodrug forms of compounds that have been modified to facilitate administration and deliver the compound to the active site. Note that in describing the present compounds, many substituents and, in particular, variables associated therewith are described. Those skilled in the art will understand that the molecules described herein are stable compounds, as outlined below. Where bonds are shown, both double and single bonds are depicted or understood in the context of the compounds shown and known rules regarding valency interactions.

[0044] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, together with or alone with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to lysine on a target protein, thereby targeting the specific protein substrate for proteasomal degradation. Thus, either in a complex with an E2 ubiquitin-conjugating enzyme or alone, an E3 ubiquitin ligase is involved in the transfer of ubiquitin to a targeted protein. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, and a third ubiquitin is attached to the second ubiquitin. Polyubiquitination marks a protein for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation, but may instead change their cellular location or function, for example, through binding to other proteins that contain domains that can bind ubiquitin. To further complicate the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is degraded by the proteasome. It is the lysine used to generate polyubiquitin, which is recognized by

[0045] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of an infection, condition, or pathology specific to a particular animal, e.g., a human patient, the term patient refers to the particular animal, including domestic animals, e.g., dogs or cats, or agricultural animals, e.g., horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by the context in which the term is used.

[0046] The term "effective," when used within the context of its intended use, is used to describe an amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms that are otherwise described or used in this application. Compounds and Compositions In one embodiment, the present disclosure provides a cereblon E3 ubiquitin ligase binding moiety (CLM) In one embodiment, a compound is provided comprising an E3 ubiquitin ligase binding moiety (ULM) In the formula (I), the CLM is linked to a chemical linker (L) according to the following structure: (I) L-CLM wherein L is a chemical linker group, and CLM is a cereblon E3 ubiquitin ligase binding moiety. The number and / or relative positions of the moieties in the compounds described herein are provided for illustrative purposes 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 positions of each functional moiety.

[0047] The terms ULM and CLM are used in their inclusive sense unless the context indicates otherwise. For example, the term ULM refers to any molecule that binds to cereblon (i.e., CLM ), and the term CLM also encompasses all potential cereblon E3 ubiquitin ligase binding moieties.

[0048] In another aspect, the present disclosure provides bifunctional or multifunctional PROTAC compounds useful for controlling protein activity by inducing degradation of a target protein. In certain embodiments, the compounds comprise a CLM linked directly or indirectly, e.g., covalently, to a moiety that binds to the target protein (i.e., a protein targeting moiety or "PTM"). In certain embodiments, the CLM and PTM are linked or connected via a chemical linker (L). The CLM is Cereblon E3 ubiquitin ligase recognizes the target protein, and the PTM recognizes the target By placing the protein and the ubiquitin ligase protein in close proximity, the interaction of each moiety with its target promotes the degradation of the target protein. An exemplary bifunctional compound can be depicted as follows: (II) PTM-CLM In certain embodiments, the bifunctional compound further comprises a chemical linker (L). For example, the bifunctional compound can be depicted as follows: (III) PTM-L-CLM where PTM is a protein / polypeptide targeting moiety, L is a linker, and CLM is a cereblon E3 ligase binding moiety.

[0049] In certain embodiments, the compounds described herein may contain multiple PTMs (same or different proteins). The present invention provides a method for the preparation of ubiquitin ligases (e.g., ubiquitin ligases) that specifically bind to a target protein, multiple CLMs, one or more ULMs (i.e., a moiety that specifically binds to another E3 ubiquitin ligase, e.g., VHL), or a combination thereof. In any of the aspects of the embodiments described herein, the PTM, CLM, and ULM are directly or They may be linked via one or more chemical linkers, or a combination thereof. In additional embodiments, when a compound has multiple ULMs, the ULMs may be directed to the same E3 ubiquitin ligase, or each ULM may be directed to a different E3 ubiquitin ligase. In yet a further embodiment, the compound may have multiple PTMs. When so configured, the PTMs may bind to the same target protein, or each PTM may specifically bind to a different target protein.

[0050] In another embodiment, the present invention provides a compound that is linked via a chemical linker moiety (L) or directly. For example, a compound having two CLMs may be can be illustrated as: (IV) CLM-CLM or (V) CLM-L-CLM In certain embodiments, when a compound comprises multiple CLMs, the CLMs are identical. In additional embodiments, the compound comprising multiple CLMs further comprises at least one PTM attached to the CLM directly, via a chemical linker (L), or both. In certain additional embodiments, the compound comprising multiple CLMs further comprises multiple PTMs. In still further embodiments, the PTMs are the same or, optionally, different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets.

[0051] In additional embodiments, the present disclosure provides a method for the preparation of a hydroxyl group-containing hydroxyl group, either directly or via a chemical linker (L), provides compounds comprising at least two different CLMs linked via both of them. For example, such a compound with two different CLMs can be illustrated as follows: (VI) CLM-CLM' or (VII) CLM-L-CLM' wherein CLM' represents a cereblon E3 ubiquitin ligase binding moiety that is structurally distinct from CLM. In certain embodiments, the compound comprises multiple CLMs and / or multiple CLM's. In a further embodiment, compounds comprising at least two different CLMs, multiple CLMs, and / or multiple CLM's may be linked together directly or via chemical linkers or other suitable linkers. The present invention further comprises at least one PTM linked to a CLM or a CLM' via both a CLM and a CLM'. In any of the embodiments described herein, the compound comprising at least two different CLMs is It may further comprise multiple PTMs. In yet further embodiments, the PTMs are identical or or optionally different. In still further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to a different protein target. In still further embodiments, the PTM itself is a ULM or CLM (or a ULM' or CLM').

[0052] In a preferred embodiment, the CLM is a ligator for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM comprises a chemical species derived from an "imide" species molecule. In certain additional embodiments, the CLM comprises a phthalimide group or an analog or derivative thereof. In yet further embodiments, the CLM comprises a phthalimide-glutarimide group or an analog or derivative thereof. In yet other embodiments, the CLM comprises a member of the group consisting of thalidomide, lenalidomide, pomalidomide, and analogs or derivatives thereof.

[0053] In additional embodiments, the present disclosure provides compounds described herein, including their enantiomers, diastereomers, solvates, and polymorphs, including their pharmaceutically acceptable salt forms, e.g., acid and base salt forms.

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

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] During the ceremony: W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl; Q1, Q2, Q3, Q4, and Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N, or N-oxide; R 1 is selected from absent, H, OH, CN, C1-C3 alkyl, C=O; R 2 is selected from the group consisting of: absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, and C(=O)NH2. Selected; R 3 is absent, H, alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), substituted alkyl alkyl (e.g., substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (e.g., C1-C6 alkoxy or C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C6 alkoxyl or C1-C3 alkoxyl); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently H, halogen, C(=O)R'; CN, OH, or CF3; X is C, CH, C═O or N; X1 is C=O, N, CH or CH2; R' is H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl; n is 0 to 4; and

[0060] [ka]

[0061] is a single or double bond. Exemplary CLM In any of the compounds described herein, the CLM may have a chemical structure selected from the group consisting of: Construction includes:

[0062] [ka]

[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] During the ceremony: W is independently selected from CH2, CHR, C=O, SO2, NH and N-alkyl; Q1, Q2, Q3, Q4, and Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N, or N-oxide; R 1is selected from absent, H, OH, CN, C1-C3 alkyl, C=O; R 2 is selected from the group consisting of: absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, and C(=O)NH2. Selected; R 3 is H, alkyl (e.g., C1-C6 alkyl or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 alkyl or C1-C3 alkyl), alkoxy (e.g., C1-C6 alkoxy), alkoxy (e.g., substituted C1-C6 alkoxy or C1-C3 alkoxy); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently H, halogen, C(=O)R', CN, OH, or CF3; X is C, CH, C═O or N; X1 is C=O, N, CH or CH2; R' is H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl; n is 0 to 4;

[0067] [ka]

[0068] is a single or double bond; and The CLM is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof.

[0069] In any aspect or embodiment described herein, the CLM or CLM′ may be selected from the group R ( For example, R, R 1 , R 2 , R 3 , R 4 or R′), W, X, or Q groups (e.g., Q1, Q2, Q3, Q4, or Q5) to connect to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM′, or a combination thereof is covalently bonded to

[0070] In any of the embodiments described herein, CLM or CLM′ is selected from the group consisting of W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R', Q1, Q2, Q3, Q4, and Q5 via PTM chemical linkers Group (L) is covalently bonded to ULM, CLM, CLM', or a combination thereof.

[0071] In any of the embodiments described herein, W, X, R 1 , R 2 , R 3 , R 4 , R', Q1 Q2, Q3, Q4, and Q5 may independently be covalently bonded to a linker; and / or is covalently attached to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups. This may also be done.

[0072] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0073] The term "alkyl" shall mean, within its context, a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical or group of alkyl, preferably C-C10 , more preferably C1-C6 or C1-C3 alkyl groups, which may be optionally substituted. Examples of alkyl groups are, inter alia, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclo ... Examples of alkyl groups include propyl, cyclopropyl-methyl, 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 generally contain a side chain (often attached via a polyethylene glycol group) that terminates in an alkyl group with a halogen substituent (often chlorine or bromine) at its distal end, thereby forming a covalent bond between the compound containing the moiety and the protein.

[0074] The term "alkoxy" refers to an alkyl group attached solely to oxygen. The term "alkenyl" refers to straight, branched or alkyl groups containing at least one C=C bond. or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon radicals.

[0075] The term "alkynyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C≡C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0076] The term "alkylene," when used, refers to an optionally substituted -(CH) n - group (where n is generally an integer from 0 to 6). When substituted, an alkylene group refers to a methylene group. It is preferably substituted with one or more C1-C6 alkyl groups (including cyclopropyl or t-butyl groups), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, O—(C1-C6 alkyl) groups, or any group otherwise specified herein. The disclosed amino acid side chains may be substituted. In certain embodiments, the alkylene groups may be substituted with urethane or alkoxy groups (or other groups), which may further be terminated with polyethylene glycol chains (1-10, preferably 1-6, and often 1-4 ethylene glycol chains). In yet another embodiment, the alkylene (often methylene) group is substituted with, for example, a natural or unnatural amino acid, e.g., alanine, β-alanine, argin ... the side chains of leucine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine The amino acid may be substituted with an amino acid side chain group such as a group.

[0077] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with an H. Thus, a range of carbon atoms from C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with an H replacing the carbon for C0.

[0078] The terms "substituted" or "optionally substituted" shall mean independently (i.e., when there are multiple substituents, each substituent is independent of the other substituents) one or more substituents (independently up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents, on a moiety in a compound according to the present disclosure, which may include substituents that may themselves be further substituted) at any carbon (or nitrogen) position on the molecule in context, and include as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogens (especially alkyl, especially methyl groups such as trifluoromethyl, preferably 1, 2 or 3 halogens), alkyl groups (preferably C-C 10 , more preferably C1-6), aryl (especially phenyl and substituted phenyl, for example benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl). thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl) ), ester or thioester (preferably C1-C6 alkyl or aryl), alkylene esters (where the bond is not on the ester functionality but on the alkylene group, and is preferably substituted with a C1-C6 alkyl or aryl group), preferably those containing C1-C6 alkyl or aryl, halogens (preferably F or Cl), amines (5- or 6-membered cyclic alkyl groups), and optionally substituted amines, including C1-C6 alkylamines or C1-C6 dialkylamines, wherein the alkyl groups may be substituted with one or two hydroxyl groups. -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) groups (which may optionally be substituted with a polyethylene glycol chain to which an alkyl group containing one halogen, preferably chlorine, is further attached), hydrazines, amides, which preferably contain one or two C1-C6 alkyl groups (one or (including carboxamido optionally substituted with one or two C1-C6 alkyl groups), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure include, for example, -SiR 1sub R 2sub R 3sub group, where R 1sub and R 2sub each of which is as otherwise described herein, and R 3sub is H or a C1-C6 alkyl group, and is preferably Preferably R 1sub , R 2sub , R 3sub is a C1-C3 alkyl group (including an isopropyl or t-butyl group). Each of the above groups may be directly attached to the substituted moiety, or the substituent may be an optionally substituted (CH2) m - or optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) m The alkylene group -(CH) may be linked to a substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via a - group, which may be substituted with any one or more of the above-mentioned substituents. m -or-(CH2) n - groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen, or C1-C6 (preferably and C1-C3) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or an amino acid side chain as otherwise described herein, and optionally substituted amide (preferably carboxamide, substituted as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which may also be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or an amino acid side chain as otherwise described herein. Moieties in the molecules disclosed herein may be optionally substituted with up to five substituents, preferably up to three substituents. In most cases, substituted moieties in the disclosure will be substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or an amino acid side chain as otherwise described herein. It is substituted with one or two substituents.

[0079] The term "substituted" (each substituent is independent of any other substituent) includes, within the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfone including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane-OC(O)-NR 1sub R 2sub Also -N(R 1sub )-C(O)-OR 1sub , nitro, cyano, and amine (especially C1-C6 alkylene-NR 1sub R 2sub "Alkyl-, mono- or di-C1-C6 alkyl-substituted amines, including those optionally substituted with one or two hydroxyl groups, are also intended to mean amines containing 1 to 6 carbon atoms, unless otherwise indicated within the context. In certain embodiments, preferred substituents, depending on the context in which the substituent is used, include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (wherein m and n are 1, 2, 3, 4, 5 or 6 within the context of this specification), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) nC(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R 1sub , -(CH2) n C(O)-NR 1sub R 2sub , -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R 1sub , -(CHO) n C(O)-NR 1sub R 2sub , -S(O)2-R S , -S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR 1sub R 2sub R is a substituted or unsubstituted alkyl group), NO, CN or halogen (F, Cl, Br, I, preferably F or Cl). 1sub and R 2sub Each represents, within the context, H or a C1-C6 alkyl group (one or two hydroxyl groups). The term "substituted" is also intended to mean, within the chemical context of the specified compound and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein. Alkylene groups may also be substituted as otherwise disclosed herein, and are preferably optionally substituted C1-C6 alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxy). Ethyl is preferred, thereby providing a chiral center), the side chain of an amino acid group as otherwise described herein, an amide group as described above, or a urethane group, OC(O)—NR1sub R 2sub group, wherein R 1sub and R 2sub may be substituted with groups as otherwise described herein, although many other groups can also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds where substitution is required at a particular position of the molecule (primarily for valence reasons) but no substitution is indicated, the substituent is assumed or understood to be H unless the context of the substitution suggests otherwise.

[0080] The terms "aryl" or "aromatic," in context, refer to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenylphenyl, phenanthrenyl, etc.), which may be attached to a compound in accordance with the present disclosure at any available stable position on the ring or as otherwise specified in the provided chemical structure. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as heteroaromatic ring systems, e.g., imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, among others, which may be optionally substituted as described above. Among the heteroaryl groups that may be mentioned in particular are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroquinoline, Isoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan, pyran, cyclopentene, etc. thiazolidin, benzofuran, and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen, such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0081] The term "substituted aryl" refers to an aromatic carbocyclic ring composed of at least one aromatic ring or composed of multiple fused rings, at least one of which is aromatic, in which the ring is substituted with one or more substituents. For example, an aryl group can include a substituent selected from the following: -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6) alkyl, -(CH2) n -OC(O)(C0-C6) alkyl, amine, mono- or di-(C1-C6 alkyl)amine wherein the alkyl group on the amine is optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), an optionally substituted phenyl group (which itself is preferably substituted with a linker group attached to a PTM group, including a ULM group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN groups (at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, or methyl-substituted thiazole. optionally substituted thiazoles including methyl-substituted isothiazoles, optionally substituted pyrroles including methyl-substituted pyrroles, optionally substituted imidazoles including methylimidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oximidazoles or methyloximidazoles, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl-substituted triazole groups, optionally substituted pyridine groups including halo- (preferably F) or methyl-substituted pyridine groups or oxapyridine groups, where the pyridine group is attached to the phenyl group by an oxygen, optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines, and combinations thereof.

[0082] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, while these generic substituents have the same meaning as the corresponding group definitions defined herein.

[0083] The term "heteroaryl" or "hetaryl" includes, but is not limited to, optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), indolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted (CH m -O-C1-C6 alkyl group, or optionally substituted (CH2) m It may refer to a 1,2,3-triazole substituted with a —C(O)—O—C1-C6 alkyl group), an optionally substituted pyridine (2, 3, or 4-pyridine), or a group according to the following chemical structure:

[0084] [ka]

[0085] During the ceremony, S c is CHR SS , N.R. URE , or O; R HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group, -C≡CR a wherein R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C-C alkyl (preferably H or C-C alkyl), or —C(O)(C-C alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halo groups, preferably fluorine groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C alkyl hydroxyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CRa wherein R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl).

[0086] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Heteroaryl moieties are therefore encompassed under the definition of heterocycle, depending on the context of their use. Exemplary heteroaryl groups are described herein above.

[0087] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, and the like. furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl , pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio Ranil and Chiang are examples.

[0088] Heterocyclic groups can be optionally substituted with groups selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also refers to any of the heterocycles. Also included are bicyclic groups in which is fused to a benzene or cyclohexane ring or to another heterocycle (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0089] The term "cycloalkyl" refers to alkyl groups having 3 to 20 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "substituted cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, such as, but not limited to, a saturated monocyclic hydrocarbon group having in the ring, for example, amino, halogen, alkyl, It refers to monocyclic or polycyclic alkyl groups substituted with one or more substituents such as, but not limited to, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, and these generic substituents have the same meaning as the definition of the corresponding group provided in this Description. The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0090] The term "lower alkyl" refers to methyl, ethyl, or propyl. The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0091] More specifically, non-limiting examples of CLMs include the following compounds: These include "hybrid" molecules or compounds resulting from the combination of one or more properties of Can be:

[0092] [ka]

[0093] [ka]

[0094] [ka]

[0095] During the ceremony: W is independently selected from the group consisting of CH2, CHR, C=O, SO2, NH and N-alkyl; R 1 is selected from the group consisting of absent, H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl; R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R 4 is methyl or ethyl; R 5 is H or halo; R 6 is H or halo; R in CLM is H; R' is H or a PTM, PTM', chemical linker group (L), ULM, CLM , CLM' is the attachment point, Q1 and Q2 are each independently H or C or N substituted with a group independently selected from C1-C3 alkyl;

[0096] [ka]

[0097] is a single or double bond; and Rn includes functional groups or atoms.

[0098] In any of the embodiments described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, and and Rn may independently be covalently bonded to a linker and / or to a linker that is attached to one or more PTM, ULM, ULM', CLM or CLM' groups.

[0099] In any of the embodiments described herein, R 1 , R 2Q1, Q2, Q3, Q4, and Rn may independently be covalently linked to a linker, and / or one or more PTMs, ULMs, , ULM′, CLM or a linker that is attached to the CLM′ group.

[0100] In any of the embodiments described herein, Q1, Q2, Q3, Q4, and Rn may independently be covalently coupled to a linker and / or to a linker that is attached to one or more PTM, ULM, ULM', CLM, or CLM' groups.

[0101] In any aspect or embodiment described herein, R n is modified to be covalently attached to a linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM', a second linker, or any multiple or combination thereof.

[0102] In any aspect or embodiment described herein, the CLM is selected from: R:

[0103] [ka]

[0104] [ka]

[0105] where R' is a halogen and R 1 may be any of the aspects or embodiments described herein. As stated.

[0106] In certain instances, the "CLM" may be an imide that binds to cereblon E3 ligase. These imide and linker attachment points may be, but are not limited to, the following structures:

[0107] [ka]

[0108] Exemplary Linkers In certain embodiments, the compounds described herein can be linked together via one or more chemical linkers (L). In certain embodiments, the PTMs include one or more CLMs chemically bonded or linked to the PTMs (e.g., PTMs and / or PTM's), ULMs (e.g., ULMs, ULM's and / or CLM's). The linker group L is a group comprising one or more covalently linked structural units (e.g., -A L 1… (A L ) q -or-(A L ) q -), in which A1 is a group linked to a PTM and Aq is a group linked to at least one of a ULM, a ULM', a CLM, a CLM', or a combination thereof. In certain embodiments, A L 1. The CLM or CLM' may be combined with another ULM, PTM, or is directly attached to the combination. L 1, CLM or CLM', A q is indirectly linked to another ULM, PTM, or combination thereof via

[0109] In certain embodiments, the linker group is -(A L ) q - in which (A L ) q is linked to at least one of a ULM moiety, a PTM moiety, or a combination thereof is a group; q of the linker is an integer of 1 or greater; Each A L is a bond, CR L1 R L2 , O, S, SO, SO2, NRL3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO2)NR L4 , optionally 0 to 6 R L1 and / or R L2 substituted with a group RuC 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with a group 5-13 vinegar pyrocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with a group 3-11 Hetero Cyclyl, optionally 0 to 8 R L1 and / or R L2 C substituted with group 5-13 spiroheterocycloalkyl, optionally 0 to 6 R L1 and / or R L2 aryl substituted with a group, optionally 0 to 6 R L1 and / or R L2 Independently selected from the group consisting of heteroaryl substituted with a group where R L1 or R L2 are each independently optionally bonded to other groups and optionally have 0 to 4 R L5 forming a cycloalkyl and / or heterocyclyl moiety substituted with a group, and R L1 , R L2, R L3 , R L4 and R L5 are independently H, halo, and C 1-8 Alkyl, OC 1-8 Al Kill, 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 Cycloal Kill, NHC 1-8 Cycloalkyl, N(C 1-8 cycloalkyl)2, N(C 1-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5 , SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl) SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, NH SO2 NH2.

[0110] In certain embodiments, the q of the linker is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1.

[0111] In certain embodiments, for example when q is greater than 2, A L q is a ULM or ULM' moiety (e.g., A is a group bonded to a L 1 and A L q are linked via a structural unit of a linker (L).

[0112] In certain embodiments, for example, when q of the linker is 2, A L q is A L 1, and ULM or is a group attached to the ULM′ moiety (e.g., CLM or CLM′).

[0113] In certain embodiments, for example when the linker has q=1, the linker group L has the structure -A L 1- and A L 1 is a group that is attached to a ULM or ULM' moiety (e.g., a CLM or CLM') and a PTM moiety.

[0114] In certain embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -NR(CH2) n-(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(Low-level Arco -OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -( (chloroalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(Low grade alkyl)-O-aryl-CH2, -NR(CH2CH2O) n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocycle)- CH 2, -NR(CH2CH2) n -(heterocycle)-(heterocycle)-2, -N(R1R2)-(heterocycle)-CH2; n in the linker may be 0 to 10; R of the linker can be H, lower alkyl; The linkers R1 and R2 may form a ring with an N bond.

[0115] In certain embodiments, the linker (L) comprises a group represented by a general structure selected from the group consisting of: -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-, -O-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -N(R)-(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -O-; -(CH2) m -O(CH2) n -O(CH2) o -O(CH2) p -O(CH2) q -O(CH2) r -OCH2-;

[0116] [ka]

[0117] [ka]

[0118] During the ceremony, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; If the number is zero, there are no NO or OO bonds, R of the linker is H, methyl and ethyl; X of the linker is H and F;

[0119] [ka]

[0120] wherein m in the linker can be 2, 3, 4, or 5;

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] [ka]

[0130] wherein m and n of the linker may each independently be 0, 1, 2, 3, 4, 5, or 6. good.

[0131] In any aspect or embodiment described herein, the linker (L) may be one of: Selected from the group consisting of:

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6. In any aspect or embodiment described herein, the linker (L) may be one of: Selected from the group consisting of:

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147]

change

[0148]

change

[0149]

change

[0150]

change

[0151]

change

[0152]

change

[0153]

change

[0154]

change

[0155]

change

[0156]

change

[0157] [ka]

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka]

[0163] [ka]

[0164] [ka]

[0165] [ka]

[0166] wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0167] In any aspect or embodiment described herein, L is selected from the group consisting of: Selected:

[0168] [ka]

[0169] [ka]

[0170] [ka]

[0171] [ka]

[0172] [ka]

[0173] [ka]

[0174] [ka]

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka]

[0179] In additional embodiments, the linker (L) comprises a structure selected from, but not limited to, the structures shown below, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0180] [ka]

[0181] During the ceremony: W L1 and W L2 are each independently, R Q 4 with 0-4 heteroatoms, optionally substituted with 8-membered ring, and each R Q are independently H, halo, OH, CN, CF, C-C alkyl (optionally substituted straight or branched chain), C-C alkoxy (optionally substituted straight or branched chain); or two R's Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, C1-C6 alkyl (optionally substituted straight chain, branched chain), and optionally one or more C atoms are O, or C1-C6 alkoxy (optionally substituted straight chain, branched chain), , branched chain); n is 0 to 10; and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0182] In additional embodiments, the linker (L) may be selected from, but is not limited to, the structures shown below: The selected structures include, where the dashed line indicates the point of attachment to the PTM or ULM moiety:

[0183] [ka]

[0184] During the ceremony: W L1 and W L2 are each independently aryl, heteroaryl, cyclic, heterocyclic, C 1~6 alkyl, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each of which Optionally, R Q Each R is replaced by Q are independently H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2~6 Alkenyl, C 2~6 Alkynyl, C1-C6 alkyl (optionally substituted straight or branched chain), C1-C6 alkoxy (optionally substituted straight or branched chain), OC 1~3 Alkyl ( (optionally substituted with one or more -F), OH, NH2, NR Y1 R Y2 , CN or two R Q the groups, together with the atoms to which they are attached, form a 4-8 membered ring system containing 0-4 heteroatoms; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted), and optionally one or more C atoms is substituted with O, C1-C6 alkoxy (optionally substituted straight chain, branched chain); Q L is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, and optionally containing 0-6 R Q Each R is replaced by Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 substituted with alkoxyl) or two R Qgroups together with the atoms to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); R YL1 , R YL2 are independently H, OH, and C 1-6 Alkyl (straight or branched chain, optionally with one or more Upper halo, C 1-6 substituted with alkoxyl) or R 1 , R 2 together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); n is 0 to 10; and The dashed lines indicate the points of attachment to the PTM or ULM moieties.

[0185] In additional embodiments, the linker group comprises from about 1 to about 100 ethylene glycol units, from about 1 to about 100 ethylene glycol units, An optionally substituted (poly)ethylene glycol having about 50 ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, about 2 to 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0186] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0187] In another embodiment, the present disclosure is directed to compounds comprising PTM groups, The group binds to a target protein or polypeptide, ubiquitinating it with a ubiquitin ligase and chemically linking it directly to a ULM group (e.g., CLM) or through a linker moiety, L. Alternatively, the PTM is a ULM' group (e.g., CLM'), which is also a ubiquitin ligase binding moiety and may be the same as or different from the ULM group described above; is attached to the ULM group through a linker moiety or directly, and L is a linker moiety as described above, which may or may not be present, that chemically couples (covalently bonds) the ULM and PTM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

[0188] In certain embodiments, the linker group L is one or more independently selected from the group consisting of: is a group containing the above covalently bonded structural units:

[0189] [ka]

[0190] X is selected from the group consisting of O, N, S, S(O), and SO2; n is an integer from 1 to 5; RL 1 is water is a nitrogen or alkyl;

[0191] [ka]

[0192] is a monocyclic or bicyclic aryl or heteroaryl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano;

[0193] [ka]

[0194] is a monocyclic or bicyclic cycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; and the phenyl ring fragment is a monocyclic or bicyclic cycloalkyl or heterocycloalkyl optionally substituted with 1 to 3 substituents selected from alkyl, halogen, haloalkyl, hydroxy, alkoxy, or cyano; The linker group L may be optionally substituted with one, two, or three substituents selected from the group consisting of alkyl, hydroxy, alkoxy, and cyano. In certain embodiments, the linker group L comprises up to 10 covalently linked structural units as described above.

[0195] The ULM and PTM groups may be covalently attached to the linker group via any group that is appropriate and stable for the linker chemistry, and in preferred embodiments of the disclosure, the linker is independently covalently attached to the ULM and PTM groups, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which groups is inserted either on the ULM or PTM group to maximize binding of the ULM group to the ubiquitin ligase and its degradation. (In particular, the PTM group may be a ULM group.) (Note that in certain preferred embodiments, the target protein to be degraded can also 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 group.

[0196] In additional embodiments, q is an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 1 to 20, or 1 to 10.

[0197] In certain embodiments, the linker (L) is selected from the group consisting of:

[0198] [ka]

[0199] [ka]

[0200] In additional embodiments, the linker group comprises from about 1 to about 100 ethylene glycol units, from about 1 to about 100 ethylene glycol units, An optionally substituted (poly)ethylene glycol having about 50 ethylene glycol units, about 1 to about 25 ethylene glycol units, about 1 to 10 ethylene glycol units, 1 to about 8 ethylene glycol units, and 1 to 6 ethylene glycol units, about 2 to 4 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P, or Si atoms. In certain embodiments, the linker is substituted with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic group. In certain embodiments, the linker may be asymmetric or symmetric.

[0201] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety described herein. In one embodiment, the linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, from 1 to about 10 ethylene glycol units, from about 2 to 6 ethylene glycol units, from about 2 to 5 ethylene glycol units, or from about 2 to 4 ethylene glycol units.

[0202] The CLM (or ULM) and PTM groups are suitable for the linker chemistry and are suitable for stable selection. In a preferred embodiment of the present disclosure, the linker is independently covalently attached to the CLM group and the PTM group, preferably via an amide, ester, thioester, keto group, carbamate (urethane), carbon, or ether, each of which is inserted on either the CLM group or the PTM group, to provide maximum binding of the CLM group to the ubiquitin ligase. This can provide for maximum binding of the PTM group to the target protein to be degraded. (In certain embodiments, the PTM group is a ULM group, the target protein to be degraded is the ubiquitin ligase itself. (Note that it can also be a CLM group.) In certain preferred embodiments, the linker comprises a CLM group and and / or optionally substituted alkyl, alkylene, alkene or alkylene groups on the PTM group. The aryl group may be bonded to a phenyl group, an aryl group or a heterocyclic group.

[0203] In certain embodiments, "L" may be a straight chain with 4 to 24 linear atoms, and the carbon atoms in the straight chain may be substituted with oxygen, nitrogen, amide, fluorinated carbon, etc., e.g., For example:

[0204] [ka]

[0205] [ka]

[0206] In certain embodiments, "L" may be non-linear, aliphatic or aromatic or polycyclic. Some examples of "L" include, but are not limited to, These include:

[0207] [ka]

[0208] [ka]

[0209] During the ceremony: "X" in the above structure may be a straight chain with a range of 2-14 atoms, said chain may contain heteroatoms such as oxygen; and "Y" in the above structure is O, N, S(O) n (n=0, 1, 2) may also be used. Exemplary PTMs In a preferred embodiment of the present disclosure, the PTM group is a group that binds to a target protein. The target of the PTM group is a variety of proteins, at least a portion of whose sequence is present in the cell and can bind to the PTM group. The target is selected from proteins expressed in cells, such as: The term "protein" refers to an oligonucleotide sequence of sufficient length that can be attached to a PTM group in accordance with the present disclosure. and polypeptide sequences. As otherwise described herein, any protein in a eukaryotic system or a microbial system, including viruses, bacteria, or fungi, is a target for ubiquitination regulated by the disclosed compounds. Preferably, the target protein is a eukaryotic protein. In certain embodiments, the protein-binding moiety is a haloalkane (preferably C1-C 10 an alkyl group and at least one halo group, preferably at the distal end of the alkyl group; substituted with a terminal halo group, i.e., a halo group distal to the linker or CLM group), The dehalogenase may be covalently attached to a subject or a dehalogenase in a diagnostic assay.

[0210] PTM groups according to the present disclosure include, for example, any moiety that specifically binds to a protein (binds to a target protein), and include the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, androgen receptor inhibitors, HDM2 & MDM2 inhibitors, human BET Compounds targeting bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds specifically targeting the aryl hydrocarbon receptor (AHR). The compositions below exemplify some of the components of these nine types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. These binding moieties are attached to ubiquitin ligase binding moieties, preferably through a linker, to present the target protein (to which the protein target moiety is attached) in proximity to the ubiquitin ligase for ubiquitination and degradation.

[0211] Any protein that can be bound to a protein targeting moiety or PTM group and acted upon or degraded by a ubiquitin ligase is a target protein in accordance with the present disclosure. In general, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, and proteins involved in cellular integration functions, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, redox activity, transferase activity, hydrolytic activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, iron transport activity, channel transport activity, carrier activity, permeability activity, secretion activity, electron transport activity), phagocytosis, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular integration and biosynthetic activity, and translation regulatory activity. Proteins of interest include proteins from eukaryotes and prokaryotes, including humans and other animals as targets for drug therapy, including livestock animals, microorganisms for determining targets for antibiotics and other antimicrobial agents, and plants, and especially viruses.

[0212] In yet other embodiments, the PTM groups are haloalkyl groups, the alkyl groups generally being Sizes from about 1 or 2 to about 12 carbons long, often about 2 to 10 carbons long Haloalkyl groups are generally linear alkyl groups (although branched alkyl groups can also be used) and contain at least one halogen group, preferably a single halogen group, and often a single halogen group. The haloalkyl P group used in this disclosure preferably has the chemical structure -(CH) v -halo, where v is any integer from 2 to about 12. , often about 3 to about 8, more often about 4 to about 6. Halo can be any halogen, but is preferably Cl or Br, and is often Cl.

[0213] In another embodiment, the disclosure provides a library of compounds. The library comprises a plurality of compounds, wherein each compound has the formula AB, where A is a ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin ligase as otherwise disclosed herein). A is a ubiquitin-binding protein (preferably a linker moiety), and B is a protein binding agent of a molecular library, in which case A is linked to B (preferably via a linker moiety), and in which case A is a ubiquitin-binding protein. The cereblon pathway protein binding moieties recognize ubiquitin pathway proteins, particularly E3 ubiquitin ligases such as cereblon. In certain embodiments, the library contains specific cereblon E3 ubiquitin ligase binding moieties bound to random target protein binding factors (e.g., a chemical compound library). Thus, the target protein is not predetermined, and the method can be used to determine the activity of the putative protein binding factor and its pharmacological value as a target for degradation by ubiquitin ligase.

[0214] The present disclosure may be used to treat many disease states and / or conditions, including any disease state and / or condition in which a protein is deregulated and in which the patient would benefit from protein degradation.

[0215] In a further aspect, the present disclosure provides therapeutic compositions comprising an effective amount of a compound described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally, an additional bioactive agent. The therapeutic compositions can be used to regulate protein degradation in a patient or subject, e.g., an animal such as a human, and to treat or improve a disease state or condition regulated through the degraded protein. In certain embodiments, the therapeutic compositions described herein can be used to cause the degradation of a target protein for the purpose of treating or improving a disease, such as cancer (e.g., prostate cancer) and Kennedy's disease. In certain additional embodiments, the disease is prostate cancer.

[0216] In another aspect, the present disclosure relates to a method for treating a pathology or ameliorating the symptoms of a disease or condition in a subject in need thereof by degrading a protein or polypeptide, wherein the pathology or condition is regulated via the protein or polypeptide, the method comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described above, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle, and optionally an additional bioactive agent, wherein the composition is effective in treating or ameliorating the disease or disorder or its symptoms in the subject. Using the disclosed methods, many conditions or symptoms can be treated by administering an effective amount of at least one compound described herein. The pathology or condition may be a disease caused by a microbial organism or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a pathology caused by overexpression of a protein resulting in the pathology and / or condition.

[0217] In another aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0218] The term "target protein" is used hereinafter to describe a protein or polypeptide to which the disclosed compounds bind and are targeted for degradation by ubiquitin ligase. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target a protein of interest. These binding moieties are linked via a linker group to a CLM or is attached to a ULM group.

[0219] Target proteins that can be bound to a protein target moiety and to which a ubiquitin ligase binding moiety can bind and be degraded by the ligase include any protein or peptide, fragment thereof, analog thereof, and / or homolog thereof. Target proteins include proteins and peptides with any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, conservation, transport, and signal transduction. In certain embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, and proteins with catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, redox activity, transferase activity, hydrolytic activity, lyase activity, isomerase activity, ligase activity, enzyme regulation activity, signal transduction activity, structural molecule activity, binding activity (proteins, lipids carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulus response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity, etc.). (including phagocytosis, chaperone regulation, nucleic acid Proteins involved in the cellular integration function include proteins involved in binding activity, transcriptional regulation activity, extracellular integration and biosynthesis activity, and translational regulation activity. Proteins of interest include proteins from eukaryotes and prokaryotes, including microorganisms, viruses, fungi, and parasites, other animals, including humans, particularly as targets for drug therapy, microorganisms, viruses, fungi, and parasites, including livestock animals, microorganisms for determining targets for antibiotics and other antimicrobial agents, and plants, particularly viruses.

[0220] More specifically, many of the drug targets for human therapy are protein targets to which protein targeting moieties can be bound and incorporated into compounds according to the present disclosure. These proteins include proteins that can be used to restore function in many polygenic diseases, such as B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, BclIBax and other partner factors in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase, PDE IV phosphodiesterase 4, PDEI, PDEII, PDEIII , squalane cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo- Oxygenase 1, cyclo-oxygenase 2, 5HT receptor, dopamine receptor, G protein Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomes Mal, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1 integrase, influenza neuraminidase, hepatitis B virus reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 alteration Recombinase, Caspase, HCV, NS3 protease, HCV NS3 RNA helicase, Glycinamide nucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly ... ADP-ribose polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5α-reductase inhibitors, angiotensin I, glycine receptors, noradrenaline reuptake receptors, endothelin receptors, neuropeptide Y and receptors, estrogen receptors, and gen receptor (AR), adenosine receptor, adenosine kinase and AMP deaminase, Purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA NGF receptor, beta-amyloid, Tyrosine kinases Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neu, telomerase inhibitor, cytosolic phospholipase A2, and EGF receptor tyrosine kinase Additional protein targets include, for example, ecdysone 20-monooxygenase. These include acetyl-CoA carboxylase, adenosine triphosphate (APT), GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. These include succinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0221] Haloalkane dehydrogenase enzymes are another target of certain compounds according to the present disclosure. 12 , often around C2-C 10 Compounds according to the present disclosure containing an alkylhalo group may be used to inhibit and / or degrade haloalkane dehydrogenase enzymes used in fusion proteins or related diagnostic proteins as described in PCT / US2012 / 063401, filed December 6, 2011, and published June 14, 2012 as WO 2012 / 078559, the contents of which are incorporated herein by reference. No. 60 / 699,493, filed on Oct. 1, 2003, and incorporated herein by reference.

[0222] These various protein targets may be used in screens to identify compound moieties that bind to the protein, and by incorporating the moieties into the disclosed compounds, the activity level of the protein can be altered for therapeutic end results.

[0223] The term "protein targeting moiety" or "PTM" refers to a target protein or other molecule of interest. The term "small molecule" is used to describe a small molecule that binds to a protein or polypeptide and positions / presents the protein or polypeptide in proximity to a ubiquitin ligase so that degradation of the protein or polypeptide by the ubiquitin ligase can occur. Non-limiting examples of small molecule target protein binding moieties include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds that specifically target the aryl hydrocarbon receptor (AHR). The compositions described below target components of these nine types of small molecule target proteins. Here are some examples:

[0224] Examples of protein targeting moieties in accordance with the present disclosure include Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).

[0225] The compositions below exemplify some of these types of small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest. The references cited herein below are incorporated by reference in their entirety. I. Heat Shock Protein 90 (HSP90) Inhibitors: As used herein, HSP90 inhibitors include, but are not limited to: Available: 1. Vallee, et al., "Tricyclic Series of Heat Shock Protein 90 (HSP90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the HSP90 Molecular Chaperone (2011) J. Med. Chem. 54: 7206 P90 inhibitor: YKB (N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]- Cinnamid) containing:

[0226] [ka]

[0227] derivatized, with a linker group L or -(L-CLM) group attached, for example, via a terminal amide group; 2. HSP90 inhibitor p54 (modified) (8-[(2,4-dimethylphenyl)sulfanyl]-3]pent-4-yn-1-yl-3H-purin-6-amine):

[0228] [ka]

[0229] derivatized, with a linker group L or -(L-CLM) group attached, for example, via a terminal acetylene group; 3. Brough, et al., "4,5-Diarylisoxazole HSP90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer", J.MED.CHEM. vol: 51, p: 196 (2008), HSP90 inhibitor (modified type), compound 2GJ (5-[2,4- dihydroxy-5-(1-methylethyl)phenyl]-n-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide):

[0230] [ka]

[0231] Derivatized, the linker group L or -(L-CLM) group can be attached, for example, via an amide group (an amine, or alkyl groups on the amine); 4. HSP90 inhibitors (modified) identified in Wright, et al., Structure-Activity Relationships in Purine-Based Inhibitor Binding to HSP90 Isoforms, Chem Biol. 2004 Jun;11(6):775-85, including the HSP90 inhibitor PU3 having the following structure:

[0232] [ka]

[0233] derivatized, and a linker group L or -(L-CLM) is attached, for example, via a butyl group; and 5. HSP90 inhibitor geldanamycin ((4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[4.1.2.1]methyl) B [16.3.1] (derivatized) or its derivatives (e.g., 17-alkylamino-17-desmethoxamine) 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (17-AAG) or 17-(2-dimethylaminoethyl)amino-17-desmethoxygeldanamycin (17-DMAG)) (derivatized, with a linker group L or -(L-CLM) group, e.g. For example, via an amide group). II. Kinase and Phosphatase Inhibitors: As used herein, kinase inhibitors include, but are not limited to: 1. Erlotinib derivative tyrosine kinase inhibitors:

[0234] [ka]

[0235] wherein R is a linker group L or a -(L-CLM) group attached, for example, via an ether group. ; 2. Kinase inhibitor sunitinib (derivatized):

[0236] [ka]

[0237] derivatized, where R is, for example, a linker group L or a -(L-CLM) group attached to the pyrrole moiety; 3. Kinase inhibitor sorafenib (derivatized):

[0238] [ka]

[0239] derivatized, where R is a linker group L or -(L-CLM) attached to, for example, the amide moiety. It is a base; 4. Kinase inhibitor desatinib (derivatized):

[0240] [ka]

[0241] derivatized, where R is a linker group L or -(L-CLM), for example, attached to the pyrimidine; 5. Kinase inhibitor Lapatinib (derivatized):

[0242] [ka]

[0243] derivatized, with a linker group L or -(L-CLM) group attached, for example, via the terminal methyl of the sulfonylmethyl group; 6. Kinase inhibitor U09-CX-5279 (derivatized):

[0244] [ka]

[0245] derivatized, wherein the linker group L or -(L-CLM) group is attached to the cyclopropyl group or the cyclopropyl group via, for example, an amine (aniline), a carboxylic acid, or an amine alpha; 7. Kinase inhibitors identified in Millan, et al., Design and Synthesis of Inhaled P38 Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease, J.MED.CHEM. vol:54, pag:7797 (2011), including kinase inhibitors Y1W and Y1X (derivatized) having the following structures:

[0246] [ka]

[0247] YIX (1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea, derivatized, the linker group L or the -(L-CLM) group can be e.g. i attached via a propyl group;

[0248] [ka]

[0249] YIW 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 derivatized, with a linker group L or -(L-CLM) group attached, for example, preferably via either an i-propyl group or a t-butyl group; 8. Kinase inhibitors identified in Schenkel, et al., "Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors," J. Med. Chem., 2011, 54 (24), pp. 8440-8450, include compounds 6TP and 0TP (derivatized) having the following structures:

[0250] [ka]

[0251] 6TP 4-Amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide Thienopyridine 19 derivatized, with a linker group L or -(L-CLM) group attached, for example, via a terminal methyl group attached to the amide moiety;

[0252] [ka]

[0253] 0TP 4-Amino-N-methyl-2-[4-(morpholin-4-yl)phenyl]thieno[3,2-c]pyridine-7-carboxamide Voxamide Thienopyridine 8 derivatized, with a linker group L or -(L-CLM) group attached, for example, via a terminal methyl group attached to the amide moiety; 9. A kinase inhibitor identified in Van Eis, et al., "2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes," Biorg. Med. Chem. Lett. 2011 Dec 15;21(24):7367-72. The kinase inhibitor O7U having the following structure was used: include:

[0254] [ka]

[0255] 07U 2-Methyl-N~1~-[3-(pyridin-4-yl)-2,6-naphthyridin-1-yl]propane-1,2-diamine derivatized, such that a linker group L or -(L-CLM) group is attached, for example, via a secondary amine or terminal amino group; 10. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011). Kinases having the following structure: Contains enzyme inhibitor YCF:

[0256] [ka]

[0257] derivatized, with a linker group L or -(L-CLM) group attached, for example, via one of the terminal hydroxyl groups; 11. Kinase inhibitors identified in Lountos, et al., "Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy", J.STRUCT.BIOL. vol:176, pag:292 (2011). Kinases having the following structure: Enzyme inhibitors XK9 and NXP (derivatized):

[0258] [ka]

[0259] XK9 N-{4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide;

[0260] [ka]

[0261] NXP N-{4-[(1E)-N-carbamimidoylethanehydrazonoyl]phenyl}-1H-indole-3-carboxamide derivatized, the linker group L or -(L-CLM) group is, for example, a terminal hydroxyl group (XK9) or or hydrazone groups (NXP); 12. Kinase inhibitor afatinib (derivatized) (N-[4-[(3-chloro-4-fluorophenyl) (3S)-tetrahydro-3-furanyloxy]-6-quinazolinyl]-4(dimethylamino)-7-[[(3S)-tetrahydro-3-furanyloxy]-6-quinazolinyl]-4(dimethylamino) and the linker group L or -(L-CLM) group is, for example, a lipid attached via an aliphatic amine group); 13. Kinase inhibitor fostamatinib (derivatized) ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b]-1,4-oxazin-4-yl]methyl phosphate disodium hexahydrate) (derivatized, the linker group L or -(L-CLM) group is attached, for example, via a methoxy group ru); 14. Kinase inhibitor gefitinib (derivatized) (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine):

[0262] [ka]

[0263] derivatized, where a linker group L or -(L-CLM) group is attached, for example, via a methoxy group or an ether group; 15. Kinase inhibitor Lenvatinib (derivatized) (4-[3-chloro-4-(cyclopropylcarbamate) bamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide) (derivatized , wherein the linker group L or -(L-CLM) group is attached, for example, via a cyclopropyl group; 16. The kinase inhibitor vandetanib (derivatized) (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) (derivatized, the linker group L or -(L-CLM) group being attached, for example, via a methoxy group or a hydroxyl group); 17. Kinase inhibitor Vemurafenib (derivatized) (propane-1-sulfonic acid {3-[5-(4- derivatized with a linker group L or -(L-CLM) group, for example, a sulfonyl group. attached via a propyl group; 18. Kinase inhibitor Gleevec (derivatized):

[0264] [ka]

[0265] derivatized, where R as a linker group L or -(L-CLM) group is derivatized, for example via an amide group. or attached via an aniline amine group; 19. Kinase inhibitor Pazopanib (derivatized) (VEGFR3 inhibitor):

[0266] [ka]

[0267] derivatized, where R is attached to, for example, a phenyl moiety, or an aniline amine group a linker group L or a -(L-CLM) group attached via 20. Kinase Inhibitor AT-9283 (Derivatized) Aurora Kinase Inhibitor

[0268] [ka]

[0269] wherein R is a linker group L or a -(L-CLM) group attached to, for example, the phenyl moiety; 21. Kinase inhibitor TAE684 (derivatized) ALK inhibitor

[0270] [ka]

[0271] wherein R is a linker group L or a -(L-CLM) group attached to, for example, the phenyl moiety; 22. Kinase inhibitor Nilotanib (derivatized) Abl inhibitor:

[0272] [ka]

[0273] derivatized, where R is a phenyl moiety or a phenylamine group attached to the aniline moiety. an anchor group L or a -(L-CLM) group; 23. Kinase inhibitor NVP-BSK805 (derivatized) JAK2 inhibitor

[0274] [ka]

[0275] derivatized, where R is a linker attached to, for example, a phenyl moiety or a diazole group. - a group L or a group -(L-CLM); 24. Kinase inhibitor Crizotinib-derivatized Alk inhibitor

[0276] [ka]

[0277] derivatized, where R is a linker attached to, for example, a phenyl moiety or a diazole group. - a group L or a group -(L-CLM); 25. Kinase inhibitor JNJ FMS (derivatized) inhibitor

[0278] [ka]

[0279] derivatized, where R is, for example, a linker group L or a -(L-CLM) group attached to the phenyl moiety; 26. Kinase inhibitor Foretinib (derivatized) Met inhibitor

[0280] [ka]

[0281] derivatized, where R is, for example, a phenyl moiety, or a hydroxyl on the quinoline moiety. a linker group L or -(L-CLM) group attached to a group or ether group; 27. Allosteric Protein Tyrosine Phosphatase Inhibitor PTP1B (Derivatized) :

[0282] [ka]

[0283] derivatized, where the linker group L or -(L-CLM) group is attached, for example, at R where specified. be; 28. Inhibitors of the SHP-2 domain of tyrosine phosphatases (derivatized):

[0284] [ka]

[0285] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R; 29. BRAF inhibitors (derivatized) (BRAF V600E ) / MEK:

[0286] [ka]

[0287] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R; 30. Tyrosine kinase ABL inhibitor (derivatized)

[0288] [ka]

[0289] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R; 31. Kinase inhibitor OSI-027 (derivatized) mTORC1 / 2 inhibitor

[0290] [ka]

[0291] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R; 32. Kinase inhibitor OSI-930 (derivatized) c-Kit / KDR inhibitor

[0292] [ka]

[0293] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R; and 33. Kinase inhibitor OSI-906 (derivatized) IGF1R / IR inhibitor

[0294] [ka]

[0295] derivatized, where a linker group L or -(L-CLM) group is attached, for example, at R. In any of the embodiments described in Sections I-XVII, "R" may be a linker group L, or designates the attachment site of the -(L-CLM) group on the piperazine moiety. III. HDM2 / MDM2 inhibitors: As used herein, HDM2 / MDM2 inhibitors include, but are not limited to, the following: Examples include: 1. HDM2 / MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol: 303, pag: 844-848 (2004), and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908. The compounds Nutrin-3, Nutrin-2, and Nutrin-3 described below are HDM2 / MDM2 inhibitors identified in Vassilev, et al., In vivo activation of the p53 pathway by small-molecule antagonists of MDM2, SCIENCE vol: 303, pag: 844-848 (2004), and Schneekloth, et al., Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics, Bioorg. Med. Chem. Lett. 18 (2008) 5904-5908. and Nutrin-1 (derivatized), and all derivatives and analogs thereof, including (or additionally including):

[0296] [ka]

[0297] (derivatized, where the linker group L or -(L-CLM) group is attached, for example, at a methoxy group or as a hydroxyl group);

[0298] [ka]

[0299] (derivatized, where the linker group L or -(L-CLM) group is attached, for example, through a methoxy group or a hydroxyl group);

[0300] [ka]

[0301] (derivatized, where the linker group L or -(L-CLM) group is attached, for example, via a methoxy group or as a hydroxyl group); and 2. trans-4-iodo-4'-boranyl-chalcone

[0302] [ka]

[0303] (derivatized, where the linker group L or the linker group L or -(L-CLM) group is attached, for example, via a hydroxy group). IV. Compounds targeting human BET bromodomain-containing proteins: In certain embodiments, a "PTM" is a bromo- and specific end (BET) protein. The human BET bromodome may be a ligand that binds to BRD2, BRD3, and BRD4. Compounds that target amino acid-containing proteins include, but are not limited to, compounds that associate with targets as described below, where "R" or "Linker" designates the site of attachment of the linker group L or -(L-CLM) group, for example: 1. JQ1, Filippakopoulos et al. Selectiveinhibition of BET bromodomains. Nature (2010):

[0304] [ka]

[0305] 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):

[0306] [ka]

[0307] 3. Compounds described in Hewings et al. 3,5-Dimethylisoxazoles Act as Acetyl-lysine Bromodomain Ligands. J. Med. Chem. (2011) 54 6761-6770.

[0308] [ka]

[0309] 4. I-BET151, Dawson et al.Inhibition of BET Recruitment to Chromatin as an Effective Treatment forMLL-fusion Leukemia. Nature (2011):

[0310] [ka]

[0311] 5. Carbazole type (US 2015 / 0256700)

[0312] [ka]

[0313] 6. Pyrrolopyridone type (US 2015 / 0148342)

[0314] [ka]

[0315] 7. Tetrahydroquinoline type (WO2015 / 074064)

[0316] [ka]

[0317] 8. Triazolopyrazine type (WO 2015 / 067770)

[0318] [ka]

[0319] 9. Pyridone type (WO 2015 / 022332)

[0320] [ka]

[0321] 10. Quinazolinone type (WO 2015 / 015318)

[0322] [ka]

[0323] 11. Dihydropyridopyrazinone type (WO2015 / 011084)

[0324] [ka]

[0325] where R or L or linker in each instance designates the site of attachment of, for example, a linker group L or a -(L-CLM) group.

[0326] In any aspect or embodiment described herein, the claimed structure of the PTM may be comprised of a tricyclic diazepine or tricyclic azepine as a BET / BRD4 ligand (PTM-a), where the dashed line indicates the trajectory of the linker attachment and three sites to which the linker may be attached. is provided:

[0327] [ka]

[0328] During the ceremony: A and B are independently an aromatic ring, an aromatic heterocycle, a 5-membered carbocycle, a 6-membered carbocycle, or a 5-membered heterocycle. Formula, 6-membered heterocyclic, thiophene, pyrrole, pyrazole, pyridine, pyrimidine, pyrazine are optionally substituted with alkyl, aroxy, halogen, nitrile, or another aromatic or heteroaromatic ring, where A is fused to a central azepine (Y1=C) or diazepine (Y1=N) moiety; Y1, Y2, and Y3 and Y4 may be carbon, nitrogen, or oxygen, and are intended to form a fused 5-membered aromatic ring as in triazole or isoxazole; and Z1 is methyl or a lower alkyl group.

[0329] Fragments of PTM-a as BET / BRD4 ligands are described in the literature (WO 2016 / 069578; WO2014 / 001356; WO2016 / 050821; WO 2015 / 195863; WO2014 / 128111).

[0330] In any aspect or embodiment described herein that includes the structure of CLM-L-PTM-a, PTM-a can be represented by the following general structure, where the dashed lines indicate potential linker attachment points: In the structures of PTM-aa through PTM-ai, the substitution patterns of X and Y can be mono- or di-substituted.

[0331] [ka]

[0332] [ka]

[0333] [ka]

[0334] In any aspect or embodiment described herein, the structure of PTM-a as a BET / BRD4 ligand includes the following, where the dashed line indicates the point of attachment between BET / BRD4 and the linker: Showing:

[0335] [ka]

[0336] [ka]

[0337] [ka]

[0338] In certain embodiments, the present specification provides, but is not limited to, the following exemplary BET PROTACs (compounds 1 or 2), including salts, prodrugs, polymorphs, analogs, derivatives, and deuterated forms thereof:

[0339] [ka]

[0340] [ka]

[0341] V. HDAC Inhibitors: HDAC inhibitors (derivatized) include, but are not limited to: 1. Finnin, MS et al. Structures of HistoneDeacetylase Homologue Bound to the TSA and SAHA Inhibitors. Nature 40, 188-193(1999).

[0342] [ka]

[0343] (derivatized, where "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group); and 2. Compounds defined by formula (I) of PCTWO0222577 (deacetylase inhibitors) (inducing wherein the linker group L or -(L-CLM) group is attached, for example, via a hydroxyl group. be); VI. Human Lysine Methyltransferase Inhibitors: Human lysine methyltransferase inhibitors include, but are not limited to: 1. Chang et al. Structural Basis for G9a-Like proteinLysine Methyltransferase Inhibition by BIX-1294. Nat. Struct. Biol. (2009) 16(3) 312.

[0344] [ka]

[0345] (derivatized, where "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group); 2. Liu, F. et al Discovery of a 2,4-Diamino-7-aminoalkoxyquinazolineas a Potent and Selective Inhibitor of Histone Methyltransferase G9a. J. Med.Chem. (2009) 52(24) 7950.

[0346] [ka]

[0347] (derivatized, where "R" designates a potential attachment site, e.g., for a linker group L or a -(L-CLM) group); 3. Azacitidine (derivatized) (4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one) (derivatized, where the linker group L or -(L-CLM) group is, for example, a hydroxyl group). attached via a hydroxyl or amino group; and 4. Decitabine (derivatized) (4-amino-1-(2-deoxy-bD-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) (derivatized, where the linker group L or -(L-CLM) The group may be attached, for example, via one of the hydroxy groups or at the amino group). VII. Angiogenesis inhibitors: Angiogenesis inhibitors (derivatized) include, but are not limited to: 1. Sakamoto, et al., Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation, Mol CellProteomics 2003 Dec;2(12):1350-8 GA-1 (derivatized) and derivatives and analogs thereof, having the structure set forth in 2. Estradiols that can be attached to the linker group L or -(L-CLM) group, as outlined in Rodriguez-Gonzalez, et al., Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer, Oncogene (2008) 27, 7201-7211. ol (derivatized); 3. Estradiol, testosterone, including DHT and its derivatives and analogs, having the structure outlined 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, linked to a linker group L or -(L-CLM) group. ron (derivatized) and related derivatives; and 4. Ovalicin, fumagillin (derivatized), and derivatives and analogs thereof, having the structure outlined in Sakamoto, et al., Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation Proc Natl Acad Sci USA. 2001 Jul 17;98(15):8554-9 and U.S. Patent No. 7,208,157, and linked to a linker group L or -(L-CLM) group. VIII. Immunosuppressive compounds: Immunosuppressant compounds include, but are not limited to: 1. Overview provided in Schneekloth, et al., Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation, J. AM. CHEM. SOC. 2004,126, 3748-3754 and AP21998 (derivatized) having the structure shown below and attached to a linker group L or -(L-CLM) group; 2. Glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone) and methylprednisolone) (derivatized where a linker group L or -(L-CLM) group is attached, for example, to one of the hydroxyls), and beclomethasone dipropionate (derivatized where a linker group or -(L-CLM) is attached, for example, to proprionate); 3. Methotrexate (derivatized, where a linker group or -(L-CLM) group can be attached, for example, to either of the terminal hydroxyls); 4. Cyclosporin (derivatized, where the linker group or -(L-CLM) group can be attached, for example, either through a butyl group); 5. Tacrolimus (FK-506) and rapamycin (derivatized, where the linker group The L or -(L-CLM) group can be attached, for example, at one of the methoxy groups; and 6. Actinomycin (derivatized, where the linker group L or -(L-CLM) group can be attached, for example, at one of the isopropyl groups). IX. Compounds targeting the aryl hydrocarbon receptor (AHR): Compounds that target the aryl hydrocarbon receptor (AHR) include, but are not limited to, the following: 1. Apigenin (Lee, et al., Targeted Degradation of the Aryl Hydrocarbon Receptor by the PROTAC Approach: A Useful Chemical Genetic Tool, ChemBioChem Volume 8, Issue 17, pages 2058-2062, November 23, 2007) is used as a linker group L or or derivatized to attach to a -(L-CLM) group; and 2. SR1 and LGC006 (Boitano, et al., Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells, Science 10 September 2010: Vol. 329 no. 5997 pp. 1345-1348, the linker group L or -(L-CLM) derivatized to bind to X. Compounds targeting RAF receptors (kinases):

[0348] [ka]

[0349] PLX4032 (derivatized, where "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group). XI. Compounds targeting FKBP:

[0350] [ka]

[0351] (derivatized, where "R" designates the site of attachment of, for example, a linker group L or a -(L-CLM) group). XII. Compounds Targeting the Androgen Receptor (AR) 1. RU59063 Ligand (Derivatized) of the Androgen Receptor

[0352] [ka]

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

[0354] 2. Androgen receptor SARM ligands (derivatized)

[0355] [ka]

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

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

[0358] [ka]

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

[0360] 4. MDV3100 Ligand (Derivatization)

[0361] [ka]

[0362] 5. ARN-509 Ligand (Derivatization)

[0363] [ka]

[0364] 6. Hexahydrobenzisoxazole

[0365] [ka]

[0366] 7. Tetramethylcyclobutane

[0367] [ka]

[0368] 8. In any aspect or embodiment described herein, the PTM is an androgen receptor (AR) binding chemical moiety (ABM). Various androgen receptor binding compounds have been reported in the literature, including various anti-inflammatory drugs such as testosterone, dihydrotestosterone, and metribolone (also known as methyltrienolone or R1881). These compounds include androgen receptor binding compounds, such as androgen derivatives, as well as non-steroidal compounds, such as bicalutamide and enzalutamide, some of which are described above. Those skilled in the art will recognize that these androgen receptor binding compounds are potential compounds that can be used as the ABM portion in 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; PK Poutiainen et. al, J.Med. Chem. 2012, 55, 6316-6327; A. Pepe et al., J. Med. Chem. 2013, 56, 8280-8297; ME Jung et al., J. Med. Chem. 2010, 53, 2779-2796, which are incorporated herein by reference.

[0369] In any aspect or embodiment described herein, the ABM may have the structure shown below: wherein the dashed line indicates the point of attachment of a linker moiety or ULM, e.g., a CLM:

[0370] [ka]

[0371] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently and one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (optionally substituted straight chain, branched chain, e.g., one or more halo, C 1~6 Optionally substituted with alkoxyl ), C 1~6Alkoxyl (optionally substituted straight or branched chain, e.g., optionally substituted with one or more halo), C 2~6 Alkenyl, C 2~6 substituted by alkynyl or CF3 ; Y 1 , Y 2 are each independently NR Y1 ,O,S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is a 3-6 membered ring with 0-4 heteroatoms, optionally 0-6 R Q Each R is replaced by Q are independently H, C 1~6 Alkyl (optionally substituted straight or branched chain, e.g., one or more halo, C 1~6 optionally substituted with alkoxyl), halogen, C 1~6 Alkoxy or or two R Q The groups are 3-8 membered rings containing 0-2 heteroatoms along with the atoms to which they are attached. Form a system; R 1 , R 2 , R a , R b , R Y1 , R Y2 are each independently H, C 1~6 Alkyl (optionally substituted straight chain, Branched chain, e.g., one or more halo, C 1~6 optionally substituted with alkoxyl), halogen, C 1~6 alkoxy, cyclic, heterocyclic, or R 1 , R 2 form, together with the atom to which they are attached, a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C 1~6 Alkyl, C1~6 heteroalkyl, O, aryl, heteroaryl, alicyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 is replaced by; Each R W2 are independently H, halo, and C 1~6 Alkyl (optionally substituted straight or branched chain, e.g., one (Optionally replaced by F above), -OR W2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkynyl Lu, C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OC 1-3 Alkyl (optionally substituted), OH, NH2, NR Y1 R Y2 , CN; Call R W2A is H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC 1~3 A compound substituted with alkyl.

[0372] In any aspect or embodiment described herein, W 2 is one or more ULMs or a linker that is attached to one or more ULM or CLM groups as described herein.

[0373] In any aspect or embodiment described herein, W 1 teeth,

[0374] [ka]

[0375] where each R 22 is independently halo, H, optionally substituted alkyl, haloalkyl, cyano, or nitro, and each R 23 are independently H, halo, CF3, optionally substituted alkyl The alkyl group is aryl, alkoxy, haloalkyl, cyano, or nitro.

[0376] In any aspect or embodiment described herein, W 1 is selected from the group consisting of:

[0377] [ka]

[0378] In any aspect or embodiment described herein, the ABM may be any of the following: It comprises a structure selected from the structures below, wherein:

[0379] [ka]

[0380] indicates the point of attachment of the linker or ULM:

[0381] [ka]

[0382] [ka]

[0383] During the ceremony: R Q2 is H, halogen, CH3 or CF3; R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6Alkyl (straight chain, branched chain) , optionally one or more halo, C 1~6 substituted by alkoxyl), C 1~6 Alkoxyl (direct chain, branched chain, optionally substituted with one or more halo), C 2~6 Alkenyl, C 2~6 alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C═O, heteroaryl, or aryl; R Y1 , R Y2 are each independently H or C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 alkoxy, cyclic or heterocyclic); and R Q are each independently H, C1-C6 alkyl (linear or branched, optionally with one or more halo, or C 1~6 substituted by alkoxyl) or two R Q together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms.

[0384] In any aspect or embodiment described herein, each R Q is independently H or CH. In another embodiment, R Q3 is CN.

[0385] In any aspect or embodiment described herein, the ABM may be any of the following: It comprises a structure selected from the structures below, wherein:

[0386] [ka]

[0387] indicates the point of attachment of the linker or ULM:

[0388] [ka]

[0389] During the ceremony: R Q2 is H, halogen, CN, CH3 or CF3; and R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight chain, branched chain, Optionally one or more halo, C 1~6 substituted by alkoxyl), C 1~6 Alkoxyl (straight chain , branched chain, optionally substituted with one or more halo), C 2~6 Alkenyl, C 2~6 alkynyl, or CF3; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C═O, heteroaryl, or aryl; and R Y1 , R Y2 are each independently H or C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 alkoxy, cyclic or heterocyclic); and X is N or C.

[0390] In any aspect or embodiment described herein, R Q3 is CN. In any aspect or embodiment described herein, the ABM may have the structure shown below: wherein the dashed line indicates the point of attachment of the linker moiety or ULM or CLM:

[0391] [ka]

[0392] During the ceremony: W 1 teeth,

[0393] [ka]

[0394] is; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, C1-C6 alkyl (optionally substituted straight or branched chain), C1- C6 alkoxy, or -CF3; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 are each independently H or C1-6 alkyl (optionally substituted straight or branched chain, e.g., one or more halo, or C 1~6 optionally substituted with alkoxyl); W 2 is a bond, C 1~6 Aryl, C1-6 heteroaryl, C 1~6 alicyclic, or C heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each optionally containing 1 to 10 R W2 is replaced by; and Each R W2 are independently H or halo; and

[0395] [ka]

[0396] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific. In any aspect or embodiment described herein, W 2 is one or more ULMs or a linker that is attached to one or more ULM or CLM groups as described herein.

[0397] In any aspect or embodiment described herein, W 1 is selected from the group consisting of:

[0398] [ka]

[0399] In any aspect or embodiment described herein, W 2 is selected from the group consisting of:

[0400] [ka]

[0401] In any aspect or embodiment described herein, the ABM may have the structure shown below: wherein the dashed line indicates the point of attachment of the linker moiety or ULM:

[0402] [ka]

[0403] During the ceremony: W 1 teeth,

[0404] [ka]

[0405] is; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 1 , Y 2 are each independently O or S; R 1 , R 2 are each independently H or a methyl group; W 2 is a bond, C 1~6 aryl, or heteroaryl, each of which may have one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1~6 alkyl (optionally substituted with one or more F), OC1 ~3 alkyl (optionally substituted with one or more -F).

[0406] In any of the embodiments described herein, W 2 is covalently attached to one or more ULM or CLM groups, or to a linker that is attached to one or more ULM or CLM groups as described herein.

[0407] In certain additional embodiments, W 1 is selected from the group consisting of:

[0408] [ka]

[0409] In any aspect or embodiment described herein, W2 is

[0410] [ka]

[0411] is selected from the group consisting of: In any aspect or embodiment described herein, the ABM is selected from the group consisting of: Select from:

[0412] [ka]

[0413] [ka]

[0414] [ka]

[0415] [ka]

[0416] [ka]

[0417] [ka]

[0418] In any aspect or embodiment described herein, the ABM comprises the structure: :

[0419] [ka]

[0420] During the ceremony: W 1 are aryl or heteroaryl, each independently consisting of one or more of H, halo, hydro, Xyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight or branched chain, optionally containing one or more halo groups) , C 1~6 substituted by alkoxyl), C 1~6 Alkoxy (straight chain, branched chain, optionally monovalent) (substituted by more than one halo), C 2~6 Alkenyl, C 2~6 Alkynyl, or CF3 be replaced; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is a 4-membered alicyclic ring with 0-2 heteroatoms, optionally 0-6 R Q Each R is replaced by Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 a substituted with alkoxyl) or two R Q Groups, along with the atoms to which they are attached, forming a 3-8 membered ring system containing 0-2 heteroatoms; R Y1 , R Y2 are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 substituted by alkoxyl); W 2 is a bond, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, C 1~6 alicyclic, heterocyclic, aryl, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6Alkyl (straight or branched chain, optionally with one or more F) (substituted), C 1-6 heteroalkyl (straight chain, branched chain, optionally substituted), -OR W2A O.C. 1-3 alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 cycloheteroalkyl (optionally substituted), C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), heteroaryl (optionally substituted), bicyclic heteroaryl (optionally substituted), bicyclic aryl, OH, NH2, NR Y1 R Y2 , or CN; and R W2A is H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC 1~3 A compound substituted with alkyl.

[0421] In any aspect or embodiment described herein, there is provided an androgen receptor binding compound comprising the following structure:

[0422] [ka]

[0423] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently containing one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight chain, branched chain, Optionally, one or more halo, C 1~6 substituted by alkoxyl), C 1~6Alkoxyl (straight or branched chain, optionally substituted with one or more halo), C 2~6 Alkenyl, C 2~6 substituted by alkynyl, or CF3; Y 1 , Y 2 are each independently NR Y1 , O, or S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, SO2, heteroaryl, or aryl; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally 0-6 R Q Each R is replaced by Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 substituted with alkoxyl) or two R Q the groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms); R 1 , R 2 , R a , R b , R Y1 , R Y2 are each independently H, C 1~6 Alkyl (straight or branched chain, with one or more halo, C 1~6 optionally substituted with alkoxyl) or R 1 , R 2 are they forms, together with the atom to which it is attached, a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, C 1~6 Alicyclic, heterocyclic, aryl aryl, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; Each R W2 are independently H, halo, and C 1-6 Alkyl (straight chain, branched chain, optionally substituted with one or more F), C 1-6 heteroalkyl (straight chain, branched chain, optionally substituted), -OR W2A , O.C. 1-3 alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 S Chloroheteroalkyl, C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH, NR Y1 R Y2 , CN; and R W2A is H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC 1~3 A compound substituted with alkyl.

[0424] In any aspect or embodiment described herein, the androgen receptor binding moiety has the following structure:

[0425] [ka]

[0426] During the ceremony: W 1 teeth,

[0427] [ka]

[0428] is; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 3 is a bond or O; Q is a 4-membered ring, optionally containing 0 to 4 R Q Each R is replaced by 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 of which is 1, 2 or 3 of W2 and each R W2 are independently H, halo, or a 6-membered alicyclic ring having 1 or 2 heteroatoms, or a 5-membered alicyclic ring having 1, 2, or 3 heteroatoms. is an aromatic ring.

[0429] In any aspect or embodiment described herein, W 2 is selected from the group consisting of:

[0430] [ka]

[0431] In any aspect or embodiment described herein, W 2 is one or more ULMs or a linker that is attached to one or more ULM or CLM groups as described herein.

[0432] In any aspect or embodiment described herein, W 1 is selected from the group consisting of:

[0433] [ka]

[0434] In any aspect or embodiment described herein, the androgen binding moiety has the following structure:

[0435] [ka]

[0436] During the ceremony: W 1 is aryl, independently substituted by one or more halo, CN; Y 3 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , where C=O; Q is a 5-membered aromatic ring having 1 or 2 heteroatoms; R Y1 , R Y2 are independently H, C 1-6 It is alkyl (straight chain, branched chain); W 2 is a bond, aryl, or heteroaryl, each of which may optionally occur 1, 2, or 3 times; R W2 is replaced by; and Each R W2 are independently H, halo, and C 1~6 alkyl (optionally substituted with one or more F), OC1 ~3 alkyl (optionally substituted with one or more -F).

[0437] In any aspect or embodiment described herein, W 2 is one or more ULMs or a linker that is attached to one or more ULM or CLM groups as described herein.

[0438] In any aspect or embodiment described herein, W 1 teeth,

[0439] [ka]

[0440] is; In the formula, each R 22 is independently halo or CN; and Each R 23 are independently H or halo.

[0441] In any aspect or embodiment described herein, W 1 is selected from the group consisting of:

[0442] [ka]

[0443] In any aspect or embodiment described herein, Q is

[0444] [ka]

[0445] is. In any aspect or embodiment described herein, W 2 teeth,

[0446] [ka]

[0447] is. In any aspect or embodiment described herein, (Y 3 ) 0-5 teeth,

[0448] [ka]

[0449] is. In any aspect or embodiment described herein, the ABM may have the structure shown below: wherein the dashed line indicates the point of attachment of a linker moiety or ULM, e.g., a CLM:

[0450] [ka]

[0451] During the ceremony: W 1 teeth,

[0452] [ka]

[0453] is; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 1 , Y 2 are each independently O or S; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, C=S, SO, or SO2 ru; R 1 , R 2 are each independently H or a methyl group; W 2 is a bond, C 1~6 aryl, or heteroaryl, each of which may have one, two, or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1~6 alkyl (optionally substituted with one or more F), C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl, OC 1-3 Alkyl (optionally with one or more -F) (replaced by ).

[0454] In any aspect or embodiment described herein, W 2 is one or more ULMs or a linker that is attached to one or more ULM or CLM groups as described herein.

[0455] In any aspect or embodiment described herein, W 1 is selected from the group consisting of:

[0456] [ka]

[0457] In any aspect or embodiment described herein, W2 is selected from the group consisting of:

[0458] [ka]

[0459] In any aspect or embodiment described herein, the ABM may have the structure shown below: wherein the dashed line indicates the point of attachment of the linker moiety or ULM or CLM:

[0460] [ka]

[0461] During the ceremony: W 1 teeth,

[0462] [ka]

[0463] is; Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF3; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 are each independently H or C1-C6 alkyl (straight or branched chain, with one or more halo or C 1-6 optionally substituted with alkoxyl); W 2 is a bond, C 1~6 Aryl, C1-6 heteroaryl, C 1~6 Alicyclic or C1-6 heterocyclic and each of them is optionally 1 to 10 R W2 is replaced by; and Each R W2 are independently H or halo; and

[0464] [ka]

[0465] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific. In any of the embodiments described herein, W 2 is covalently attached to one or more ULM or CLM groups, or to a linker that is attached to one or more ULM or CLM groups as described herein.

[0466] In certain additional embodiments, W 1 is selected from the group consisting of:

[0467] [ka]

[0468] In certain additional embodiments, W 2 is selected from the group consisting of:

[0469] [ka]

[0470] [ka]

[0471] In certain embodiments, the androgen receptor binding compound of the ABM is selected from the group consisting of: Selected: 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.

[0472] In certain embodiments, the present specification provides, but is not limited to, the following exemplary androgen receptor PROTAC molecules (PROTAC3 through PROTAC-30), including salts, prodrugs, polymorphs, analogs, derivatives, and deuterated forms thereof:

[0473] [ka]

[0474] [ka]

[0475] [ka]

[0476] [ka]

[0477] [ka]

[0478] [ka]

[0479] [ka]

[0480] [ka]

[0481] XIII. Compounds targeting estrogen receptor (ER) ICI-182780 1. Estrogen receptor ligands

[0482] [ka]

[0483] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group).

[0484] In any aspect or embodiment described herein, the PTM may be represented by the following formula: PTM-I:

[0485] [ka]

[0486] During the ceremony: X PTM is O or C=O; X PTM1 and X PTM2 each is independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is the alkyl or aryl group of the ester; At least one R PTM2 are each independently H, OH, halogen, CN, CF3, SO2-alkyl, O-low selected from alkyl groups; At least one R PTM3 are each independently selected from H, halogen; and The dashed lines indicate the binding sites for at least one linker, CLM, CLM', PTM, PTM', or combinations thereof.

[0487] In any aspect or embodiment described herein, the PTM may be represented by the following formula: PTM-I:

[0488] [ka]

[0489] During the ceremony: X PTM is O or C=O; X PTM1 and X PTM2 each is independently selected from N or CH; R PTM1are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is the alkyl or aryl group of the ester; Each R PTM2 are independently selected from H, OH, halogen, CN, CF3, SO2-alkyl, and O-lower alkyl. be selected; Each R PTM3 is independently selected from H, halogen; PTM-I is a nucleotide sequence of at least one R PTM2 , at least one R PTM3 , or a combination thereof on each ring; and The dashed lines indicate the binding sites for at least one linker, CLM, CLM', PTM, PTM', or combinations thereof.

[0490] In any aspect or embodiment described herein, PTM-I may comprise two R PTM2 , 2 pieces R PTM3 or a combination thereof.

[0491] In any aspect or embodiment described herein, the PTM may be represented by the formula PTM-II: can be expressed as:

[0492] [ka]

[0493] During the ceremony: X PTM is O or C=O; X PTM1 and X PTM2 each is independently selected from N or CH; R PTM1 are independently OH, O(CO)R PTM , O-lower alkyl, wherein R PTM is the alkyl or aryl group of the ester; R PTM2 and R PTM4 are independently selected from H, OH, halogen, CN, CF3, SO2-alkyl, O-lower alkyl; R PTM3 and R PTM5 is independently selected from H, halogen; and The dashed lines indicate the binding sites for at least one linker, CLM, CLM', PTM, PTM', or combinations thereof.

[0494] In any aspect or embodiment described herein, O(CO)R PTM functions as a prodrug of the corresponding phenol in formula PTM-I or PTM-II.

[0495] In any embodiment or aspect described herein, the O-low A dialkyl is an alkyl chain having 1 to 3 carbon atoms.

[0496] In any aspect or embodiment described herein, the present disclosure provides a compound of formula (I): PTM ) a compound or PTM of:

[0497] [ka]

[0498] During the ceremony: each X PTM are independently CH, N;

[0499] [ka]

[0500] indicates a binding site for at least one linker, CLM, CLM', PTM, PTM', or combination thereof; Each R PTM1 are independently OH, halogen, O(CO)RPTM where R PTM is 1 to 6 carbon atoms or an aryl group having the following group: Each R PTM2 are independently H, halogen, CN, CF3, alkoxy, and the substitutions are mono- or di-substituted. may be substituted; and Each R PTM3 are independently H, halogen, and the substitution can be mono- or di-substituted.

[0501] In any aspect or embodiment described herein, the PTM has the following formula (II PTM ) is represented by:

[0502] [ka]

[0503] During the ceremony: X PTM is CH,N;

[0504] [ka]

[0505] indicates a binding site for at least one linker, CLM, CLM', PTM, PTM', or combination thereof; Each R PTM1 are independently OH, halogen (e.g., F); Each R PTM2 are independently H, halogen (e.g., F), CF3, and may be mono- or disubstituted; and Each R PTM3 is independently halogen (e.g., F), and the substitution can be mono- or di-substituted.

[0506] In certain embodiments, at least one of the following: Formula (IIPTM )X PTM is CH; Formula (II PTM )R PTM1 is OH; Formula (II PTM )R PTM2 is H; Formula (II PTM ) each R PTM3 are independently H or F; or It's a combination of those. XIV. Compounds Targeting Thyroid Hormone Receptors (TRs) 1. Thyroid hormone receptor ligands (derivatized)

[0507] [ka]

[0508] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group, and MOMO denotes a methoxymethoxy group). XV. Compounds that Target HIV Protease 1. HIV protease inhibitors (derivatized)

[0509] [ka]

[0510] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53,521-538.

[0511] 2. HIV protease inhibitors

[0512] [ka]

[0513] (derivatized, where "R" is a possible attachment point for a linker group L or a -(L-CLM) group) (Specify the position.) See J. Med. Chem. 2010, 53, 521-538. XVI. Compounds that target HIV integrase 1. HIV integrase inhibitors (derivatized)

[0514] [ka]

[0515] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53,6466.

[0516] 2. HIV integrase inhibitors (derivatized)

[0517] [ka]

[0518] 3. HIV integrase inhibitor Isentress (derivatized)

[0519] [ka]

[0520] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See J. Med. Chem. 2010, 53,6466. XVII. Compounds Targeting HCV Protease 1. HCV protease inhibitor (derivatized)

[0521] [ka]

[0522] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). XVIII. Acyl-protein thioesterases-1 and -2 (APT1 and APT2) Targeted Compounds 1. APT1 and APT2 inhibitors (derivatized)

[0523] [ka]

[0524] (derivatized, where "R" designates the site of attachment of the linker group L or -(L-CLM) group). See Angew. Chem. Int. Ed. 2011, 50, 9838-9842. Wherein L is a hydroxyl group as defined herein. wherein said CLM groups are as otherwise described herein. and -(L-CLM) attaches a CLM group to a PTM group, as otherwise described herein. VIV. Compounds Targeting Tau Protein In any aspect or embodiment described herein, the PTM is a tau protein binding For example, the PTM may comprise a binding moiety represented by the following formula I, II, III, IV, V, VI, VII, , Formula VIII, Formula IX, Formula X, or Formula XI:

[0525] [ka]

[0526] During the ceremony: A, B, C, D, E, and F are independently selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings, optionally substituted 4- to 7-membered cycloalkyl or heterocycloalkyl, where contact between the rings indicates ring fusion; and L PTM is selected from a bond, alkyl, alkenyl, or alkynyl, and optionally one The ring (i.e., cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) may be interrupted by one or more functional groups, such as —O—, —S—, —NR 1 PTM -(In the formula, R 1 PTM is selected from H or alkyl), —N═N—, —S(O)—, —SO—, —C(O)—, —NHC(O)—, —C(O)NH—, —NHSO—, —NHC(O)NH—, —NHC(O)O—, or —OC(O)NH—, , the functional groups are optionally located at either end of the linker.

[0527] In any aspect or embodiment described herein, PTMs A, B, C, D, E and The aryl and heteroaryl rings of F are alkyl, alkenyl, haloalkyl, haloalkyl, haloaryl ... and optionally substituted with 1 to 3 substituents each independently selected from halogen, hydroxyl, alkoxy, fluoroalkoxy, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, and cyano, wherein said alkyl and alkenyl groups are further optionally substituted.

[0528] In any aspect or embodiment described herein, the ring of at least one of A, B, C, F, or any combination thereof is selected from optionally substituted 5- or 6-membered aryl or heteroaryl rings.

[0529] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula I, wherein: The A, B, and C rings are independently 5- or 6-membered fused aryl or heteroaryl rings. the law of nature; L PTM is selected from a bond or alkyl, and D is selected from a 6-membered aryl, heteroaryl, or heterocycloalkyl; wherein A, B, C and D are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino or cyano.

[0530] In any aspect or embodiment described herein, the PTM has the chemical structure of Formula I, wherein: A and C are phenyl or a 6-membered heteroaryl ring; B is a 5-membered heteroaryl ring; L PTM is a bond; and D is a 6-membered heteroaryl or 6-membered heterocycloalkyl ring; wherein each of A, B, C, and D is optionally independently substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, or cyano, and wherein a nitrogen atom in any of the A, B, C, and D rings is not directly bonded to a heteroatom or carbon atom to which another heteroatom is directly attached.

[0531] In any aspect or embodiment described herein, the PTM has a chemical structure of Formula III or Formula IV, where A, B, and C are 5- or 6-membered fused aryl or heteroaryl groups. L is a aryl ring; PTM is selected from a bond or alkyl; D and E are each independently 5 and R is a 1- or 6-membered fused aryl or heteroaryl ring, wherein A, B, C, D, and E are optionally substituted with alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, or cyano.

[0532] In any aspect or embodiment described herein, the PTM has the following chemical structure: is represented as:

[0533] [ka]

[0534] [ka]

[0535] During the ceremony: R 1 , R 2 and R 3 are independently H, methyl, ethyl, 2-fluoroethyl, and 2,2,2-trimethyl fluoroethyl; R 4 and R 5 is independently selected from H, methyl, ethyl, and halogen; and R 6 is 1 to 2 substituents independently selected from H, methyl, ethyl and halogen; , The PTM is attached to the ULM via L.

[0536] In any of the embodiments or aspects described herein, the PTM is covalently attached to one or more ULM (VLM or CLM) groups, or to a linker that is attached to one or more ULM (VLM or CLM) groups as described herein.

[0537] In any aspect or embodiment described herein, the PTM has the following chemical structure: is represented as:

[0538] [ka]

[0539] [ka]

[0540] During the ceremony: R 1 , R 2 and R 3are independently H, optionally substituted alkyl, methyl, ethyl, 2-fluoro and 2,2,2-trifluoroethyl; and R 7 , R 8 , R 9 and R 10 are 1 to 8 substituents independently selected from H, optionally substituted alkyl, haloalkyl, halogen, hydroxyl, alkoxy, amino, dialkylamino, acetylamino, trifluoromethyl, or cyano, and PTM is connected via L to ULM. (VLM or CLM).

[0541] In any aspect or embodiment described herein, the PTM has the following chemical structure: is represented as:

[0542] [ka]

[0543] [ka]

[0544] [ka]

[0545] In any aspect or embodiment described herein, the linker attachment point to the PTM is as indicated by the dotted line:

[0546] [ka]

[0547] therapeutic composition Pharmaceutical compositions comprising an effective amount of at least one bifunctional compound described herein, and a combination of effective amounts of one or more of the compounds described elsewhere herein, in combination with a pharmaceutically effective amount of a carrier, additive, or excipient, represent a further aspect of the present disclosure.

[0548] The present disclosure includes compositions containing pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein, where applicable. The acids used to prepare pharmaceutically acceptable acid addition salts of the above-described base compounds useful according to this embodiment form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, among many others, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, perphosphate, acetate, lactate, citrate, percitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. It is an acid.

[0549] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds or derivatives according to the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, base salts derived from pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium, or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium, as well as other base salts. Examples of pharmaceutically acceptable base salts of organic amines include:

[0550] The compounds described herein may be administered orally, parenterally, or topically in single or divided doses in accordance with the present disclosure. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes of administration. Enteric-coated oral tablets may be used to enhance the bioavailability of the compound from oral administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease. Administration of compounds according to the present disclosure as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration may also be used. Accordingly, the present disclosure also contemplates pharmaceutical compositions comprising an effective amount of a compound described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. The compounds according to the present disclosure may be administered in immediate-release, intermediate-release, or sustained- or controlled-release forms. Slow-release or controlled-release forms are preferably administered orally, but also via suppositories and transdermal or other topical forms. Intramuscular injections in liposomal form may also be used to control or sustain the release of the compound at the injection site.

[0551] The compositions described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may be administered in controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool. Fat is one example.

[0552] The compositions described herein may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted container. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions are preferably administered orally, intraperitoneally, or intravenously.

[0553] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions 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 used as solvents or suspending media. For this purpose, any bland fixed oil may be employed, 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 oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helvetica or similar alcohols.

[0554] The pharmaceutical compositions described herein may be in the form of, but not limited to, capsules, tablets, aqueous suspensions or water. It can be orally administered in any orally acceptable dosage form, including solution.For tablets for oral use, commonly used carriers include lactose and cornstarch.Usually, lubricants such as magnesium stearate are also added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0555] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore will melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0556] The pharmaceutical compositions described herein may also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically acceptable transdermal patches may also be used.

[0557] For topical application, pharmaceutical compositions can be formulated with suitable ointments, which contain the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.In certain preferred embodiments of the present invention, the compound can be coated on the stent that is surgically implanted in patients, thereby preventing or reducing the possibility of stent blockage in patients.

[0558] Alternatively, the pharmaceutical compositions may be formulated with a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0559] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a solution in isotonic, pH-adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum.

[0560] The pharmaceutical compositions described herein may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the pharmaceutical formulation art and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0561] The amount of compound in the pharmaceutical compositions described herein that can be combined with carrier materials to produce a single dosage form will vary depending on the host and condition being treated, and the particular mode of administration. Preferably, the composition is administered alone or in combination with at least one other compound according to the present disclosure. In combination with the active ingredient, about 0.05 milligrams to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams It should be formulated to contain

[0562] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0563] A patient or subject in need of treatment using a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, including a pharmaceutically acceptable salt, solvate or polymorph thereof, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with other known erythropoiesis-stimulating agents as otherwise specified herein.

[0564] These compounds can be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, for example, transdermally in liquid, cream, gel, or solid form, or in aerosol form.

[0565] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication, but which does not cause serious toxic effects in the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein range from about 10 ng / kg to 300 mg / kg, preferably from 0.1 to 100 mg / kg per day, more usually from 0.5 to about 25 mg per kg of recipient / patient body weight per day. Typical topical dosages can range from 0.01 to 5% wt / wt in a suitable carrier.

[0566] The compound is conveniently administered in any suitable unit dosage form, including but not limited to, containing less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dose of is often convenient.

[0567] The active ingredient is administered to a patient in need thereof at a peak plasma concentration of the active compound of about 0.00001 to 30 mM, preferably about 0.1 to 30 μM. It is preferable to administer the active ingredient in a manner that achieves a desired concentration. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in a saline solution or aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for achieving an effective plasma concentration of the active agent.

[0568] The concentration of the active compound in the drug composition will depend on the absorption, distribution, inactivation, and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once, or may be divided into multiple smaller doses to be administered at varying time intervals.

[0569] Oral compositions generally contain an inert diluent or an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets.For oral therapeutic administration, the active compound or its prodrug derivatives may be combined with excipients and used in the form of tablets, lozenges, or capsules.Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition.

[0570] 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; dispersing agents such as alginic acid, Primogel, or cornstarch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. 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 acid. Furthermore, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, such as sugar coatings, shellac, or enteric agents.

[0571] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and / or certain preservatives, dyes and colorings, and flavors.

[0572] Furthermore, the active compounds, or pharmaceutically acceptable salts thereof, may be used in combination with other active substances that do not impair the desired action, including, but not limited to, EPO and dalbapoetin alfa. In certain preferred embodiments of the present invention, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an erythropoiesis-stimulating agent, or a wound healing agent, including an antibiotic, as otherwise described herein.

[0573] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0574] When administered intravenously, preferred carriers are saline or phosphate buffered saline (PBS )

[0575] In one embodiment, active compound is prepared with a carrier that protects compound from rapid excretion from the body, for example, controlled release formulations, including implants and microencapsulated delivery systems.For example, biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.The preparation method of such formulations will be clear to those skilled in the art.

[0576] Liposomal suspensions can also be pharmaceutically acceptable carriers.They can be prepared according to the methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (incorporated herein in its entirety by reference).For example, liposomal preparations can be prepared by dissolving suitable lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, and then evaporating, leaving a thin film of dried lipid on the surface of the container.Then, an aqueous solution of the active compound is placed in the container.Then, Rotate the container by hand at 150°C to remove lipid material from the sides of the container and disperse lipid clumps, forming a liposomal suspension. Treatment method In an additional aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound described herein, or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to modulate protein degradation in a patient or subject, e.g., an animal such as a human, and to treat or ameliorate a disease state or condition mediated by the degraded protein.

[0577] As used herein, the terms "treat," "treating," and "treatment" refer to any action that benefits a patient, including the treatment of any disease state or condition for which the compounds may be administered that is modulated via the protein to which the compounds bind. Symptoms or conditions, including cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0578] Provided herein are therapeutic compositions, as described herein, for causing degradation of a protein of interest for the treatment or amelioration of a disease, e.g., cancer. In certain additional embodiments, the disease is multiple myeloma. Accordingly, in another aspect, provided herein are methods for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound, as described herein, comprising, e.g., a CLM and a PTM, preferably linked via a linker moiety, wherein the CLM is linked to a PTM, and the CLM is linked to a ubiquitin pathway protein (e.g., a ubiquitin pathway protein), as described elsewhere herein. The PTM recognizes a target protein, thereby allowing the target protein to bind to the ubiquitin ligase. When placed in proximity to a target protein, degradation of the target protein occurs, resulting in a concomitant reduction / inhibition of the target protein's action, resulting in protein level control. The protein level control provided by the present disclosure provides treatment for a disease state or condition regulated via the target protein by reducing the level of that protein in a cell, e.g., a patient's cell. In certain embodiments, the method comprises administering an effective amount of a compound described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0579] In additional embodiments, the present specification provides methods for treating or ameliorating a disease, disorder, or symptom thereof in a subject or patient, e.g., an animal, e.g., a human, the method comprising administering to a subject in need thereof a composition comprising an effective, e.g., therapeutically effective, amount of a compound as described herein, or a salt form thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder, or symptom thereof, in the subject.

[0580] In another aspect, the present specification provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0581] In another embodiment, the present disclosure is directed to a method of treating a human patient in need for a disease state or condition regulated through a protein, where degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of the present disclosure, optionally in combination with another bioactive agent. The disease state or condition may be a disease caused by a microbial organism or other foreign agent, such as a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease caused by overexpression of a protein resulting in the disease state and / or condition.

[0582] The term "disease state or condition" refers to the dysregulation of a protein (i.e., the level of its expression in a patient). The patient develops a condition called the breakdown of one or more proteins (an increase in the amount of proteins present in the body). is used to describe any disease state or condition that provides beneficial treatment or symptomatic relief to a patient in need thereof. In certain instances, the disease state or condition may be cured.

[0583] Disease states or conditions that may be treated using compounds according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related diseases, 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 (PDK2) Prader-Willi syndrome, These include sickle cell disease, Tay-Sachs disease, and Turner syndrome.

[0584] Disease states 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, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type I diabetes, type II diabetes, epilepsy, gill disease, and the like. These include: Chin-Barré syndrome, irritable bowel syndrome, lupus erythematosus, 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.

[0585] Additional disease states or conditions that may be treated with compounds according to the present disclosure include aceruloplasminemia, type II achondroplasia, achondroplasia, acicular cephaly, type 2 Gaucher disease, acute intermittent thromboembolism, and rheumatoid arthritis. porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, Adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-Dpo Alkaptonuria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, Alkaptonuria Kaptonuric ochronosis, α1-antitrypsin deficiency, α1-proteinase inhibitor, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen Refractoriness, anemia, diffuse angiokeratoma corporis, retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, arachnodactyly (Marfan syndrome), Stickler syndrome, congenital multiple Joint laxity (Ehlers-Danlos syndrome, arthrochalasia type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome, familial Mediterranean fever, Benjamin syndrome, beta-thalassemia, bilateral acoustic neuromas (neurofibromatosis type II), factor V Leiden thrombophilia, Bloch-Sulzberger disease Incontinentia pigmenti syndrome, Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prion diseases, Birt-Hogg-De Hube syndrome, brittle bone disease (osteogenesis imperfecta), broad hallux syndrome (Rubinstein-Taybi syndrome), bronze diabetes mellitus / bronze cirrhosis (hemochromatosis), spinal-bulbar muscular atrophy (Kennedy disease), Buerger-Grütz syndrome (lipoprotein lipase deficiency), CGD chronic granulomatous disorder , flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cri-a-cat syndrome, CAVD (congenital absence of the vas deferens), Caylor cardio-facial syndrome (CBAVD), CEP (congenital erythropoietic porphyria) thyroiditis), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (achondroplasia) , Oto-spondylotic-giant epiphyseal dysplasia, Lesch-Nyhan syndrome, Galactosemia, Ehlers-Danlos syndrome, Thanatophoric dysplasia, Coffin-Lowry syndrome, Cockayne syndrome, (Familial adenomatous polyposis), Congenital erythropoietic porphyria, Congenital heart disease, Methemoglobinemia / congenital methemoglobinemia, Achondroplasia, X-linked sideroblastic anemia, Connective tissue disease, Conotruncal dysfacies syndrome, Cooley anemia (β-thalassemia), Copper storage disease (Wilson) Copper transport disease (Menkes disease), hereditary coproporphyria, Cowden syndrome, craniofacial Joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome group, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystonia) Roffey), Behle-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spinal These include epiphyseal and metaphyseal dysplasia (Strudwick type), Duchenne and Becker muscular dystrophy (DBMD), Usher syndrome, de Grouch syndrome, and Dejerine-Sottas syndrome. Degenerative neurological disorders, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse Globoid sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, short stature, erythropoietic protoporphyria, erythrocyte 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia, familial paroxysmal polyserositis, porphyria cutanea tarda, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), fibrocystic pancreatic disease, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (new Hemochromatosis, Gren-Vlad-Strandberg syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's disease syndrome, sickle cell anemia, hemophilia, myeloid hepatic porphyria (HEP), Hippel-Lindau Von Hippel-Lindau disease, Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, X-linked severe combined immunodeficiency syndrome Immune system disorders including: Insley-Astley syndrome, Kennedy syndrome, Jackson-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, hyperoxaluria including renal disease, Klinefelter syndrome, Kniest dysplasia, patchy dementia, Langer-Saldino achondrogenesis, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-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 (Hutchinson-Gilford progeria syndrome), chorea progressive, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal tonic muscular dystrophy, pulmonary arterial hypertension, PXE (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis I) type), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome , Riley-Day syndrome, Lucy-Levi syndrome, Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), Li-Fraumeni syndrome, Sarcoma-Breast-Leukemia-Adrenal Carcinoma (SBLA) syndrome, Tuberous Sclerosis (Sclerosis tuberose), Tuberous Sclerosis (Tuberous sclerosis), SDAT, Spondyloepiphyseal Dysplasia Congenita (SED), Spondyloepiphyseal Dysplasia Strudwick Type (SEDc), Spondyloepiphyseal Dysplasia Congenita (SEMD) Strudwick syndrome (spondyloepiphyseal dysplasia Strudwick type), Shprintzen syndrome, dyschromia, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variegate porphyria), infantile-onset hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, sausage neuropathy (hereditary Neuropathy with palsies to pressure palsies), Treacher Collins syndrome, Triplo X syndrome (triple X syndrome), Trisomy 21 (Down syndrome), Trisomy X, VHL syndrome (von Hippel-Lindau disease), Visual impairment and blindness (Alström syndrome), Frolik disease, Waardenburg syndrome syndrome, Warburg-Schäfer-Frederius syndrome, Weissenbacher-Zweymuller syndrome, Wolff-Hirschorn syndrome, Wolff periodic disorder, Weissenbacher-Zweymuller syndrome, and xeroderma pigmentosum.

[0586] The terms "neoplasm" or "cancer" are used throughout this specification to refer to a cancerous or malignant neoplasm. The term neoplasm is used to refer to a pathological process that results in the formation and growth of abnormal tissue, that is, tissue that grows by cell proliferation, often much faster than normal, and continues to grow after stimuli that would otherwise stop the new growth that has been initiated. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and have a high probability of patient death unless properly treated. As used herein, the term neoplasm is used to describe all cancerous conditions and includes pathological processes associated with malignant hematopoietic cells, ascites, and solid tumors. Examples of cancers that may be treated by the present compounds alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma sarcomas, including Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and schwannoma; 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, and teratocarcinoma. Additional cancers that may be treated using compounds according to the present disclosure include, for example, T-cell-based acute lymphoblastic leukemia, T-cell lymphoblastic leukemia (T-ALL), T-lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell lymphoma, precursor B-cell ALL, precursor B-cell lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia stain Examples include somatic positive CML.

[0587] The term "bioactive agent" is used to describe an agent other than a compound according to the present disclosure, which is used in combination with the present compound as an agent having biological activity to supplement the therapeutic, inhibitory, and / or preventative / prophylactic effects for which the present compound is used. Preferred bioactive agents for use herein include agents having pharmacological activity similar to that for which the present compound is used or administered, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, anti-microbial agents, anti-fungal agents, etc.

[0588] The term "additional anti-cancer agent" is used to describe an anti-cancer agent that may be combined with a compound according to the present disclosure to treat cancer. These agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (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 inhibitors, 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 agents, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, Erlotinib, Dasatinib, Nilotinib, Deca Decatanib, panitumumab, amrubicin, Oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, Bio 140, CC8490, cilengitide, gimatecan atecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx102, Tara Talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil ), vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide 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, ana Anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate , medroxyprogesterone acetate, hydroxyprogesterone cephalosporin caprylate, 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, Ionafarnib, BMS-214662, Tipifarnib, Amifostine, NVP-LAQ824, Suberoyl analidehydroxamic acid, Valproic acid, Trichostatin A, FK-228, SU11248, Sorafenib, KRN951, Aminoglutethimide, Arnsacrine, Ana 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 (hydroxyurea), idarubicin, ifosfamide, Imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan ), 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoid 13-cis-retinoic acid, phenylalanine mustard ), uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valproate, Valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin , marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone Spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel Docetaxel, Epithilone B, BMS-247550, BMS-310705, Droloxifene, 4-hydroxytamoxifen , pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646 , wortmannin, ZM336372, L-779,450, PEG-filgrastim, 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- Sparginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydrazine Hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol droperidol, dronabinol, dexamethasone ), methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0589] The term "anti-HIV agent" or "additional anti-HIV agent" includes, for example, nucleotide reverse transcriptase inhibitors (NRTIs), other non-nucleoside reverse transcriptase inhibitors (i.e., agents not representative of the present disclosure), protease inhibitors, fusion inhibitors, exemplary compounds of which include, for example, 3TC (lamivudine), AZT (zidovudine), (-)-FTC, ddI (didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverse Transcriptase Inhibitor), and ribozyme inhibitors. )), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir) These include fusion inhibitors such as T20, including T20-1, T20-2, T20-3, T20-4, T20-5, T20-6, T20-7, T20-8, T20-9, T20-10, T20-11, T20-22, T20-3, T20-4, T20-5, T20-6, T20-7, T20-8, T20-9, T20-12, T20-13, T20-14, T20-15, T20-16, T20-17, T20-18, T20-19, T20-21, T20-22, T20-23, T20-32, T20-4, T20-5, T20-6, T20-7, T20-8, T20-9, T20-1

[0590] Other anti-HIV agents that may be used for co-administration with compounds in accordance with the present disclosure include, for example, other NNRTIs (i.e., other than NNRTIs in accordance with the present disclosure), particularly nevirapine (BI-R6-587), delavirdine (U-90152S / T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2-butenyloxy)furan]), and the like. [phenyl]-2-methyl-3-furancarbothiamidamide), etravirine (TMC125), trovirdine (Ly300046.HCl), MKC-442 (emivirine, coactinon), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, baicalin (TJN-151), ADAM-II (3',3'-dichloro-4',4"-dimethoxy-5',5"-bis(methoxycarbonyl)-6,6-diphenylhexanoate methyl ester) phenyl), 3-bromo-5-(1-5-bromo-4-methoxy-3-(methoxycarbonyl)phenyl)hepta-1- methyl (5-enyl)-2-methoxybenzoate (alkenyldiarylmethane analog, Adam analog), (5-chloro-3-(phenylsulfinyl)-2'-indolecarboxamide) , AAP-BHAP (U-104489 or PNU-104489), capravirine (AG-1549, S-1153), atevirdine (U-87201E), aurin tricarboxylic acid acid) (SD-095345), 1-[(6-cyano-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[5-[[N-(methyl)methylsulfonylamino]-2-indolylcarbonyl-4-[3-(isopropylamino)-2-pyridinyl]piperazine, 1-[3-(ethylamino)-2-[pyridinyl]-4-[(5-hydroxy-2-indolyl)carbonyl]piperazine, 1-[(6-formyl-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl] Piperazine, 1-[[5-(methylsulfonyloxy)-2-indolyl)carbonyl]-4-[3-(isopropylamino)-2-pyridinyl]piperazine, U88204E, bis(2-nitrophenyl) sulfone (NSC633001), calanolide A (NSC675451), calanolide B (Non-Alcoholic Acid), ), 6-benzyl-5-methyl-2-(cyclohexyloxy)pyrimidin-4-one (DABO-546), DPC 961, E-EBU, E-EBU-dm, E-EPSeU, E-EPU, Foscarnet (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), Innophy Inophyllum P, L-737,126, Michellamine A (NSC650898), Michellamine B (NSC 649324), Michellamine F, 6-(3,5-dimethylbenzyl)-1-[(2-hydroxyethoxy)methyl]-5-isopropyluracil, 6-(3,5-dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil, NPPS, E-BPTU (NSC 648400), Oltipraz (4-methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione), N-{2-(2-chloro-6-fluorophenethyl]-N'-(2-thiazolyl)thiourea (PETT Cl, F derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-bromopyridyl)]thiourea {PETT derivative), N-{2-(2,6-difluorophenethyl]-N'-[2-(5-methylpyridyl)] Thiourea {PETT pyridyl derivative), N-[2-(3-fluorofuranyl)ethyl]-N'-[2-(5-chlorophenyl)- N-[2-(2-fluoro-6-ethoxyphenethyl)]-N'-[2-(5-bromopyridyl)]thiourea, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (LY-73497) , L-697,639, L-697,593, L-697,661, 3-[2-(4,7-difluorobenzoxazol-2-yl) ethyl}-5-ethyl-6-methyl(pyridine-2(1H)-thione (2-pyridinone derivative), 3-[[(2-methyl 5-Ethyl-6-methyl(pyridine-2(1H)-tox-5,6-dimethyl-3-pyridyl)methyl]amine Thione, R82150, R82913, R87232, R88703, R89439 (Loviride), R90385, S-2720, Suramin Sodium, TBZ (thiazolobenzimidazole, NSC 625487), thiazoloisoindol-5-one, (+)(R)-9b-(3,5-dimethylphenyl-2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-one, Tivirapine (R86183), UC-38 and UC-84.

[0591] The term "pharmaceutically acceptable salt" is used throughout the specification to describe, where appropriate, one or more salt forms of the compounds described herein, which salt forms increase the solubility of the compound in the gastric juices of a patient's digestive tract, facilitating the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where appropriate, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, and ammonium salts, among many other acids and bases known in the pharmaceutical arts. Sodium and potassium salts are particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0592] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (e.g., esters, amides, other prodrug groups, etc.) which, upon administration to a patient, yields, directly or indirectly, the compound, or an active metabolite of the compound. General synthesis method The synthesis and optimization of the bifunctional molecules described herein may be approached in a stepwise or modular fashion. For example, the identification of compounds that bind to a target molecule may involve high-throughput or medium-throughput screening campaigns when suitable ligands are not readily available. Initial ligands may be used to improve suboptimal aspects identified by appropriate in vitro pharmacological and / or ADMET assay data. It is not uncommon for iterative design and cycle optimization to be required for a ligand. Part of the optimization / SAR campaign is to probe ligand positions that tolerate substitution and may be suitable locations for attaching the linker chemistries referenced herein above. When crystallographic or NMR structural data are available, these can be used to identify Such synthetic efforts can be focused.

[0593] In a very similar manner, ligands of E3 ligases, i.e., ULM / CLM / CL M can be specified and optimized.

[0594] Those skilled in the art can utilize readily available PTMs and ULMs (e.g., CLMs) to Known synthetic methods for the combination, with or without a linker moiety, can be used. Linker moieties can be synthesized and functionalized with a range of compositions, lengths, and flexibility so that PTM and ULM groups can be sequentially attached to the distal end of the linker. Thus, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with the PTM and ULM groups, the final bifunctional molecule can be subjected to cycles of iterative design and optimization to identify molecules with desired properties.

[0595] The exemplary compounds described herein can be synthesized by connecting the key fragments prepared according to Schemes 2-30, 2-31, 2-40, 2-41, 2-45, and 2-46. Detailed preparations of representative compounds claimed in this application are shown in Schemes 3-10, 3-56, 3 ~58, and further described in 3~72.

[0596] A. General synthetic scheme for exemplary cereblon ligands Synthetic Schemes 2-30, 2-31, 2-40, 2-41, 2-45, and 2-46 describe routes used in the preparation of CRBN ligands, as well as CRBN ligands with attached partial linker moieties.

[0597] General synthetic scheme 2-30 for preparing intermediates.

[0598] [ka]

[0599] General synthetic schemes for preparing intermediates 2-31.

[0600] [ka]

[0601] General synthetic scheme 2-40 for preparing intermediates.

[0602] [ka]

[0603] General synthetic scheme for preparing intermediates 2-41.

[0604] [ka]

[0605] General synthetic scheme 2-45 for preparing intermediates.

[0606] [ka]

[0607] [ka]

[0608] General synthetic scheme for preparing intermediates 2-46.

[0609] [ka]

[0610] B. General Synthetic Scheme of Exemplary PROTACs Synthetic Schemes 3-10, 3-56, 3-58, and 3-72 describe routes used in the preparation of representative chimeric compounds claimed in this application.

[0611] General synthetic schemes 3-10 for preparing the claimed compounds

[0612] [ka]

[0613] General synthetic schemes 3-56 for preparing the claimed compounds

[0614] [ka]

[0615] General synthetic schemes 3-58 for preparing the claimed compounds

[0616] [ka]

[0617] General synthetic schemes 3-72 for preparing the claimed compounds

[0618] [ka]

[0619] Synthesis of Exemplary PROTAC1

[0620] [ka]

[0621] 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(3-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yl)oxy)propoxy)propyl)acetamide Synthesis scheme:

[0622] [ka]

[0623] (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (20.6 mg, 0.051 mmol) and 1-(5-(3-(3-amino To a solution of (propoxy)(quinolin-3-yl)pyrimidine-2,4(1H,3H)-dione hydrochloride (21.6 mg, 0.053 mmol) in DCM (1 mL), diisopropylethylamine (0.022 mL, 0.128 mmol) and HATU (20.1 mg, 0.053 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then soaked in NaHCO3 solution The product was purified by column chromatography on silica (10% MeOH / DCM). Purification by column chromatography gave 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(3-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yl)oxy)propoxy)propyl)acetamide (25 mg, 65%).

[0624] LCMS (m / e+) = 753.35 [M+H] + and m / e+ = 377.17 [M+2H] 2+ Synthesis of Exemplary PROTAC29

[0625] [ka]

[0626] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yl)oxy)hexyl)piperazin-1-yl)nicotinamide Synthetic Scheme Part 1 Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide

[0627] [ka]

[0628] Step 1: Synthesis of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid

[0629] [ka]

[0630] 6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in N,N-dimethylacetamide (15 mL), and tert-butyl piperazine-1-carboxylate (1.9 g, 10.0 mmol) and ethyldiisopropylamine (2.6 g, 20 mmol) were added, followed by stirring overnight at 130° C. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added 1M aqueous NaOH (10 mL), which was then washed with CHCl3 (50 mL). The pH of the aqueous layer was adjusted to about 6-7 by adding 1 M hydrochloric acid, and then CHCl3 (50 mL x 3 The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl / MeOH = 10 / 1) to give 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (2.0 g, 65% yield as a white solid.

[0631] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm*4,6 mm*3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] in 1.6 min and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then 1.4 min under these conditions. Finally 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], then 0.7 min under these conditions. Purity 83.17%, Rt = 1.312 min; MS calculated: 307.15; MS found: 308.2 [M+H] + . Chemical formula:C 15 H 21 N3O4, molecular weight: 307.34 Step 2: 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl) Synthesis of tert-butyl [2-(butylcarbamoyl)]pyridin-2-yl)piperazine-1-carboxylate

[0632] [ka]

[0633] 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid (614 mg, 2.0 mmol), 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy-2-chlorobenzonitrile hydrochloride A mixture of the salt (630 mg, 2.0 mmol), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 g, 3.0 mmol), and ethyldiisopropylamine (516 mg, 4.0 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue. This was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1). Purification gave tert-butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl]pyridin-2-yl)piperazine-1-carboxylate (977 mg, 86% yield) as a white solid.

[0634] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4,6 mm*3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Purity: 88.26%, Rt = 2.161 min; MS calculated: 567.26; MS found: 568.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ1.12 (6H, s), 1.22 (6H, s), 1.43(9H, s), 3.42-3.44 (4H, m), 3.60-3.63 (4H, m), 4.02-4.07 (1H, m), 4.31 (1H, s),6.88 (1H, d, J = 8.8 Hz), 7.00 (1H, dd, J = 8.4, 2.4 Hz), 7.21 (1H, d, J = 2.4Hz), 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 (1 H, d, J = 2.4 Hz). Chemical formula:C 30 H 38 ClN5O4, molecular weight: 568.11 Total H from HNMR data: 38. Step 3: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Synthesis of (butyl)-6-(piperazin-1-yl)nicotinamide hydrochloride

[0635] [ka]

[0636] tert-Butyl 4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl)pyridin-2-yl)piperazine-1-carboxylate (405 mg, 0.7 mmol) A mixture of HCl / 1,4-dioxane (10 ml) was stirred at room temperature for 4 hours. The solvent was removed in vacuo. and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl (1-methyl-6-(piperazin-1-yl)nicotinamide hydrochloride (353 mg, 100% yield) was obtained as a white solid. And got it.

[0637] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4,6 mm*3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Rt = 1.791 min; MS calculated: 467.21; MS observed: 468.3 [M+H] + . Chemical formula:C 25 H 31 Cl2N5O2, molecular weight: 504.45 Synthesis Scheme Part 2

[0638] [ka]

[0639] Step 4: Synthesis of 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0640] [ka]

[0641] 4,5-Dichloropyridazin-3(2H)-one (5.0 g, 30.5 mmol), 1-(chloromethyl)-4-methoxy of benzene (7.1 g, 45.7 mmol) and potassium carbonate (12.6 g, 91.5 mmol). N',N'-di Methylformamide The mixture (100 mL) was stirred at room temperature for 12 hours. The mixture was poured into water. The combined organic phase was concentrated in vacuo and the residue was evaporated to dryness. The mixture was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1). , 4,5-dichloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (6.3 g, 73% yield) was obtained as a white solid.

[0642] LC-MS (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 0.05% TFA] in 1.5 min; and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.5 min. Finally, change to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under these conditions for 0.1 min. Rt = 1.220 min; MS calculated: 284.0; MS found: 285.1 [M+H] + . Chemical formula:C 12 H 10 Cl2N2O2, molecular weight: 285.13 Step 5: Synthesis of 5-(6-(benzyloxy)hexyloxy)-4-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0643] [ka]

[0644] To a solution of 6-(benzyloxy)hexan-1-ol (1.04 g, 50 mmol) in anhydrous THF (100 mL) 60% NaH (240 mg, 60 mmol) was added at 0°C, and the mixture was stirred for 30 minutes to give 4,5-dichloro-2-(4-methyl- (2H)-(2-hydroxybenzyl)pyridazin-3(2H)-one (1.42 g, 50 mmol) was added, and the resulting mixture was refluxed overnight. After cooling to room temperature, the mixture was quenched with aqueous NH4Cl, followed by ethyl acetate. The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give 5-(6-benzyloxy)hexyl 2-(4-methyl-2-propanol). (4-Cyclobenzyl)-4-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (1.59 g, 70% yield) was obtained as a colorless gel.

[0645] 1 H NMR (400 MHz,CDCl3) δ 1.40-1.47 (4H, m), 1.59-1.65 (2H,m), 1.69-1.75 (2H, m), 3.46 (2H, t, J = 6.4 Hz), 3.78 (3H, s), 4.50 (2H, s),4.56 (2H, t, J = 6.4 Hz), 5.21 (2H, s), 6.85 (2H, d, J = 8.4 Hz), 7.26-7.29 (1H, m), 7.33-7.38 (6H,m), 7.69 (1H, s). Total H from HNMR data: 29. Step 6: Synthesis of 5-(6-(benzyloxy)hexyloxy)-4-chloropyridazin-3(2H)-one

[0646] [ka]

[0647] To a solution of 5-(6-(benzyloxy)hexyloxy)-4-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (450 mg, 1 mmol) in CHCN (30 mL) at 0 °C, CAN (1.37 g, 2.5 mmol) was added. (10 mL) was added and the solution was allowed to warm to room temperature and stirred overnight. Partitioned between ethyl acetate (30 mL) and half-saturated brine (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL) followed by CH2Cl2 (30 mL). The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give 5-(6-(benzyloxy)hexyloxy)-4-chloropyridazin-3(2H)-one (250 mg, 74% yield). Obtained as a yellow gel.

[0648] LC-MS (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 0.05% TFA] in 1.5 min; and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.5 min. Finally, change to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under these conditions for 0.1 min. Rt = 1.346 min; MS calculated: 336.1; MS found: 337.3 [M+H] + . Chemical formula:C 17 H 21ClN2O3, molecular weight: 336.81.

[0649] Step 7: Synthesis of 3-(4-(6-(benzyloxy)hexyloxy)-5-chloro-6-oxopyridazin-1(6H)-yl)piperidine-2,6-dione

[0650] [ka]

[0651] A mixture of 5-(6-(benzyloxy)hexyloxy)-4-chloropyridazin-3(2H)-one (250 mg, 0.74 mmol), 3-bromopiperidine-2,6-dione (143 mg, 0.74 mmol), and potassium carbonate (205 mg, 1.48 mmol) in acetonitrile (40 mL) was stirred at room temperature for 3 days and then filtered. The filtrate was concentrated and purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 2). The product was purified by HPLC to give 3-(4-(6-(benzyloxy)hexyloxy)-5-chloro-6- Oxopyridazin-1(6H)-yl)piperidine-2,6-dione (180 mg, 54% yield) was obtained as a light yellow gel.

[0652] 1 H NMR (400 MHz,CDCl3) δ 1.40-1.49 (4H, m), 1.61-1.66 (2H,m), 1.72-1.78 (2H, m), 2.20-2.24 (1H, m), 2.65-2.79 (2H, m), 2.86-2.90 (1H, m),3.47 (2H, t, J = 6.4 Hz), 4.50 (2H, s), 4.55-4.61 (2H, m), 5.65 (1H, dd, J=10.8, 5.6 Hz), 7.26-7.34 (5H, m), 7.76 (1H, s), 8.46 (1H, s). Total H from HNMR data: 26. Step 8: 3-(4-(6-hydroxyhexyloxy)-6-oxypyridazin-1(6H)-yl)piperidine Synthesis of din-2,6-dione

[0653] [ka]

[0654] 3-(4-(6-(benzyloxy)hexyloxy)-5-chloro-6-oxypyridazin-1(6H)-yl)piperidine-2,6-dione (180 mg, 0.4 mmol) and 10% palladium on activated carbon (100 mg) in MeOH The mixture (20 mL) was stirred under 1 atm of hydrogen atmosphere for 2 hours at room temperature. The solvent was removed and the filtrate was concentrated to give 3-(4-(6-hydroxyhexyloxy)-6-oxypyridazin-1(6H)-yl)piperidine-2,6-dione (118 mg, 90% yield) as a light yellow solid.

[0655] 1 H NMR (400 MHz,DMSO-d6) δ 1.34-1.45 (6H, m), 1.71-1.77 (2H,m), 2.04-2.08 (1H, m), 2.46-2.60 (2H, m), 2.84-2.90 (1H, m), 3.39 (2H, t, J =6.4 Hz), 4.02 (2H, t, J = 6.4 Hz), 4.72 (1H, brs), 5.69 (1H, dd, J =12.4, 5.2Hz), 6.77 (1H, d, J =5.2 Hz), 7.82 (1H, d, J =4.8 Hz), 11.03 (1H, s). Total H from HNMR data: 21. Step 9: Synthesis of 6-(1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)hexanal

[0656] [ka]

[0657] A solution of 3-(4-(6-hydroxyhexyloxy)-6-oxypyridazin-1(6H)-yl)piperidine-2,6-dione (64 mg, 0.2 mmol) in CHCl (30 mL) was added to Dess-Martin reagent (127 mg, 0.6 (mmol) and the mixture was stirred at room temperature overnight. Undissolved solids were removed by suction. After that, the filtrate was concentrated at room temperature to give crude 6-(1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)hexanal (64 mg, 99% yield) as a white semi-solid, which was used directly in the next step without further purification.

[0658] LC-MS (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.5 mL / min; mobile phase: 95% [water + 0.05% TFA] in 1.5 min; and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA], then under these conditions for 0.5 min. Finally, change to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.1 min and under these conditions for 0.1 min. Rt = 0.721 min; MS calculated: 321.1; MS found: 322.3 [M+H] + . Chemical formula:C 15 H 19 N3O5, molecular weight: 321.33.

[0659] Step 10: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Synthesis of (butyl)-6-(4-(6-(1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)hexyl)piperazin-1-yl)nicotinamide

[0660] [ka]

[0661] To a solution of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (100 mg, 0.2 mmol) in MeOH (5 mL) was added 6-(1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy) A solution of hexanal (64 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added, followed by NaBH3CN (40 mg, 0.6 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated and diluted with water (10 mL). The organic extract was washed with brine (20 mL), dried over NaSO, filtered, concentrated, and purified by Prep-TLC and then by Prep-HPLC to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexane). butyl)-6-(4-(6-(1-(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)hexyl)piperazin-1-yl)nicotinamide (20 mg, 13% yield) as a white solid.

[0662] LC-MS (Agilent LCMS 1200-6120, mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 3.0 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then 1.0 min under these conditions. Finally, 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN]. Then 0.7 min under these conditions. Purity was 94.07%, Rt = 2.741 min; MS calculated: 772.4; MS found: 773.3 [M+H]. + . HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then 5 min under these conditions; finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 5 min under these conditions). Purity: 93.35%, Rt = 9.681 min.

[0663] 1H NMR (400 MHz,CDCl3) δ 1.21 (6H, s), 1.25 (6H, s),1.39-1.44 (2H, m), 1.49-1.62 (4H, m), 1.87-1.93 (2H, m), 2.24-2.28 (1H, m),2.36-2.43 (2H, m), 2.56 (4H, s), 2.70-2.81 (2H, m), 2.87-2.92 (1H, m),3.66-3.69 (4H, m), 4.00-4.04 (3H, m), 4.14 (1H, d, J = 8.0 Hz), 5.74 (1H, dd, J= 11.2, 5.6 Hz), 6.07 (1H, d, J = 8.4 Hz), 6.40 (1H, d, J = 4.8 Hz), 6.66 (1 H,d, J = 8.8 Hz), 6.80 (1H, dd, J = 8.8, 2.4 Hz), 6.96 (1H, d, J = 2.4 Hz), 7.57(1H, d, J = 8.8 Hz), 7.71 (1H, d, J = 4.8 Hz), 7.93 (1H, dd, J = 8.8, 2.4 Hz), 8.16( 1H, brs), 8.58 (1H, d, J = 2.4 Hz),. Chemical formula:C 40 H 49 ClN8O6, molecular weight: 773.32 Total H from HNMR data: 49. Synthesis of Exemplary PROTAC30

[0664] [ka]

[0665] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolidin-3-yl)- (pentyl-8-yl)oxy)pentyl)piperazin-1-yl)nicotinamide Synthesis scheme

[0666] [ka]

[0667] Step 1: Synthesis of 3-(8-hydroxy-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

[0668] [ka]

[0669] To a stirred mixture of 2-amino-3-hydroxybenzoic acid (2.0 g, 13.1 mmol) and imidazole (2.0 g, 29.4 mmol) in acetonitrile (30 mL) was added acetyl chloride (2.0 mL, 28.7 mmol). The mixture was stirred at room temperature for 2 days, and 3-amino-piperidine-2,6-dione hydrochloride (2.2 g, 13.1 mmol), imidazole (2.0 g, 29.4 mmol) and triphosphorous acid were added to the mixture. Phenyl (4.11 mL, 15.7 mmol) was added and heated to reflux for 3 days. To this mixture was added water (60 mL) and concentrated hydrochloric acid until pH = 1. The solvent was removed in vacuo. To the residue was added water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL x 2). Sodium bicarbonate (1.8 g ) was added until the pH reached 7-8, and the mixture was stirred at room temperature to obtain a suspension. The suspension was filtered and dried. Drying gave 3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (230 mg, 6% yield) as a grey solid.

[0670] 1H NMR (400 MHz,DMSO-d6) δ 2.14-2.19 (1H, m), 2.57-2.69 (5H,m), 2.80-2.87 (1H, m), 5.26 (1H, dd, J = 11.6, 5.6 Hz), 7.19 (1H, dd, J = 8.0,1.6 Hz), 7.30 (1H, t, J = 8.0 Hz), 7.45 (1H, dd, J = 8.0, 1.6 Hz), 9.66 (1H,s), 11.03 (1H, s). Total H from HNMR data: 13. Step 2: Synthesis of 3-(8-(5-chloropentyloxy)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

[0671] [ka]

[0672] To a solution of 3-(8-hydroxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (91 mg, 0.32 mmol) and 5-chloropentyl 4-methylbenzenesulfonate (88 mg, 0.32 mmol) in DMF (10 mL) was added K2CO3 (88 mg, 0.64 mmol) at room temperature, and then the mixture was heated to 40 °C. The mixture was heated and stirred for 2 days. The mixture was purified by reverse phase HPLC to give 3-(8-(5-chloropentyloxy)-2-oxo-2-methylpropional. (4H)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (19 mg, 15% yield) was obtained as a white solid.

[0673] 1H NMR (400 MHz,CDCl3) δ 1.65-1.73 (2H, m), 1.87-2.02 (4H,m), 2.13-2.17 (1H, m), 2.66-2.74 (4H, m), 2.89-3.02 (2H, m), 3.60 (2H, t, J =6.4 Hz), 4.19 (2H, t, J = 6.4 Hz), 4.77 (1H, dd, J = 11.6, 6.4 Hz), 7.21 (1H,d, J = 8.0 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.76 (1H, d, J = 7.2 Hz). Total H from HNMR data: 21. Step 3: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro Synthesis of quinazolin-8-yloxy)pentyl)piperazin-1-yl)nicotinamide

[0674] [ka]

[0675] 3-(8-(5-chloropentyloxy)-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidin Benzene-2,6-dione (15 mg, 0.038 mmol), DIEA (25 mg, 0.19 mmol), KI (6 mg, 0.038 mmol) and A mixture of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (20 mg, 0.038 mmol) in CH3CN (10 mL) was The mixture was stirred at 0°C overnight. It was then evaporated and the residue was treated with DIEA (25 mg, 0.19 mmol) and EtCN (10 mL) and the solution was stirred at 100° C. overnight, at which point the mixture was diluted with water (10 mL) The resulting mixture was extracted with ethyl acetate (20 mL x 2). The organic extract was washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-8-yloxy)pentyl)piperazin-1-yl)nicotinamide (5.5 mg, 17% yield) as a white solid. Obtained as a solid.

[0676] LC-MS (Agilent LCMS 1200-6120, mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 3.0 min to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then 1.0 min under these conditions. Finally, 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN]. Then 0.7 min under these conditions. Purity was 93.89%, Rt = 1.987 min; MS calculated: 822.4; MS found: 823.4 [M+H]. + . HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then 5 min under these conditions; finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 5 min under these conditions). Purity: 93.92%, Rt = 9.851 min.

[0677] 1H NMR (400 MHz,CDCl3) δ 1.21 (6H, s), 1.25 (6H, s),1.59-1.62 (4H, m), 1.90-2.00 (2H, m), 2.14-2.17 (1H, m), 2.70-2.79 (5H, m),2.86-2.96 (6H, m), 3.15 (1H, dd, J = 14.8, 7.2 Hz), 3.88 (4H, s), 4.05 (1H, s),4.13-4.20 (3H, m), 4.82 (1H, dd, J = 11.2, 5.6 Hz), 6.14 (1H, d, J = 8.4 Hz),6.68 (1H, d, J = 9.2 Hz), 6.80 (1H, dd, J = 8.8, 2.4 Hz), 6.96 (1H, d, J = 2.4Hz), 7.20 (1H, d, J = 8.0 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.57 (1H, d, J = 8.8Hz), 7.74 (1H, d, J = 8.0 Hz), 7.94 (1H, dd, J = 8.8, 2.0 Hz), 8.30 ( 1H, brs),8.57 (1H, d, J = 2.0 Hz). Chemical formula:C 44 H 51 ClN8O6, molecular weight: 823.38 Total H from HNMR data: 51. Synthesis of Exemplary PROTAC33

[0678] [ka]

[0679] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,1-dioxide-3-oxo-2,3-dihydrobenzyl) Benzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide Synthesis scheme

[0680] [ka]

[0681] Step 1: Synthesis of 6-((5-hydroxypentyl)oxy)benzo[d]isothiazol-3(2H)-one 1,1-dioxide

[0682] [ka]

[0683] To a solution of pentane-1,5-diol (1.73 g, 16.7 mmol) in N,N-dimethylformamide (15.0 mL) was added sodium hydride (266 mg, 6.66 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. 6-Nitrobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (760 mg, 3.33 mmol) was then added and stirred at 70 °C for 12 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was extracted with ethyl acetate (30 mL × 3) and water (30 mL). The organic layer was washed with brine (5 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was washed with methanol (3 mL) to give 6-((5-hydroxypentyl)oxy)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (560 mg, 59% yield) as a pale yellow solid.

[0684] Agilent LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm*4,6 mm*3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min. Then, this condition was 1.4 min under HCl; 0.1 min under 95% [water + 10 mM NH₄HCO₃] and 5% [CH₃CN]; and 0.7 min under these conditions). Purity was 78.69%, Rt = 1.159 min; MS calculated: 285.1; MS found: 284.2 [MH]. + . Step 2: Synthesis of 5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl methanesulfonate

[0685] [ka]

[0686] 6-((5-hydroxypentyl)oxy)benzo[d]isothiazol-3(2H)-one (120 mg, 0.42 To a solution of 1 mmol) in tetrahydrofuran (10.0 mL) was added triethylamine (85.1 mg, 0.841 mmol) and methanesulfonyl chloride (38.5 mg, 0.336 mmol) under nitrogen. The resulting reaction mixture was stirred at room temperature for 0.5 h. The solvent was concentrated in vacuo. The residue was Extraction with dichloromethane (10 ml x 3) and water (20 mL) was performed. The organic layer was dried and concentrated in vacuo to give crude 5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)o[4-(4-methyl-2-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)-2-oxo-4-methyl ... (Xy)pentyl methanesulfonate was obtained as a yellow oil, which was used in the next step without further purification.

[0687] Agilent LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then 1.5 min under this condition, and finally 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min, and then under this condition. (0.5 min below). Purity 77.93%, Rt = 0.613 min; MS calculated: 363.0; MS found: 362.0 [M−H] + . Step 3: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide

[0688] [ka]

[0689] To a solution of 5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl methanesulfonate (0.421 mmol) in acetonitrile (5 mL) was added potassium carbonate (291 mg, 2.11 mmol) and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (212 mg, 0.421 mmol). The resulting reaction mixture was stirred at 90° C. for 16 hours. The solvent was concentrated in vacuo. The residue The residue was extracted with ethyl acetate (20 mL x 3) and water (20 mL). The organic layer was dried and concentrated in vacuo. The residue was concentrated and purified by prep-HPLC to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotine The amide (34 mg, 11% for two steps) was obtained as a pale yellow solid.

[0690] Agilent LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.5 min, then 1.5 min under this condition, and finally 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.1 min, and then under this condition. (0.5 min below). Purity 97.67%, Rt = 1.037 min; MS calculated: 734.3; MS found: 735.0 [M+H] + . Step 4: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotine Synthesis of amides

[0691] [ka]

[0692] To a solution of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (30 mg, 0.0408 mmol) in 1,4-dioxane / N,N-dimethylformamide (5 mL / 0.5 mL) was added 3-bromopiperidine-2,6-dione (11.8 mg, 0.0612 mmol) and potassium tert-butoxide (9.16 mg, 0.0816 mmol). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, ice water (2.0 mL) was added, and the mixture was adjusted to pH 2-3 with hydrochloric acid (1N), followed by extraction with ethyl acetate (20.0 mL × 3). The combined organic layer was washed with brine (5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC and prep-TLC (dichloromethane / methanol = 10:1) to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl-2,4,6-tri ... cyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,1-dioxide-3-oxo So-2,3-dihydrobenzo[d]isothiazol-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (6.8 mg, 20%) was obtained as a white solid.

[0693] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm*4,6 mm*3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 3.0 min, then 1.0 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Purity: 99.03%, Rt = 3.087 min; MS calculated: 845.3; MS found: 846.3 [M+H] + . HPLC (Agilent HPLC 1200, Column: Waters X-Bridge C18 (150 mm*4.6 mm*3.5 μm); Column temperature: 40 °C; Flow rate: 1.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then 5 min under these conditions; finally 95% [water + 10 mMNH4HCO3] and 5% [CH3CN] in 0.1 min, then 5 min under these conditions). Purity: 96.34%, Rt = 10.536 min.

[0694] 1 H NMR (400 MHz,DMSO-d6) δ 1.19 (6H, s), 1.22 (6H, s),1.46-1.55 (4H, m), 1.79-1.80 (2H, m), 2.34-2.40 (3H, m), 2.45 (4H, s),2.54-2.92 (3H, m), 3.59 (4H, s), 4.06 (1H, d, J = 9.2 Hz), 4.20-4.25 (2H, m),4.30 (1H, s), 5.23-5.28 (0.5H, m), 5.98 (0.5H, t, J = 9.2 Hz), 6.87 (1H, d, J =9.2 Hz), 6.99-7.02 (1H, m), 7.21 (1H, d, J = 2.0 Hz), 7.35-7.50 (1H, m), 7.63 (1H, d, J = 9.2 Hz), 7.81-7.83(1H, m), 7.90-8.02 (3H, m), 8.62 (1H, d, J= 2.0 Hz), 11.19 (1H, t, J = 9.6 Hz). Chemical formula:C 42 H 48 ClN7O8S, molecular weight: 846.39 Total H number from HNMR data: 48. Synthesis of Exemplary PROTAC39

[0695] [ka]

[0696] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)nicotinamide Synthesis scheme:

[0697] [ka]

[0698] Step 1: Synthesis of N-(2,4-difluorophenyl)-3-methoxy-2-methylbenzamide

[0699] [ka]

[0700] A mixture of 3-methoxy-2-methylbenzoic acid (5 g, 30 mmol), oxalyl chloride (5.6 g, 150 mmol), and N,N-dimethylformamide (0.1 ml) in dichloromethane (20 ml) was stirred at room temperature for 2 hours. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure, and the 3-methoxy-2-methylbenzoic acid was obtained. 2-Methylbenzoyl chloride (crude) was obtained as a yellow oil, which was not further purified. Used in the next step without further purification. 3-Methoxy-2-methylbenzoyl chloride (crude), 2,4-di A mixture of fluoroaniline (3.8 g, 30 mmol) and triethylamine (12 g, 120 mmol) in dichloromethane (20 ml) was stirred at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction mixture was diluted with dichloromethane (20 ml), washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography to give N-(2,4-difluorophenyl)-3-methoxy-2-methylbenzamide (5.8 g, 69% yield) as a yellow oil.

[0701] Step 2: Synthesis of 2-(bromomethyl)-N-(2,4-difluorophenyl)-3-methoxybenzamide Growth

[0702] [ka]

[0703] N-(2,4-difluorophenyl)-3-methoxy-2-methylbenzamide (5.8 g, 20.9 mmol), N-bromosuccinimide (3.9 g, 31.4 mmol), and AIBN (2,2'-azobis(2-methylpropionyl)amino) A mixture of 2-(bromomethyl)-N-(2,4-difluorobenzoyl)propanol (342 mg, 2.09 mmol) and carbon tetrachloride (30 ml) was stirred at 70°C overnight. The volatile components were evaporated under reduced pressure, and the resulting mixture was purified by silica gel flash column chromatography (eluted with 10-20% ethyl acetate in hexane) to give 2-(bromomethyl)-N-(2,4-difluorobenzoyl)propanol. (fluorophenyl)-3-methoxybenzamide (5.9 g, 80% yield) as a white solid .

[0704] LC_MS:(ES + ): m / z 356.0, 357.9 [M+H] + .t R = 2.907 minutes. Step 3: Synthesis of 2-(2,4-difluorophenyl)-4-methoxyisoindolin-1-one

[0705] [ka]

[0706] A solution of 2-(bromomethyl)-N-(2,4-difluorophenyl)-3-methoxybenzamide (2.0 g, 5.6 mmol) in anhydrous tetrahydrofuran (20 ml) was added to potassium tert-butanolate (tetrahydrofuran). (1M in toluene, 8.4 ml, 8.4 mmol) was added at 0°C, and the resulting mixture was stirred at 0°C for 2 hours. TLC showed the reaction was complete. The reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The organic layer was collected, washed with brine (20 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluted with 20% ethyl acetate in hexane) to give 2-(2,4-difluoromethyl-2-methyl-2-methylpropional). (phenyl)-4-methoxyisoindolin-1-one (500 mg, 33% yield) was obtained as a yellow solid. Ta.

[0707] Step 4: Synthesis of 2-(2,4-difluorophenyl)-4-hydroxyisoindolin-1-one

[0708] [ka]

[0709] 2-(2,4-difluorophenyl)-4-methoxyisoindolin-1-one (200mg) in hydrogen bromide A solution of 2,4-difluorophenyl)-4-hydroxyisoindolin-1-one (180 mg, 95% yield) in acetic acid (33%, 3 ml) was stirred at 100°C for 2 days. TLC showed the reaction was complete. Evaporation of the volatiles under reduced pressure gave a crude residue, which was purified by silica gel flash chromatography (eluting with 30-50% ethyl acetate in hexane) to give 2-(2,4-difluorophenyl)-4-hydroxyisoindolin-1-one (180 mg, 95% yield) as a yellow solid. Obtained as an oil.

[0710] LC_MS:(ES+): m / z 262.1 [M+H] + .t R = 2.64 minutes. Step 5: Synthesis of 4-(allyloxy)-2-(2,4-difluorophenyl)isoindolin-1-one

[0711] [ka]

[0712] To a solution of 2-(2,4-difluorophenyl)-4-hydroxyisoindolin-1-one (180 mg, 0.68 mmol), triphenylphosphine (539 mg, 2.06 mmol) and prop-2-en-1-ol (119 mg, 2.06 mmol) in tetrahydrofuran (5 ml) was added a solution of diisopropyl azodicarboxylate (416 mg, 2.06 mmol) in tetrahydrofuran (2 ml) at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. TLC showed the reaction was complete. The volatiles were evaporated under reduced pressure and the crude residue This was purified by silica gel flash chromatography (eluting with 10-20% ethyl acetate in hexane) to give 4-(allyloxy)-2-(2,4-difluorophenyl)isoindoline. Lin-1-one (180 mg, 87% yield) was obtained as a colorless oil.

[0713] LC_MS:(ES+): m / z 302.2 [M+H] + .t R = 2.86 minutes. Step 6: 2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)a Synthesis of cetoaldehyde

[0714] [ka]

[0715] Ozone-enriched oxygen steam is reacted with 4-(allyloxy)-2-(2,4-difluorophenyl) Through a solution of isoindolin-1-one (180 mg, 0.59 mmol) in dichloromethane (20 ml), The reaction mixture was allowed to bubble at -78°C until it turned dark blue. The solution was then stirred for 20 minutes at -78°C with acid. The reaction mixture was then purged with dimethyl sulfide (1.5 ml, 20.4 mmol) was added at -78°C. The mixture was allowed to warm to room temperature and stirred overnight. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give 2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)acetaldehyde (180 mg, 100%), This was used in the next step without further purification.

[0716] 1H NMR (400 MHz,DMSO-d6): δ 4.68-4.69 (m, 2H), 4.77-4.79 (m, 2H),6.86-6.93 (m, 4H), 7.33-7.55 (m, 2H), 9.80 (s, 1H). Chemical formula:C 16 H 11 F2NO3;Molecular weight:303.26; Total H from HNMR data: 11; Step 7: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)nicotinamide

[0717] [ka]

[0718] 2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)acetaldehyde (160 mg, 0.53 mmol), N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrafluoroethylene To a solution of (tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (300 mg, 0.6 mmol, an intermediate in the synthesis of exemplary PROTAC 29) and acetic acid (2 drops) in methanol (3 mL) was added sodium cyanoborohydride (150 mg, 2.4 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. TLC showed the reaction was complete. The reaction mixture was diluted with ethyl acetate (40 mL) and water. (20 ml). The organic layers were collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by prep-TLC (eluting with 10% methanol in dichloromethane) to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-(4-methyl-2-propanol)-2-one. (2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,4-difluorophenyl)-1-oxoisoindolin-4-yl)oxy)ethyl)piperazin-1-yl)nicotinamide (50 mg, 12% yield, 3 steps) as a light yellow solid.

[0719] 1 H NMR (400 MHz, CD3OD):δ 1.23 (s, 6H), 1.29 (s, 6H), 2.67-2.82 (m, 4H),2.92-3.01 (m, 2H), 3.72 (s, 4H), 4.15 (s, 1H), 4.29-4.39 (m, 3H), 4.88 (s, 2H),6.85-6.87 (m, 2H), 7.10-7.34 (m, 4H), 7.47-7.75 (m, 4H), 7.96-7.98 (m, 1H),8.61 (s, 1H). Chemical formula:C 41 H 41 ClF2N6O4;Molecular weight:755.25; Total H number from HNMR data: 40; LC_MS:(ES+): m / z 755.6 [M+H] + .t R = 2.534 minutes.

[0720] Synthesis of Exemplary PROTAC41

[0721] [ka]

[0722] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,4-difluorophenyl)-1,3-dioxoisoindolin-5-yl)oxy)pentaerythritol ... (Ci)piperazin-1-yl)nicotinamide Synthesis scheme:

[0723] [ka]

[0724] Step 1: Synthesis of 2-(2,4-difluorophenyl)-5-hydroxyisoindoline-1,3-dione

[0725] [ka]

[0726] To a solution of 4-hydroxyphthalic acid (2 g, 10.98 mmol) in acetonitrile (50 ml), 1,1'-carbonyldiimidazole (3.9 g, 24.16 mmol) was added portionwise at room temperature. After stirring for 30 minutes, 2,4-difluoroaniline (1.6 g, 12.08 mmol) was added, and the resulting mixture was stirred at 70 °C for 3 hours. TLC showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (50 ml) and water (50 ml). ), and the organic layer was washed with brine (50 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 25% to 35% ethyl acetate in hexane) to give 2-(2,4-difluorophenyl)- ... (2.1 g, 70% yield)-5-hydroxyisoindoline-1,3-dione as a yellow solid Got it.

[0727] LC_MS:(ES + ): m / z276.1 [M+H] + .t R = 2.462 minutes. 1 H NMR (400 MHz,DMSO-d6): δ 7.21-7.31 (m, 3H), 7.51-7.56 (m,1H), 7.60-7.66 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 11.17 (br, 1H). Chemical formula:C 14 H7F2NO3;Molecular weight:275.21; Total H from HNMR data: 7. Step 2: Synthesis of 2-(2,4-difluorophenyl)-5-((5-hydroxypentyl)oxy)isoindoline-1,3-dione

[0728] [ka]

[0729] A mixture of 2-(2,4-difluorophenyl)-5-hydroxyisoindoline-1,3-dione (300 mg, 1.09 mmol), 5-hydroxypentyl 4-methylbenzenesulfonate (282 mg, 1.09 mmol), and potassium carbonate (301 mg, 2.18 mmol) in N,N-dimethylformamide (5 ml) was heated overnight at 50°C. The reaction mixture was stirred at rt. TLC showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (30 ml) and The mixture was partitioned between water (30 ml) and the organic layer was washed with brine (30 ml x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 40% to 50% ethyl acetate in hexane) to give 2-(2,4-difluoromethyl-2-phenylpropanol). To the resulting solution, 217 mg (55% yield) of ((5-hydroxypentyl)oxy)isoindoline-1,3-dione was obtained as a white solid.

[0730] LC_MS:(ES + ): m / z 362.1 [M+H] + .t R = 2.658 minutes. 1 H NMR (400 MHz,CDCl3): δ 1.57-1.69 (m, 4H), 1.88-1.91 (m,2H), 3.70 (t, J = 6.2 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 6.99-7.05 (m, 2H), 7.22-7.24 (m, 1H),7.31-7.36 (m, 1H), 7.40-7.41 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H). Chemical formula:C 19 H 17 F2NO4;Molecular weight:361.34; Total H from HNMR data: 16. Step 3: Synthesis of 5-((2-(2,4-difluorophenyl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl 4-methylbenzenesulfonate

[0731] [ka]

[0732] 2-(2,4-difluorophenyl)-5-((5-hydroxypentyl)oxy)isoindoline-1,3-dione (217 mg, 0.60 mmol), triethylamine (122 mg, 1.20 mmol) and N,N-dimethylpiperidin A solution of lysine-4-amine (7.3 mg, 0.06 mmol) in dichloromethane (20 ml) was added with 4-toluenesulfonyl ether. Phenyl chloride (171 mg, 0.90 mmol) was added at 0° C., and the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed the reaction was complete. The reaction mixture was diluted with dichloromethane (30 ml). Diluted, washed with water (50 ml) then brine (50 ml), dried over anhydrous sodium sulfate The mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography (eluting with 30-50% ethyl acetate in hexanes) to give 5-((2-(2,4-difluorophenyl)-2-methyl-2-propanol). (nyl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl 4-methylbenzenesulfonate (208 mg, 67% yield) was obtained as a white solid.

[0733] LC_MS:(ES + ): m / z 516.2 [M+H] + .t R = 3.183 minutes. 1 H NMR (400 MHz,DMSO-d6): δ 1.53-1.58 (m, 2H), 1.74-1.85 (m,4H), 2.45 (s, 3H), 4.05-4.09 (m, 4H), 7.00-7.04 (m, 2H), 7.20-7.22 (m, 1H), 7.31-7.38 (m, 4H), 7.79-7.86 (m, 3H). Chemical formula:C 26 H 23 F2NO6S; molecular weight: 515.53; Total H from HNMR data: 23. Step 4: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,4-difluorophenyl)-1,3-dioxoisoindolin-5-yl)o Synthesis of (oxy)pentyl)piperazin-1-yl)nicotinamide

[0734] [ka]

[0735] 5-((2-(2,4-difluorophenyl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl 4-methylbenzenesulfonate (110 mg, 0.21 mmol), N-ethyl-N-isopropylpropionate To a solution of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl-2-methylpropan-2-amine (55 mg, 0.43 mmol) and potassium iodide (3 mg, 0.02 mmol) in N,N-dimethylformamide (2 ml) was added N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl-2-methylpropan-2-amine (55 mg, 0.43 mmol) and potassium iodide (3 mg, 0.02 mmol) (tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (100 mg, 0.21 mmol, e.g. The reaction mixture was diluted with ethyl acetate (50 ml) and water (30 ml) and stirred overnight at 50°C under nitrogen. The organic layer was collected, washed with brine (20 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash column chromatography (eluting with 2-5% methanol in dichloromethane) to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,4-difluorophenyl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (98.4 mg, 57% yield) as a white solid.

[0736] LC_MS:(ES + ): m / z 811.3 [M+H] + .t R = 2.630 minutes. 1 H NMR (400 MHz, CD3OD):δ 1.12 (s, 6H), 1.22 (s, 6H), 1.48-1.61 (m, 4H),1.80-1.83 (m, 2H), 2.35-2.44 (m, 6H), 3.59 (br, 4H), 4.06 (d, J = 9.2Hz, 1H),4.22 (t, J = 6.4 Hz, 2H), 4.31 (s, 1H), 6.88-6.90 (m, 1H), 6.99-7.02 (m, 1H),7.20-7.21 (m, 1H), 7.28-7.32 (m, 1H), 7.40-7.42 (m, 1H), 7.52-7.55 (m, 2H), 7.63-7.65(m, 2H), 7.89-7.93 (m, 2H), 7.97-7.99 (m, 1H), 8.64 (br, 1H). Chemical formula:C 44 H 45 ClF2N6O5;Molecular weight:811.32; Total H number from HNMR data: 45. Synthesis of Exemplary PROTAC42

[0737] [ka]

[0738] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(6-cyano-2-oxo-1,2-dihydropyridin-3-yl)-1,3-dioxoisoindo) Phosphorus-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide Synthesis scheme

[0739] [ka]

[0740] Step 1: Synthesis of 5-(5-hydroxy-1,3-dioxoisoindolin-2-yl)-6-methoxypicolinonitrile

[0741] [ka]

[0742] A mixture of 5-amino-6-methoxypicolinonitrile (600 mg, 4.02 mmol) and 5-hydroxyisobenzofuran-1,3-dione (660 mg, 4.02 mmol) in glacial acetic acid (4 mL) was stirred at 100 °C overnight and then cooled to room temperature. Water (40 mL) was added. The mixture was neutralized with saturated sodium bicarbonate to pH > 7. The mixture was extracted with ethyl acetate (20 mL x 3). The combined solution The organic layer was washed with brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and purified. Concentration in air was carried out and the residue was washed with ether to give 5-(5-hydroxy-1,3-dioxoisoindolin-2-yl)-6-methoxypicolinonitrile (650 mg, 55%) as a yellow solid.

[0743] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (30 mm*4.6 mm*3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 90% [water + 10 mM NH4HCO3] and 10% [CH3CN] in 0.5 min to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN], then 1.5 min under these conditions. Finally, in 0.1 min, the solution was diluted to 90% [water + 10 mM NH4HCO3] and 10% [CH3CN]. Purity: 69.2%, Rt = 0.852 min; MS calculated: 295.1; MS found: 296.0 [M+H] + . Step 2: Synthesis of 5-(5-(5-chloropentyloxy)-1,3-dioxoisoindolin-2-yl)-6-methoxypicolinonitrile

[0744] [ka]

[0745] 5-(5-hydroxy-1,3-dioxoisoindolin-2-yl)-6-methoxypicolinonitrile (200 mg, 0.68 mmol), potassium carbonate (188 mg, 1.36 mmol) and 5-chloropentyl 4-methyl A mixture of benzenesulfonate (187 mg, 0.68 mmol) and dimethyl sulfoxide (5 mL) was heated at 40°C. The mixture was stirred at rt for 2 h. The resulting mixture was cooled to room temperature. Water (20 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was identified by prep-TLC (ethyl acetate). The resulting mixture was purified with ethyl acetate / petroleum ether (1:1) to give 5-(5-(5-chloropentyloxy)-1,3-diol. xoisoindolin-2-yl)-6-methoxypicolinonitrile (100 mg, 37%) was obtained as a yellow solid.

[0746] Step 3: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-methoxypyridin-3-yl)-1,3-dioxoisoindolin-5-yloxy)pentyl)piperazin-1-yl)nicotinamide

[0747] [ka]

[0748] Methyl 5-(5-(5-chloropentyloxy)-1,3-dioxoisoindolin-2-yl)-6-methoxypicolinonitrile (100 mg, 0.25 mmol), ethyldiisopropylamine (96.8 mg, 0.75 mmol), potassium iodide (41.5 mg, 0.25 mmol), and N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-methyl-2-propanol) A mixture of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-methoxypyridin-3-yl)-1,3-dioxoisoindolin-5-yloxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide (117 mg, 0.25 mmol) in dimethyl sulfoxide (3 mL) was stirred overnight at 70° C. The resulting mixture was allowed to cool to room temperature. Water (20 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by prep-TLC (ethyl acetate) to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-methoxypyridin-3-yl)-1,3-dioxoisoindolin-5-yl ... (Pentyl)piperazin-1-yl)nicotinamide (53 mg, 34%) was obtained as a yellow solid.

[0749] Step 4: 5-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra ... Synthesis of methylcyclobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-1,3-dioxoisoindolin-2-yl)-6-hydroxypicolinamide

[0750] [ka]

[0751] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-methoxypyridin-3-yl)-1,3-dioxoisoindolin-5-yloxy)pentyl)piperazin-1-yl)nicotinamide (70 mg, 0.084 mmol) in hydrogen bromide / ice The mixture was stirred at 45°C for 5 hours with acetic acid (w / w 48%, 0.5 mL). The resulting mixture was cooled to room temperature. Water (20 mL) was added and the mixture was neutralized to pH > 7 with saturated sodium bicarbonate. The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutylcarbamoyl) To this was obtained (50 mg, 71%) of hydrochloric acid hydrochloride, ...

[0752] Step 5: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-hydroxypyridin-3-yl)-1,3-dioxoisoindolin-5-yloxy)pentyl)piperazin-1-yl)nicotinamide

[0753] [ka]

[0754] 5-(5-(5-(4-(5-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl (chlorobutylcarbamoyl)pyridin-2-yl)piperazin-1-yl)pentyloxy)-1,3-di Oxoisoindolin-2-yl)-6-hydroxypicolinamide (45 mg, 0.053 mmol) and To a solution of triethylamine (21.2 mg, 0.21 mmol) in dichloromethane (4 mL) was added trifluoroacetic anhydride (44.1 mg, 0.21 mmol). The mixture was stirred for 2 hours. The mixture was poured into ice water (40 mL). Dichloromethane (40 mL) was added. The organic layer was separated and washed with brine (10 mL x 2). The residue was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and stirred overnight. Ethyl acetate (10 mL) was added. The organic layer was separated, washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by prep-HPLC to give N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(2-(6-cyano-2-hydroxypyridin-3-yl)-1,3-dioxoisoindolin-5-yl ... C)pentyl)piperazin-1-yl)nicotinamide (6.8 mg, 16%) was obtained as a white solid.

[0755] LC-MS (Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm * 4.6 mm * 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 1.6 min. Then (1.4 min under these conditions. Finally, change to 95% [water + 0.05% TFA] and 5% [CHCN + 0.05% TFA] in 0.05 min and run under these conditions for 0.7 min.) Purity 99.5%, Rt = 1.842 min; MS calculated: 816.3; MS found: no reacted mass.

[0756] HPLC (Agilent HPLC 1200; column: L-column2 ODS (150 mm*4.6 mm*5.0 μm); column temperature: 40°C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1% TFA] in 10 min, then under these conditions for 5 min. Finally, change to 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] in 0.1 min, and this Purity was 91.3%, Rt = 8.215 min.

[0757] 1 H NMR (400 MHz, DMSO-d 6) δ 1.12 (6H, s), 1.22 (6H, s),1.42-1.60 (4H, m), 1.77-1.82 (2H, m), 2.36-2.44 (2H, m), 3.30-3.35 (4H, m),3.58-3.66 (4H, m), 4.06(1H, d,J = 9.2 Hz), 4.21 (1H, t, J = 6.2 Hz), 4.30 (1H,s), 6.88 (1H, d,J = 8.8 Hz), 6.99-7.02 (1H, m), 7.21 (1H, d, J = 2.4 Hz),7.38-7.41 (1H, m), 7.48-7.52 (2H, m), 7.64 (1H, d, J = 9.2 Hz), 7.89-7.98 (4H,m), 8.63 (1H, d, J = 2.0 Hz). Chemical formula:C 44 H 45 ClN8O6; molecular weight: 817.33 Total H from HNMR data: 45 Synthesis of Exemplary PROTAC43

[0758] [ka]

[0759] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(1,3-dioxo-2-(6-oxo-1,6-dihydropyridin-3-yl)isoindoline-5-yl) (I)piperazin-1-yl)methyl)piperidin-1-yl)benzamide Synthesis scheme

[0760] [ka]

[0761] Step 1: Synthesis of 4-[4-(hydroxymethyl)-1-piperidyl]benzoic acid

[0762] [ka]

[0763] Ethyl 4-[4-(hydroxymethyl)-1-piperidyl]benzoate (52 g, 197.47 mmol, 1 equiv.) To a solution of tetrahydrofuran (250 mL), methanol (250 mL), and water (250 mL) was added sodium hydroxide (31.6 g, 0.79 mmol, 4 equiv.). The mixture was stirred at 30°C for 12 hours. Thin layer chromatography (TLC) was performed. Chromatography (petroleum ether:ethyl acetate = 1:1) showed that the reaction was complete. The mixture was adjusted to pH 3-4 with hydrochloric acid (2M) and filtered. The filter cake was dried in vacuo. The residue was triturated with ethyl acetate (500 mL) and 4-[4-(hydroxymethyl)-1-piperidinyl]-2-(2-methyl-1-pyridinyl) ... [diyl]benzoic acid (35 g, 148.76 mmol, 75% yield) was obtained as a white solid.

[0764] 1 H NMR: (400MHz,DMSO-d6) δ: 12.19 (s, 1H), 7.74 (d, J=8.8Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.48 (br t, J=5.2 Hz, 1H), 3.90 (d, J=12.8 Hz,2H), 3.27 (br t, J=5.2 Hz, 2H), 2.86 - 2.72 (m, 2H), 1.72 (d, J=12.8 Hz, 2H),1.66 - 1.51 (m, 1H), 1.17 (dq, J=4.0, 12.0 Hz, 2H) Chemical formula:C 13 H 17 NO3, molecular weight: 235.28 Total H from HNMR data: 17. Step 2: Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide

[0765] [ka]

[0766] A solution of 4-[4-(hydroxymethyl)-1-piperidyl]benzoic acid (38 g, 161.51 mmol, 1 equiv.) and 4-(3-amino-2,2,4,4-tetramethyl-cyclobutoxy)-2-chloro-benzonitrile (50.9 g, 161.51 mmol, 1 equiv., hydrochloride salt) in dimethylformamide (800 mL) was added with diisopropyl ether. Ethylamine (83.5 g, 646.04 mmol, 112 mL, 4 equiv.) was added. The mixture was stirred for 10 min at 30 °C. Then o-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluorophosphate (64.48 g, 169.59 mmol, 1.05 equiv.) was added. The mixture was stirred at 30° C. for 1 hour. The mixture was stirred. LCMS showed that the reaction was complete and the desired MS could be detected. The mixture was poured into water (4 L) and filtered. The filter cake was concentrated and triturated with methanol (500 mL x 2). Conversion gave N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide (72 g, 137.89 mmol, 85% yield, 95% purity) as a white solid.

[0767] LCMS:MS (ESI) m / z: 496.1 [M+1] + 1H NMR: (400MHz,DMSO-d6) δ: 7.90 (d, J=8.8 Hz, 1H), 7.73 (d,J=8.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.00 (dd, J=2.4,8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 4.48 (t, J=5.2 Hz, 1H), 4.31 (s, 1H), 4.05(d, J=9.2 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 3.27 (t, J=5.6 Hz, 2H), 2.80 - 2.70(m, 2H), 1.73 (d, J=11.2 Hz, 2H), 1.63 - 1.52 (m, 1H), 1.27 - 1.15 (m, 8H),1.12 (s, 6H) Chemical formula:C 28 H 34 ClN3O3, molecular weight: 496.04 Total H from HNMR data: 34. Step 3: Synthesis of N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide

[0768] [ka]

[0769] N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-[4-(hydroxymethyl)-1-piperidyl]benzamide (65 g, 131.04 mmol, 1 equiv.) dichloromethane To a solution of ethanol (700 mL) was added Dess-Martin reagent (76.70 g, 180.83 mmol, 1.38 equiv.). The mixture was stirred at 30°C for 2 hours. Thin layer chromatography (dichloromethane:methanol = 1:1) showed that the reaction was complete. The reaction solution was adjusted to pH 8-9 with saturated sodium bicarbonate. The mixture was diluted with water (3 L) and extracted with dichloromethane (1.5 L x 3). The combined organic layers were washed with saturated brine (1.5 L x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:0 to 50:1) to give N-[3-(3-chloro-4-cyano-phenoxy)-2,2,4,4-tetramethyl-cyclobutyl]-4-(4-formyl-1-piperidyl)benzamide (34.6 g, 67.94 mmol, 51% yield, 97% purity) as a white solid.

[0770] 1 H NMR: (400MHz,DMSO-d6) δ: 9.63 (s, 1H), 7.90 (d, J=8.8 Hz,1H), 7.74 (d, J=8.8 Hz, 2H), 7.49 (d, J=9.2 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H),7.03 - 6.94 (m, 3H), 4.32 (s, 1H), 4.05 (d, J=9.2 Hz, 1H), 3.76 (td, J=3.6,12.8 Hz, 2H), 3.01 - 2.92 (m, 2H), 2.62 - 2.55 (m, 1H), 2.62 - 2.55 (m, 1H),1.92 (dd, J=3.6, 12.8 Hz, 2H), 1.62 - 1.48 (m, 2H), 1.21 (s, 6H), 1.12 (s, 6H) Chemical formula:C 28 H 32 ClN3O3, molecular weight: 494.02 Total H from HNMR data: 32. Step 4: Synthesis of 5-fluoro-2-(6-methoxypyridin-3-yl)isoindoline-1,3-dione

[0771] [ka]

[0772] 5-Fluoro-1,3-dihydro-2-benzofuran-1,3-dione (100.0 mg, 602 μmol), 6-methoxypyridin-3-amine (82.1 mg, 662 μmol), sodium acetate (59.2 mg, 722 μmol), and A mixture of 1,2-dimethyl-3-(4-(2-methyl-2-propanol)-2-one (499 μL, 8.74 mmol) and acetic acid (499 μL, 8.74 mmol) was heated at 118° C. with stirring for 2 hours. The reaction was monitored by LCMS (CF-820-1) and showed a major product with a mass consistent with the desired product. The reaction mixture was cooled to 90°C and quenched with water (2 mL). The mixture was allowed to cool to room temperature. The resulting precipitate was filtered and washed with water. The material was dried to give the desired product, 5-fluoro-2-(6-methoxypyridin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (149.1 mg, 547 μmol, 91.4% yield), as a light purple solid.

[0773] 1 H NMR (400 MHz, chloroform-d) δ 8.26 (dd, J = 0.49, 2.64 Hz, 1H), 7.98(dd, J = 4.50, 8.22 Hz, 1H), 7.65 (d, J = 2.54 Hz, 1H), 7.62 - 7.64 (m, 1H),7.48 (dt, J = 2.35, 8.51 Hz, 1H), 6.89 (dd, J = 0.78, 8.80 Hz, 1H), 4.00 (s,3H) LCMS m / e+ = 273.16 [M+H] + Step 5: 4-(2-(6-methoxypyridin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine Synthesis of tert-butyl arazine-1-carboxylate

[0774] [ka]

[0775] tert-Butyl piperazine-1-carboxylate (34.0 mg, 183 μmol) and 5-fluoro-2-(6-methyl- A solution of (2,3-dihydro-1H-isoindole-1,3-dione) (50.0 mg, 183 μmol) in methylpyrrolidone (1.0 mL) was diluted with N,N-diisopropylethylamine (95.5 μL, 549 μmol). The reaction mixture was heated at 120° C. for 2 hours. The reaction was monitored by LCMS. HPLC showed a major peak with a mass consistent with the desired product and a minor peak with a mass consistent with the starting material. The reaction was allowed to stir for an additional 16 hours at 120° C. LCMS showed The reaction mixture was diluted with water (2 mL) and the resulting eluate showed a major peak with a mass consistent with the desired product. The mixture was quenched and extracted with EtOAc (2 mL). The organic layer was washed with brine (1 mL) and washed with Na2SO4 It was dried, filtered and concentrated under reduced pressure. The crude material was dissolved in DCM / MeOH (gradient 100:0 to 95:5). The resulting mixture was purified by silica gel chromatography on a Teledyne Combiflash ISCO. The product-containing fractions were concentrated under reduced pressure to give the desired product, tert-butyl 4-[2-(6-methoxypyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (39.6 mg, 90.3 μmol, 49.3% yield), as a white solid.

[0776] LCMS m / e+ = 439.33 [M+H] + 1H NMR (400 MHz, chloroform-d) δ 8.25 (d, J = 2.15 Hz, 1H), 7.79 (d, J= 8.61 Hz, 1H), 7.64 (dd, J = 2.74, 8.80 Hz, 1H), 7.35 (d, J = 2.35 Hz, 1H),7.11 (dd, J = 2.45, 8.51 Hz, 1H), 6.87 (dd, J = 0.59, 8.80 Hz, 1H), 3.98 (s,3H), 3.60 - 3.66 (m, 4H), 3.42 - 3.48 (m, 4H), 1.50 (s, 9H) Step 6: 2-(6-oxo-1,6-dihydropyridin-3-yl)-5-(piperazin-1-yl)isoine Synthesis of doline-1,3-dione

[0777] [ka]

[0778] tert-Butyl 4-[2-(6-methoxypyridin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (39.6 mg, 90.3 μmol) in 4.0 M hydrochloric acid A solution of 2-(6-oxo-1,6-dihydropyridin-3-yl)-5-(piperazin-1-yl)-2,3-dihydropyridin-3-yl was stirred at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give 2-(6-oxo-1,6-dihydropyridin-3-yl)-5-(piperazin-1-yl)-2,3-dihydropyridin-3-yl. dro-1H-isoindole-1,3-dione hydrochloride (32.5 mg, 90.0 μmol, 100% yield) Obtained as a solid, this material was used in the next reaction without further purification.

[0779] LCMS m / e+ = 425.22 [M+H] + Step 7: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(1,3-dioxo-2-(6-oxo-1,6-dihydropyridin-3-yl)isoindo Synthesis of (phosphor-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide

[0780] [ka]

[0781] To a solution of 4-(4-formylpiperidin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (44.4 mg, 90.0 μmol) and 2-(6-oxo-1,6-dihydropyridin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride (32.5 mg, 90.0 μmol) in ethylene dichloride (1.0 mL), Triethylamine (37.4 μL, 269 μmol) and sodium triacetoxyborohydride (57.0 mg, 269 μmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was analyzed by LCMS. Monitoring by HPLC showed a peak with a mass consistent with the desired product and a peak with a mass consistent with the starting material. The reaction mixture was allowed to stir at room temperature for an additional 16 hours. LMCS showed a major peak with a mass consistent with the desired product. The reaction mixture was quenched with NaHCO3 (1 mL) and extracted with DCM (1 mL). The organic layer was dried over Na2SO4 and filtered. The crude material was purified by silica gel chromatography on a Teledyne Combiflash ISCO eluting with DCM / MeOH (gradient 100:0 to 90:10). The product-containing fractions were combined and concentrated under reduced pressure to give the desired product, N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(1,3-dioxo-2-(6-oxo-1,6-dihydropyridin-3-yl)isoindolin-5-yl)piperazin-1-yl)methyl (Il)piperidin-1-yl)benzamide (30 mg, 37.3 μmol, 41.5% yield) was obtained as a yellow solid.

[0782] 1 H NMR (400 MHz,DMSO-d6): δ 7.91 (d, J = 8.80 Hz, 1H), 7.72 (t, J =8.41 Hz, 3H), 7.56 (d, J = 2.54 Hz, 1H), 7.44 - 7.53 (m, 2H), 7.38 (d, J =1.96 Hz, 1H),7.28 (dd, J = 2.05, 8.71 Hz, 1H), 7.21 (d, J = 2.35 Hz, 1H), 7.00 (dd, J =2.35, 8.80 Hz, 1H), 6.96 (d, J = 9.00 Hz, 2H), 6.41 (d, J =9.78 Hz, 1H), 4.32 (s,1H), 4.05 (d, J = 9.00 Hz, 1H), 3.86 (d, J = 12.52 Hz, 2H), 3.45 (br. s., 4H),2.79 (t, J = 11.74 Hz, 2H), 2.21 (d, J = 6.46 Hz, 2H), 1.81 (d, J = 11.15 Hz, 3H),1.21 (s, 6H), 1.12 (s, 6H) LCMS m / e+ = 802.57 [M+ Synthesis of Exemplary PROTAC46

[0783] [ka]

[0784] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methoxy)ethoxy)ethyl)piperazin-1-yl)nicotinamide Synthesis scheme:

[0785] [ka]

[0786] Step 1: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-iodobenzamide A 100 mL round-bottom flask was charged with 2-iodobenzoic acid (5.0 g, 20.16 mmol, 1.00 equiv.), N,N-dimethylformamide (40 mL), HATU (7.66 g, 20.15 mmol, 1.00 equiv.), and DIEA (7.80 g, 60.35 mmol, 3.00 equiv.) and stirred for 10 minutes. 3-aminopiperidine-2,6-dione (3.30 g, 25.76 mmol, 1.00 equiv.) was then added. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 500 mL of water / ice. The solid was collected by filtration. The resulting mixture was concentrated in vacuo. This afforded 6.48 g (90%) of N-(2,6-dioxopiperidin-3-yl)-2-iodobenzamide as an off-white solid.

[0787] LC-MS (ES + ): m / z 358.85 [MH + ], t R =0.56 min, (1.90 min run). Step 2: ([2-[2-(prop-2-yn-1-yloxy)ethoxy]ethoxy]methyl)benzene synthesis Into a 250 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was added 2-[2-(benzyloxy)ethoxy]ethan-1-ol (10.0 g, 50.96 mmol, 1.00 equiv.), N,N-dimethylformamide (1.0 g, 1.00 equiv.), ... 2-[2-(benzyloxy)ethoxy]ethan-1-ol (10.0 g, 50.96 mmol, 1.00 equiv.), To the mixture was added sodium hydride (2.4 g, 100.00 mmol, 1.20 equiv.) in several batches at 0° C. After stirring for 30 minutes, a solution of 3-bromoprop-1-yne (7,285 g, 61.24 mmol, 1.20 equiv.) in N,N-dimethylformamide (30 mL) was added. The solution was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature overnight. Then, 300 mL The reaction was quenched by adding water / ice. The resulting solution was extracted with ethyl acetate (300 mL) and the organic layers were combined. The resulting mixture was washed with brine (300 mL). The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 4). This gave 9.5 g (80%) of ([2-[2-( Prop-2-yn-1-yloxy)ethoxy)ethoxy)methyl)benzene was obtained as a light yellow oil.

[0788] LC-MS (ES + ): m / z 234.95 [MH + ], t R = 1.15 minutes (2.00 minute run). Step 3: Synthesis of 2-(3-(2-(2-(benzyloxy)ethoxy)ethoxy)prop-1-ynyl)-N-(2,6-dioxopiperidin-3-yl)benzamide In a 25 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere, add N-(2,6-dioxo- Piperidin-3-yl)-2-iodobenzamide (1.5 g, 4.1 mmol, 1.00 equiv), N,N-dimethyl Formamide (20 mL), (PPh3)2PdCl2 (293 mg, 0.41 mmol, 0.1 equiv), CuI (79 mg, 0.41 mmol, 0.1 equiv), triethylamine (1.69 g, 16 mmol, 4.00 equiv), and (2-[2-(prop-2-yn-1-yloxy)ethoxy]ethoxymethyl)benzene (1.17 g, 5.0 mmol, 1.20 equiv) were added. The resulting solution was stirred at room temperature overnight. The resulting solution was extracted with ethyl acetate (300 mL), and the organic layers were combined. The resulting mixture was washed with brine (300 mL). The mixture was subjected to anhydrous The residue was dried over sodium sulfate and diluted with ethyl acetate / petroleum ether (7 / 3). The mixture was loaded onto a silica gel column, which gave 1.74 g of 2-(3-(2-(2-(benzyloxy)ethoxy)ethoxy)prop-1-ynyl)-N-(2,6-dioxopiperidin-3-yl)benzamide as a light yellow oil.

[0789] LC-MS (ES + ): m / z 465.10 [MH + ], t R =0.79 min, (1.90 min run). Step 4: Synthesis of 3-[3-([2-[2-(benzyloxy)ethoxy]ethoxy]methyl)-1-oxo-1,2-dihydroisoquinolin-2-yl]piperidine-2,6-dione Into a 25 mL round bottom flask purged and maintained with an inert nitrogen atmosphere was added 2-(3-[2-[2-(benzyloxy)ethoxy]ethoxy]prop-1-yn-1-yl)-N-(2,6-dioxopiperidine-3- (I)ylbenzamide (1.0 g, 2.15 mmol, 1.00 equiv.) in N,N-dimethylformamide (10 mL) Liquid, Pd(OAc)2 (24.0 mg, 0.11 mmol, 0.05 equivalent), LiCl (90.0 mg, 2.14 mmol, 1.00 equivalent), charcoal Potassium carbonate (594.0 mg, 4.30 mmol, 2.00 equiv.) was added. The resulting solution was stirred in an oil bath overnight at 100°C. The solid was filtered off. The residue was dissolved in ethyl acetate / petroleum ether (7 / 3) and The resulting solution was loaded onto a silica gel column, which gave 465.0 mg (47%) of 3-[3-([2-[2-(benzyloxy)ethoxy]ethoxy]methyl)-1-oxo-1,2-dihydroisoquinolin-2-yl]piperidine-2,6-dione as a light yellow oil.

[0790] LC-MS (ES + ): m / z 465.10 [MH + ], t R =0.74 min, (1.90 min run). Step 5: Synthesis of 3-(3-[[2-(2-hydroxyethoxy)ethoxy]methyl]-1-oxo-1,2-dihydroisoquinolin-2-yl)piperidine-2,6-dione Into a 100 mL three-necked round-bottom flask purged and maintained with an inert nitrogen atmosphere was added 3-[3-([2-[2-(benzyloxy)ethoxy]ethoxy]methyl)-1-oxo-1,2-dihydroisoquinolin-2-yl]piperidine-2,6-dione (420.0 mg, 0.90 mmol, 1.00 equiv), dichloromethane (10 mL), Then, BBr3 (1 M solution in DCM) (3.61 mL, 4.00 equiv.) was added dropwise with stirring at −78° C. The resulting solution was stirred at −78° C. in a liquid nitrogen bath for 1 hour. The reaction was then quenched by adding 20 mL of sodium bicarbonate at −78° C. The resulting solution was Extract with dichloromethane (100 mL), combine the organic layers, and dry them over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with dichloromethane / methanol (10 / 1), which gave 212.0 mg (63%) of 3-(3-[[2-(2-hydroxyethoxy)ethoxy]methyl]-2-hydroxyethoxy]methyl. To this was obtained [ethyl]-1-oxo-1,2-dihydroisoquinolin-2-yl)piperidine-2,6-dione as a light yellow oil.

[0791] LC-MS (ES + ): m / z 374.95 [MH + ], t R =0.41 min, (1.90 min run). Step 6: 2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinoline Synthesis of (phosphon-3-yl)methoxy)ethoxyethyl 4-methylbenzene-1-sulfonate In a 50 mL round-bottom flask, 3-(3-[[2-(2-hydroxyethoxy)ethoxy]methyl]-1-oxo-1,2-dihydroisoquinolin-2-yl)piperidine-2,6-dione (212.0 mg, 0.57 mmol, 1.00 Equivalents), dichloromethane (10.0 mL), TsCl (215.4 mg, 1.13 mmol, 2.00 equiv), triethylamine (171.0 mg, 1.69 mmol, 3.00 equiv), and 4-dimethylaminopyridine (6.98 mg, 0.06 mmol, 0.10 equiv) were added. The resulting solution was stirred at room temperature for 3 hours. The resulting solution was extracted with dichloromethane (100 mL), and the organic layers were combined. The resulting mixture was washed with brine (100 mL). The mixture was dried over anhydrous sodium sulfate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (4 / 1). This yielded 238.0 mg (80%) of 2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl]methoxy]ethoxy)ethyl 4-methylbenzene-1-sulfonyl The fonate salt was obtained as a light yellow oil.

[0792] LC-MS (ES + ): m / z 529.10 [MH + ], t R =0.76 min, (1.90 min run). Step 7: 6-[4-[2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydro- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide Synthesis of mido In a 20 mL microwave tube purged and maintained with an inert nitrogen atmosphere, add 6-(piperazine) (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)pyridine-3-carboxamide (65.0 mg, 0.14 mmol, 1.00 equiv.), acetonitrile (5.0 mL), potassium carbonate (71.3 mg, 0.52 mmol, 4.00 equiv.), 2-(2-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl]methoxy]ethoxy)ethyl 4- Methylbenzene-1-sulfonate (68.0 mg, 0.13 mmol, 1.00 equiv.) and NaI (19.38 mg, 0.13 mmol, 1.00 equiv.) were added. The resulting solution was stirred in an oil bath at 75°C for 24 hours. The solid was filtered off. The resulting mixture was concentrated under vacuum. Then, the mixture was filtered using a Prep-HPLC column: XBridge Shield. RP18 OBD column, 5um, 19*150mm; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: Purification by acetonitrile; flow rate: 20 mL / min; gradient: 61% B to 70% B in 8 min; 254 nm; Rt: 6.7 min gave 50.0 mg (47%) of 6-[4-[2-(2-[[2-(2,6-dioxo- Piperidin-3-yl)-1-oxo-1,2-dihydroisoquinolin-3-yl]methoxy]ethoxy)ethyl]piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl- tetramethylcyclobutyl]pyridine-3-carboxamide was obtained.

[0793] 1 H NMR (400 MHz, CDCl3): δ 8.81 (s, 1H), 8.58-8.57 (d,J=2.4Hz, 1H), 8.23-8.21 (d, J=7.6Hz, 1H), 7.92-7.89 (m, 1H), 7.57-7.48 (m, 2H),7.38-7.34 (m, 1H), 7.26-7.21 (m, 1H), 6.97-6.96 (d, J=2.0Hz, 1H), 6.81-6.78 (m,1H), 6.61-6.59 (d, J = 9.2Hz, 1H), 6.25 (s, 1H), 6.11-6.09 (d, J=8.0Hz, 1H), 4.82-4.79 (m, 1H),4.32-4.29 (m, 2H), 4.26-4.23 (m, 1H), 4.15- 4.13 (m, 1H), 4.04 (s, 1H),3.76-3.67 (m, 10H), 2.95-2.90 (m, 1H), 2.70-2.62 (m, 7H), 2.23-2.19 (m, 2H),1.25 (s, 6H), 1.21 (s, 6H); LC-MS (ES + ): m / z 824.75 / 826.75 [MH + ],t R = 2.43 min, (4.80 min run).

[0794] Chemical formula:C 44 H 50 ClN7O7[823.35 / 825.35] Total H number from HNMR data: 50 Synthesis of Exemplary PROTAC47

[0795] [ka]

[0796] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yl)oxy)pentyl)piperazin-1-yl)nicotinamide Synthesis scheme

[0797] [ka]

[0798] Step 1: Synthesis of 5-(3-bromoquinolin-6-yloxy)pentan-1-ol methyl

[0799] [ka]

[0800] A mixture of 3-bromoquinolin-6-ol (700 mg, 3.1 mmol), 5-bromopentan-1-ol (518 mg, 3.1 mmol), and potassium carbonate (856 mg, 6.2 mmol) in N,N-dimethylformamide (5 mL) was heated at 80°C for 6 hours. The reaction mixture was cooled to room temperature. Water (10 mL) was added, and ethyl acetate was added. The combined organic layer was extracted with water (20 mL x 2) and brine (20 mL). The mixture was washed with hexane and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=1 / 1) to give 5-(3-bromoquinolin-6-yloxy)pentan-1-ol (750 mg, 78% yield) as a yellow solid.

[0801] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Purity: 91.43%, Rt = 1.767 min; MS calculated: 309.04; MS found: 310.0 [M+H]. + . Step 2: Synthesis of 1-(6-(5-hydroxypentyloxy)quinolin-3-yl)pyrimidine-2,4(1H,3H)-dione

[0802] [ka]

[0803] A solution of 5-(3-bromoquinolin-6-yloxy)pentan-1-ol (496 mg, 1.6 mmol), pyrimidine-2,4(1H,3H)-dione (538 mg, 4.8 mmol), potassium phosphate (1.0 g, 4.8 mmol), cuprous iodide (304 mg, 1.6 mmol), and N-(2-cyanophenyl)picolinamide (357 mg, 1.6 mmol) in dimethyl sulfoxide (10 mL) was heated at 120 °C under an argon atmosphere for 5 hours. The mixture was cooled to room temperature. Water (10 mL) was added and extracted with ethyl acetate (20 mL × 2). The organic layer was washed with brine (10 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was subjected to column chromatography on silica gel (methanol / dichloromethane = 20 / 1). Purification by chromatography gave 1-(6-(5-hydroxypentyloxy)quinolin-3-yl)pyrimidine-2,4(1H,3H)-dione (200 mg, 37% yield) as an off-white solid.

[0804] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Rt = 1.325 min; MS calculated: 341.14; MS found: 342.2 [M+H] + . Step 3: 5-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yloxy)methylpyrimidin-1(2H)-yl Synthesis of hydroxy)pentanal

[0805] [ka]

[0806] A mixture of 1-(6-(5-hydroxypentyloxy)quinolin-3-yl)pyrimidine-2,4(1H,3H)-dione (150 mg, 0.4 mmol) and Dess-Martin periodinane (559 mg, 1.3 mmol) in dichloromethane (15 mL) was stirred overnight at room temperature. The reaction mixture was filtered, and the filter cake was washed with dichloromethane (10 mL × 2). The filtrate was concentrated, and the residue was purified by prep-TLC (dichloromethane / methanol = 5 / 1) to give 5-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yloxy)pentanal (100 mg, 67% yield) as a yellow solid.

[0807] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Rt = 1.396 min; MS calculated: 339.12; MS found: 340.2 [M+H] + . Step 4: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide

[0808] [ka]

[0809] 5-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yloxy)phenyl A mixture of methylanthanal (100 mg, 0.29 mmol), N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (149 mg, 0.29 mmol), sodium cyanoborohydride (36 mg, 0.58 mmol) in methanol (5 mL) and glacial acetic acid (0.5 mL) was stirred at room temperature overnight. Water (10 mL) was added and the mixture was diluted with dichloromethane (20 mL × 3). The combined organic layer was washed with brine (10 mL x 2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by Prep-HPLC to give a white solid. N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-6-(4-(5-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)quinolin-6-yloxy)pentyl)piperazin-1-yl)nicotinamide (23 mg, 10% yield).

[0810] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 3.0 min, then 1.0 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Purity: 94.84%, Rt = 2.864 min; MS calculated: 790.34; MS found: 791.30 [M+H]. + . HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then 5 min under these conditions. After 0.1 min in 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and 5 min under these conditions. The purity was 95.31%, Rt = 9.913 min.

[0811] 1H NMR (400 MHz,CDCl3) δ 1.21 (6H, s), 1.25 (6H, s),1.58-1.66 (4H, m), 1.90-1.94 (2H, m), 2.43-2.47 (2H, m), 2.56-2.58 (4H, m),3.67-3.70 (4H, m), 4.04 (1H, s), 4.09-4.15 (3H, m), 5.93 (1H, d, J = 8.0 Hz),6.07 (1H, d, J = 8.0 Hz), 6.66 (1H, d, J = 9.2 Hz), 6.80 (1H, dd, J = 8.8, 2.4Hz), 6.96 (1H, d, J = 2.4 Hz), 7.09 (1H, d, J = 2.8 Hz), 7.41-7.46 (2H, m), 7.57 (1H, d, J = 8.8 Hz), 7.93(1H, dd, J = 9.2, 2.4 Hz), 8.05-8.07 (2H, m), 8.58 (1H, d, J = 2.4 Hz), 8.73(1H, d, J = 2.4 Hz). Chemical formula:C 43 H 47 ClN8O5, molecular weight: 791.34 Total H number from HNMR data: 46. Synthesis of Exemplary PROTAC48

[0812] [ka]

[0813] rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(4-((2,6-dioxopiperidin-3-yl)(ethyl)carbamoyl)phenoxy)pentyl)piperazin-1-yl)nicotinamide Synthesis scheme

[0814] [ka]

[0815] Step 1: Synthesis of methyl 4-(5-hydroxypentyloxy)benzoate

[0816] [ka]

[0817] A mixture of methyl 4-hydroxybenzoate (3.0 g, 20 mmol), 5-bromopentan-1-ol (3.3 g, 20 mmol), potassium carbonate (5.5 g, 40 mmol), and potassium iodide (0.3 g, 2 mmol) in N,N-dimethylformamide (20 mL) was heated at 110 °C overnight. The reaction mixture was cooled to room temperature. Water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layer was washed with water (30 mL x 2). The residue was concentrated to give a column of silica gel (petroleum ether / ethyl acetate = 10 / 1), which was then washed with water (30 mL x 2) and brine (30 mL x 2), and dried over anhydrous sodium sulfate. Purification by chromatography gave methyl 4-(5-hydroxypentyloxy)benzoate (2.2 g, 46% yield) as a white solid.

[0818] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Purity: 98.48%, Rt = 1.637 min; MS calculated: 238.1; MS found: 239.2 [M+H]. + . Step 2: Synthesis of 4-(5-hydroxypentyloxy)benzoic acid

[0819] [ka]

[0820] A mixture of methyl 4-(5-hydroxypentyloxy)benzoate (2.2 g, 9.2 mmol), lithium hydroxide (1.6 g, 36.9 mmol), methanol (10 mL), and water (1 mL) was stirred at room temperature overnight. The solvent was removed in vacuo, and water (5 mL) was added. The mixture was extracted with ethyl acetate, and the aqueous layer was washed with 1N aqueous hydrochloric acid. The pH was adjusted to 5-6 with HCl. The solid was collected by filtration and dried in vacuo to give 4-(5-hydroxypentyloxy)benzoic acid (1.9 g, 90% yield) as a white solid.

[0821] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Rt = 1.073 min; MS calculated: 224.1; MS found: 225.3 [M+H] + . Step 3: Synthesis of 3-(ethylamino)piperidine-2,6-dione

[0822] [ka]

[0823] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (3.8 g, 23 mmol), acetaldehyde (1.0 g, 23 mmol), sodium cyanoborohydride (4.3 g, 69 mmol) in methanol (30 mL) and glacial acetic acid (0.5 mL) was stirred at room temperature overnight. Water (10 mL) was added and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (30 mL × 2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give 3-(ethylamino)piperidine-2,6-dione (3.0 g, 33% yield) as a yellow oil.

[0824] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4,6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] in 1.6 min and and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then 1.4 min under these conditions. Finally, 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], then 0.7 min under these conditions. Rt = 0.737 min; MS calculated: 156.1; MS found: 157.2 [M+H] + . Step 4: N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-hydroxypentyloxy) (c) Synthesis of benzamide

[0825] [ka]

[0826] 3-(Ethylamino)piperidine-2,6-dione (500 mg, 3.2 mmol), 4-(5-hydroxypentyloxy)benzoic acid (3.3 g, 20 mmol), ethyldiisopropylamine (826 mg, 6.4 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoride A mixture of orophosphate (1.8 g, 4.8 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature overnight. The mixture was stirred. Water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic layer was washed with water (20 mL x 2) and brine (20 mL x 2), and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-hydroxypentyloxy)benzamide (108 mg, 9% yield) as a white solid. was obtained as.

[0827] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 1.6 min, then 1.4 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, then 0.7 min under these conditions). Rt = 1.377 min; MS calculated: 362.2; MS found: 363.2 [M+H] + . Step 5: N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-oxopentyloxy) Synthesis of benzamide

[0828] [ka]

[0829] N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-hydroxypentyloxy)benzoate A mixture of benzamide (108 mg, 0.3 mmol) and Dess-Martin periodinane (254 mg, 0.6 mmol) in dichloromethane (10 mL) was stirred for 2 hours at room temperature. The reaction mixture was filtered, and the cake was washed with dichloromethane (10 mL x 2). The filtrate was concentrated, and the residue was purified by prep-TLC (dichloromethane / methanol = 5 / 1) to give N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-oxopentyloxy)benzamide (97 mg, 90% yield) as a yellow solid.

[0830] LC-MS (Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] in 1.6 min and and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN], then 1.4 min under these conditions. Finally, 0.1 min to 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], then 0.7 min under these conditions. Rt = 1.465 min; MS calculated: 360.2; MS found: 361.2 [M+H] + . Step 6: Synthesis of N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(4-((2,6-dioxopiperidin-3-yl)(ethyl)carbamoyl)phenoxy)pentyl)piperazin-1-yl)nicotinamide

[0831] [ka]

[0832] N-(2,6-dioxopiperidin-3-yl)-N-ethyl-4-(5-oxopentyloxy)benzal N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl ... A mixture of (methylcyclobutyl)-6-(piperazin-1-yl)nicotinamide hydrochloride (136 mg, 0.27 mmol), sodium cyanoborohydride (34 mg, 0.54 mmol), methanol (5 mL) and glacial acetic acid (0.5 mL) was stirred at room temperature overnight. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (10 mL x 2) and dried over anhydrous sodium sulfate. The solvent was concentrated to give a residue, which was purified by prep-HPLC to give N-((1r,3r)-3-(3-chloro-N-methyl ... (4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-(4-((2,6-dioxopiperidin-3-yl)(ethyl)carbamoyl)phenoxy)pentyl)piperazin-1-yl)nicotinamide (55 mg, 25% yield) was obtained as an off-white solid.

[0833] LC-MS (Agilent LCMS 1200-6120, Column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); Column temperature: 40 °C; Flow rate: 2.0 mL / min; Mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 3.0 min, followed by 1.0 min under these conditions, and finally 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] in 0.1 min, followed by 0.7 min under these conditions). Purity: 98.20%, Rt = 2.918 min; MS calculated: 811.38; MS found: 812.30 [M+H]. + . HPLC (Agilent HPLC 1200, column: Waters X-Bridge C18 (150 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 1.0 mL / min; mobile phase: 95% [water + 10 mM NH4HCO3] and 5% [CH3CN] to 0% [water + 10 mM NH4HCO3] and 100% [CH3CN] in 10 min, then 5 min under these conditions. After 0.1 min in 95% [water + 10 mM NH4HCO3] and 5% [CH3CN], and 5 min under these conditions. The purity was 99.92%, Rt = 10.259 min.

[0834] 1 H NMR (400 MHz,DMSO-d6) δ1.10-1.13 (9H, m), 1.21 (6H, s),1.44-1.53 ​​(4H, m), 1.74-1.77 (2H, m), 1.99-2.08 (1H, m), 2.31-2.34 (3H, m),2.42-2.45 (5H, m), 2.67-2.68 (1H, m), 3.29-3.34 (3H, m), 3.58-3.59 (4H, m),4.00-4.07 (3H, m), 4.30 (1H, s), 6.86 (1H, d, J = 8.8 Hz), 6.98-7.02 (3H, m),7.22 (1H, d, J = 2.4 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.63 (1H, d, J = 9.2 Hz),7.91 (1H, d, J = 8.8 Hz), 7.95 (1H, dd, J = 8.8, 2.4 Hz), 8.62 (1H, d, J = 2.0Hz), 10.78 (1H, s). Chemical formula:C 44 H 54 ClN7O6, molecular weight: 812.40 Total H from HNMR data: 54. Synthesis of Exemplary PROTAC50s

[0835] [ka]

[0836] 5-(3-(4-(5-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)carbamoyl)pyridin-2-yl)piperazin-1-yl)propoxy)-N-(2,6-dioxa (isopiperidin-3-yl)picolinamide Synthesis scheme

[0837] [ka]

[0838] Step 1: Synthesis of methyl 5-(3-hydroxypropoxy)picolinate

[0839] [ka]

[0840] A solution of methyl 5-hydroxypicolinate (5.0 g, 32.6 mmol) in N,N-dimethylformamide (60.0 mL) was added to 3-bromopropan-1-ol (5.45 g, 39.2 mmol), potassium carbonate (9.03 g, 65.3 mmol), and methyl 5-hydroxypicolinate (5.0 g, 32.6 mmol). mol) was added. The reaction mixture was stirred at 70°C overnight. The solvent was removed in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 20:1). , methyl 5-(3-hydroxypropoxy)picolinate (2.5 g, 36% yield) was obtained as a pale yellow solid.

[0841] 1 H NMR (400 MHz,DMSO-d6) δ 1.90 (2H, t, J= 6.0 Hz), 3.57(2H, q, J = 5.9 Hz), 3.84 (3H, s), 4.20 (2H, t, J= 6.4 Hz), 4.62 (1H, t, J =5.2 Hz), 7.52 (1H, dd, J = 8.8 Hz, 2.8 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.37 (1H, d, J = 2.8 Hz). Chemical formula:C 10 H 13 NO4, molecular weight: 211.21 Total H from HNMR data: 13. Step 2: Synthesis of 5-(3-hydroxypropoxy)picolinic acid

[0842] [ka]

[0843] Methyl 5-(3-hydroxypropoxy)picolinate (2.5 g, 11.8 mmol) in methanol (50 mL) To the solution was added lithium hydr...

Claims

1. A bifunctional compound having the following chemical structure, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof: CLM-L-PTM, During the ceremony: (a) the PTM has the structure 【Chemistry 1】 androgen receptor (AR) binding moiety (ABM) comprising: W 1 are aryl or heteroaryl, each independently consisting of one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1～6 Alkyl (one or more halo, C 1～6 Optionally substituted with alkoxy, straight or branched chain), C 1～6 Alkoxy (straight or branched chain, optionally substituted with one or more halo), C 2～6 Alkenyl, C 2～6 Alkynyl, or CF 3 is replaced by; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Ｙ1 R Y2 , C=O, C=S, SO, or SO2; Q is a 4-6 membered alicyclic ring with 0-2 heteroatoms, optionally 1-6 R Q Each R is replaced by Q are independently H, C 1～6 Alkyl (one or more halo, C 1～6 alkoxy), or two R Q the groups, together with the atom to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R Y1 and R Y2 are each independently H or C 1～6 Alkyl (one or more halo, C 1～6 (straight chain, branched chain, optionally substituted with alkoxy); W 2 is C 1～6 alicyclic, heterocyclic, aryl, biheterocyclic, biaryl, biheteroaryl, or heteroaryl, each optionally containing one, two, or three R W2 is replaced by; Each R W2 are independently H, halo, and C 1～6 Alkyl (straight or branched chain optionally substituted with one or more F), C 1～6 Heteroalkyl (optionally substituted straight or branched chain), -OR W2A , -OC 1～3 alkyl (optionally substituted with one or more -F), C 3～6 Cycloalkyl, C 4～6 Cycloheteroalkyl (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), heteroaryl (optionally substituted), bicyclic heteroaryl (optionally substituted), bicyclic aryl, OH, NH 2 , N.R. Y1 R Y2 , or CN; R W2A is H, C 1～6 Alkyl (straight chain, branched chain), or C 1～6 heteroalkyl (linear, branched), each optionally being cycloalkyl, cycloheteroalkyl, aryl, heterocycle, heteroaryl, halo, or OC; 1～3 substituted by alkyl; and The dashed line indicates the linker attachment site; (b) L is a chemical linker moiety that covalently connects the CLM and the PTM; it comprises a chemical structural unit represented by the formula: -(A L )q- During the ceremony: (A L ) q is bound to the CLM and the PTM; q is an integer greater than or equal to 1; Each A L is CR L1 R L2 , O, N.R. L3 , CO, CR L1 =CR L2 , 0 to 6 R L1 C optionally substituted with 3-11 Cycloalkyl, 0 to 6 R L1 C optionally substituted with 3-11 Heterocyclyl, 0 to 6 R L1 aryl optionally substituted with, and 0 to 6 R L1 independently selected from the group consisting of heteroaryl optionally substituted with R L1 , R L2 and R L3 are independently H, halo, and C 1-8 Alkyl, OC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 alkyl) 2 , OH, NH 2 , C.N., C.F. 3 , CHF 2 , or CH 2 F; (c) the CLM is a small molecule cereblon E3 ubiquitin ligase binding moiety that binds to or targets cereblon E3 ubiquitin ligase and has a chemical structure selected from the group consisting of: 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] During the ceremony: Q 1 , Q 2 , Q 3 , Q 4 , Q 5 each independently represents N or C substituted with R'; R 1 is not present, H, OH, CN, or C 1 -C 3 is alkyl; R 2 is absent or H; R 3 is absent, H or alkyl; R 4 is selected from H and alkyl; R 5 is H, halogen, CN, OH, or CF 3 and R' is H, halogen, amine, alkyl, alkoxy, and C(=O)OR 2 Selected from: Rn is the point of attachment of L; and 【Transformation 3】 is a single or double bond, A bifunctional compound wherein said CLM is attached to a chemical linker group (L) via Rn, R3, R', Q1, Q2, Q3, Q4 or Q5.

2. The CLM has the structure 【Chemistry 4】 2. The bifunctional compound according to claim 1, wherein:

3. The CLM has the structure 【Transformation 5】 and where, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 each independently represents C substituted with R'; R 4 is selected from H and alkyl; R' is H, halogen, alkyl and C(=O)OR 2 Selected from: R 2 is absent or is H, The bifunctional compound according to claim 2.

4. The CLM has the structure 【Transformation 6】 2. The bifunctional compound according to claim 1, wherein:

5. The CLM 【Transformation 7】 2. The bifunctional compound of claim 1, represented by the chemical structure:

6. The CLM 【Transformation 8】 2. The bifunctional compound of claim 1, represented by a chemical structure selected from the group consisting of:

7. L is selected from the group consisting of: -N(R)-(CH 2 ) m -AND 2 ) n -AND 2 ) o -AND 2 ) p -AND 2 ) q -AND 2 ) r -AND 2 -、 -O-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -OCH 2 - -O-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -O-; -N(R)-(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -O-; -(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -O-; -(CH 2 ) m -O(CH 2 ) n -O(CH 2 ) o -O(CH 2 ) p -O(CH 2 ) q -O(CH 2 ) r -OCH 2 -; 【Chemistry 9-1】 【Chemistry 9-2】 Here, m, n, o, p, q, and r of said linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; However, if m, n, o, p, q, or r is zero, there are no NO or OO bonds, R of the linker is H, methyl and ethyl; X of the linker is H and F; 【Chemistry 10】 wherein m of the linker can be 2, 3, 4, or 5; 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 wherein n and m of the linker can independently be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

8. L is selected from the group consisting of: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 7. The bifunctional compound of any one of claims 1 to 6, wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

9. The linker (L) is selected from the group consisting of: 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 [Chemistry 13-4] 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】 【Chemistry 13-8】 【Chemistry 13-9】 【Chemistry 13-10】 【Chemistry 13-11】 [Chemistry 13-12] 【Chemistry 13-13】 [Chemistry 13-14] [Chemistry 13-15] [Chemistry 13-16] [Chemistry 13-17] [Chemistry 13-18] [Chemistry 13-19] [Chemistry 13-20] [Chemistry 13-21] [Chemistry 13-22] [Chemistry 13-23] [Chemistry 13-24] [Chemistry 13-25] [Chemistry 13-26] [Chemistry 13-27] [Chemistry 13-28] [Chemistry 13-29] wherein each m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

10. The bifunctional compound according to any one of claims 1 to 6, wherein the linker (L) is selected from the group consisting of: 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 【Chemistry 14-7】 【Chemistry 14-8】 【Chemistry 14-9】 【Chemistry 14-10】 【Chemistry 14-11】 【Chemistry 14-12】 [Chemistry 14-13]

11. The linker (L) is selected from: 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 The bifunctional compound according to any one of claims 1 to 6.

12. The linker (L) 【Chemistry 16】 The bifunctional compound according to any one of claims 1 to 6, selected from:

13. The linker (L) 【Chemistry 17】 13. The bifunctional compound according to claim 12, wherein:

14. The linker (L) [Chemistry 18] 14. The bifunctional compound according to claim 13, wherein:

15. The compounds are PROTAC-27, PROTAC-29, PROTAC-47 to PROTAC-63, PROTAC-67 to PROTAC-70, PROTAC-79 and PROTAC-80: 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 【Chemistry 19-7】 【Chemistry 19-8】 2. The bifunctional compound of claim 1, selected from the group consisting of: 【Request Item 16】 【Chemistry 20】 or a pharmaceutically acceptable salt thereof.

17. 17. The bifunctional compound of any one of claims 1 to 16 for use in treating a disease state or ameliorating a disease symptom or condition in a subject in need thereof, said use comprising administering to said subject an effective amount of the compound.

18. 18. The bifunctional compound of claim 17, administered in combination with an additional bioactive agent.

19. 20. The bifunctional compound of claim 18, wherein the additional bioactive agent is an anti-cancer agent.

20. 18. The bifunctional compound of claim 17, wherein the disease or condition is cancer.

21. 21. The bifunctional compound of claim 20, wherein the cancer is prostate cancer.

22. A composition comprising an effective amount of the bifunctional compound of any one of claims 1 to 16 and a pharmaceutically acceptable carrier.

23. 23. The composition of claim 22, wherein the composition further comprises at least one additional bioactive agent, another bifunctional compound of any one of claims 1 to 16.

24. 24. The composition of claim 23, wherein the additional bioactive agent is an anti-cancer agent.

25. 17. A composition for treating a disease or disorder in a subject, comprising an effective amount of at least one compound of any one of claims 1 to 16 and a pharmaceutically acceptable carrier, additive, and / or excipient, wherein the composition is administered to a subject in need thereof, wherein the compound is effective to treat or ameliorate at least one symptom of the disease or disorder.

26. 26. The composition of claim 25, wherein the disease or disorder is associated with accumulation and / or aggregation of a target protein.

27. 27. The composition of claim 25 or 26, wherein the disease or disorder is spinal-bulbar muscular atrophy (Kennedy's disease).

28. 26. The composition of claim 24 or 25, wherein the disease or condition is cancer.

29. 29. The composition of claim 28, wherein the cancer is prostate cancer.

30. 30. The composition of any one of claims 22 to 29, further comprising an additional bioactive agent.

31. 31. The composition of claim 30, wherein the additional bioactive agent is an anti-cancer agent.

32. The anticancer drug may be everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, 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 inhibitors, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk 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 itumumab), amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR. 1 KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin 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 citrate), anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,Hydroxyprogesterone caprylate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, 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 latin), cladribine (cladribine), clodronate (clodronate), cyproterone (cyproterone), cytarabine (cytarabine), dacarbazine (dacarbazine), dactinomycin (dactinomycin), daunorubicin (daunorubicin), epirubicin (epirubicin), fludarabine (fludarabine), fludrocortisone (fludrocortisone), fluoxymesterone (fluoxymesterone), Glibac, hydroxyurea (hydroxyurea), idarubicin (idarubicin), ifosfamide (ifosfamide),Imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate onate), pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid acid), phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor,Zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin daunorubicin), Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol,32. The composition of claim 31, wherein the active ingredient is selected from the group consisting of droperidol, dronabinol, dexamethasone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

33. 20. Use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament for inducing degradation of a target protein in a cell, comprising administering to the cell an effective amount thereof, wherein the compound causes degradation of the target protein.

34. 20. A composition comprising an effective amount of a compound of any one of claims 1 to 16 for use in a method for treating cancer, said method comprising administering said composition to a patient in need thereof, wherein said composition is effective to treat or ameliorate at least one symptom of cancer in said patient.

35. 35. The composition of claim 34, wherein the cancer is hepatocellular carcinoma, renal cell carcinoma, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, or ovarian cancer.

36. 35. The composition of claim 34, wherein the cancer is prostate cancer.

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