Compounds and methods for targeted degradation of androgen receptor

Abstract

To provide bifunctional compounds found to be useful in degrading (and inhibiting) an androgen receptor.SOLUTION: The present disclosure provides compounds, which comprise on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds to an androgen receptor, so that the androgen receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the androgen receptor. The compounds present a broad range of pharmacological activity that is associated with the compounds and consistent with the degradation / inhibition of the androgen receptor.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 406,888, filed October 11, 2016, and U.S. Provisional Patent Application No. 62 / 406,888, filed July 11, 2017. This application claims priority to U.S. Provisional Patent Application No. 62 / 528,385, filed on March 3, 2013, all of which are hereby incorporated by reference. No. 60 / 339,363, filed Dec. 23, 2005, and which is incorporated herein by reference in its entirety and for all purposes.

[0002] STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was funded by the National Cancer Institute under grant number 1R44CA20319. This invention was made with Government support under US Provisional Patent Application No. 9-01. The Government has certain rights in this invention.

[0003] Incorporation by Reference U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, U.S. Patent Application Publication No. 2016 / 0058 872. U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, U.S. Patent Application Publication Published as U.S. Patent Application No. 14 / 371,956, filed July 11, 2014, U.S. Pat. Published as Patent Application Publication No. 2014 / 0356322. U.S. Patent Application No. 15 / 074,820, filed March 18, 2016. No. 2016 / 0272639, which are hereby incorporated by reference in their entirety. Additionally, all references cited herein are incorporated by reference. It is incorporated herein in its entirety.

[0004] The present invention provides an imide-based compound, and a bifunctional compound containing the compound. and related methods of use thereof. The bifunctional compounds are capable of targeting ubiquitination. These compounds are useful as regulators, and in particular can be decomposed and / or modified by the bifunctional compounds according to the present disclosure. The present invention is useful for a variety of polypeptides and other proteins that are inhibited by various means, such as by the In certain embodiments, the bifunctional compound inhibits cereblon E3 ubiquitin ligase (CR Cereblon E3 ubiquitin ligase binding moiety that binds to a target protein (e.g., A a target protein binding moiety that binds to the androgen receptor (ER) and, optionally, the cereblon binding moiety. These compounds include a linker moiety that connects the binding moiety and the target protein binding moiety. The target protein / polypeptide is brought into close proximity to the ubiquitin ligase, which then ligates the protein. in a manner that affects the degradation (and inhibition) of proteins (e.g., androgen receptors) It works. [Background technology]

[0005] Most small molecule drugs bind closely and in well-defined pockets to enzymes or receptors. On the other hand, small molecules are used to detect protein-protein interactions. Targeting is notoriously difficult because of the large size of the protein contact surfaces. Due to the large surface area and shallow grooves or flat interfaces involved E3 ubiquitin ligases, of which several hundred are known in humans, mediate the synthesis of ubiquitin. It confers substrate specificity to the catalysis. It is therefore specific for certain protein substrates and general purpose. This makes it a more attractive therapeutic target than conventional proteasome inhibitors. The development of new drugs requires disrupting protein-protein interactions. However, this has proven difficult in part because of the need to bind these ligases. Specific ligands that bind to E3 ligases have been developed in recent years. For example, the first small molecule E3 ligase inhibitors Since the discovery of nutrin, additional compounds targeting E3 ligases have been reported. However, much of this field is still underdeveloped.

[0006] One E3 ligase with therapeutic potential is encoded in humans by the CRBN gene. The orthologue of CRBN is cereblon, a protein encoded by It is highly conserved from plants to humans, which underscores its physiological importance. Cereblon binds damaged DNA-binding protein 1 (DDB1), cullin ( Cullin-4A (CUL4A) and E3 ubiquitination with regulator of cullins1 (ROC1) The complex ubiquitinates many other proteins, forming an ubiquitin ligase complex. Cereblon ubiquitinates the target protein through a mechanism that is not fully understood. The increase in fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10) levels FGF8 then mediates many developmental processes, such as the formation of limbs and otic vesicles. This ubiquitin ligase complex is known to be important for limb development in the embryo. The final conclusion is that in the absence of cereblon, DDB1 is in a complex with DDB2. and functions as a DNA damage-binding protein.

[0007] Thalidomide is approved for the treatment of many immunological indications and is used in the treatment of multiple bone diseases. It is also approved for the treatment of certain neoplastic diseases, including myeloma. Thalidomide and several of its analogues are now also being used to treat a variety of other types of cancer. The exact mechanism of thalidomide's antitumor activity is still unknown. Although the mechanism of action is still being elucidated, it is known that imides inhibit angiogenesis. Recent publications that we discuss include Lu et al. Science 343, 305 (2014) and Kronke et al. Science 343, 301 (2014).

[0008] Significantly, thalidomide and its analogues, e.g., pomolynamiod Linamiode and lenalinomide are known to bind to cereblon. These agents bind to cereblon and alter the specificity of the complex, resulting in multiple myeloma. Ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for tumor proliferation In fact, high expression and induction of cereblon in the treatment of multiple myeloma have been reported. The increased efficacy of midazolam drugs is associated with

[0009] The androgen receptor (AR) is a receptor that binds, for example, testosterone and dihydrotestosterone. It belongs to the family of nuclear hormone receptors that are activated by androgens (Pharm acol. Rev. 2006, 58(4), 782-97; Vitam. Horm. 1999, 55:309-52). In the absence of Hsp90, AR is bound to heat shock protein 90 (Hsp90) in the cytoplasm. When androgens bind to the AR, its conformation changes, releasing the AR from Hsp90. The latter exposes a nuclear localization signal (NLS), which mediates AR is able to translocate into the nucleus, where it acts as a transcription factor to mediate male sexual characteristics. (Endocr. Rev.1987, 8(1):1-28; Mol. Endocrinol.20 02, 16(10), 2181-7). AR deficiency is a condition formerly known as androgen deficient feminization syndrome. It induces vasodilatory syndrome.

[0010] The AR is involved in the development of male sexual characteristics, but in certain forms of cancer, including prostate cancer, It has also been reported that it is a gene (Endocr. Rev.2004, 25(2), 276-308). The target gene for AR activity being measured is the secretory prostate-specific antigen (PSA) protein. Current treatment regimens for prostate cancer involve inhibition of the androgen-AR axis in two ways. The first method relies on androgen depletion, and the second method relies on AR function. (Nat. Rev. Drug Discovery, 2013, 12,823-824). Despite the development of effective treatments, many patients develop resistance and progress with the disease. An alternative approach to treating prostate cancer involves ablating the AR protein. It is a key inducer of tumorigenesis in many types of prostate cancer, and its elimination is therefore a therapeutically beneficial response. This should result in:

[0011] The ongoing need for effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy's disease However, for example, transcription factors have non-specific actions and This is due to the inability to target and regulate a whole class of proteins. This remains an obstacle to the development of effective anticancer drugs. While enhancing or enhancing the expression of a wide range of proteins, they can be targeted and specifically regulated. Such "tunable" small molecule therapeutics would be extremely useful as therapeutic agents. Summary of the Invention

[0012] The present disclosure describes bifunctional compounds and methods of use thereof, the compounds being , which functions to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, the present disclosure relates to bifunctional or proteolytic targeting chimeras (PROTACs). The present invention provides a targeting chimeric compound, which is capable of binding to various polypeptides and and as a regulator of targeted ubiquitination of other proteins (e.g., the androgen receptor). All of the above polypeptides and other proteins find utility, and are disclosed herein. The bifunctional compounds provided herein are decomposed and / or otherwise inhibited. The advantage of the compounds offered is that they may have a broad range of pharmacological activity and may be useful in treating virtually any protein. The present invention is further directed to the degradation / inhibition of a target polypeptide from a protein species or family. The document describes a method for treating or ameliorating disease conditions, including cancer, e.g., prostate cancer and Kennedy's disease. Methods are provided using effective amounts of the compounds described herein.

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

[0014] In a further aspect, the present disclosure provides a bifunctional or PROTAC compound, The compound is an E3 ubiquitin ligase binding moiety (i.e., an E3 ubiquitin ligase binding moiety). ligand, or “ULM” group) and a moiety that binds to the target protein (i.e., protein targeting ligand, or "PTM" group), thereby targeting the target of interest. The protein / polypeptide is placed in close proximity to the ubiquitin ligase, which mediates the cleavage of the protein. In a preferred embodiment, ULM exerts an anti-inflammatory (and inhibitory) effect on cereblon E3. A bifunctional compound is a biquitin ligase binding moiety (i.e., a "CLM"). The structure can be shown as follows: PTM-CLM.

[0015] The respective positions of the PTM and CLM moieties exemplified herein, and These numbers are provided as examples only and are not intended to limit the compounds in any way. As will be appreciated by those of skill in the art, the bifunctional The compounds are synthesized such that the number and position of each functional moiety can be varied as desired. It is possible.

[0016] In certain embodiments, the bifunctional compound may further comprise a chemical linker (L). In the examples, the structures of the bifunctional compounds can be shown as follows: PTM-L-CLM, where PTM is a protein / polypeptide targeting moiety, L is a chemical linker moiety, or a bond that links PTM and CLM, and CLM binds cereblon E3 ubiquitin ligase. This is the joint part.

[0017] In a particular preferred embodiment, the E3 ubiquitin ligase is cereblon. In certain additional embodiments, the CLM of the bifunctional compound can be, for example, an imide, an amide, a thioa, In an additional embodiment, the CLM comprises a phthalamide, a thioimide-derived moiety, or the like. In yet further embodiments, C LM comprises a phthalimido-glutarimido group or an analog or derivative thereof. In other embodiments, the CLM is thalidomide, lenalidomide, pomalidomide, and and its analogs or derivatives.

[0018] In certain embodiments, the compounds described herein comprise multiple CLMs, multiple PTMs, multiple or a combination thereof.

[0019] The general structure is exemplary and each moiety may be, for example, CLM-L-PTM, and PTM-LC, respectively. It will be understood that the LMs, etc. may be spatially arranged in any desired order or configuration. cormorant.

[0020] In certain embodiments, the PTMs are AR binding moieties (ABMs). In certain embodiments, the ABM is selected from the following structures:

[0021] [ka]

[0022] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently At least one of H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (optionally substituted Linear or branched chain. For example, one or more halo, C1~6 Optionally substituted with alkoxyl, C 1~6 Alkoxy (straight or branched chain, optionally substituted, e.g., by one or more halo) (optionally substituted), C 2~6 Alkenyl, C 2~6 Alkynyl, or CF 3 is replaced by; 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, SO 2、 Heteroa reel, or aryl; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally with 0-6 R Q Each R Q are independently H, C 1~6 Alkyl (optionally substituted straight or branched chain, e.g. For example, one or more halo, C 1~6 alkoxyl optionally substituted), halogen, C 1~6 Al COXI or 2 R Q The groups may contain 0 to 2 heteroatoms together with the atoms to which they are attached. forming a 3-8 membered ring system containing aryl groups); 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 alkoxyl optionally substituted), halogen, C 1 ~6alkoxy, cyclic, heterocyclic or R 1 , R 2 are the atoms to which they are bonded. Forming 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 heteroaryl, biheterocyclic, biaryl, or biheteroaryl, each of Any 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 or more Optionally replaced by F above), C 1~6 Heteroalkyl (optionally substituted straight or branched chain) , -OR W2A , C 3~6 Cycloalkyl, C 4~6 Cycloheteroalkyl, OC 1~3 Alkyl (optionally Optionally substituted, for example, by one or more -F), C 1~6 Alicyclic (optionally substituted heterocyclic (optionally substituted), aryl (optionally substituted), or heterocyclic bicyclic heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH 2 , N.R. Y1 R Y2 ,CN; R W2A , H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1~3 A compound substituted with alkyl.

[0023] In an additional aspect, the present disclosure provides an effective amount of a compound described herein, or a salt form thereof, and and a pharma- ceutical acceptable carrier. The therapeutic composition may be administered to a patient or The present invention relates to a method for regulating the degradation of proteins in a subject, e.g., an animal, such as a human, and for isolating the degraded proteins. The present invention can be used to treat or ameliorate symptoms or conditions that are modulated via proteins. In certain embodiments, the therapeutic compositions described herein are used to treat or prevent diseases, such as cancer. are used to degrade and / or inhibit proteins of interest for improved In yet another aspect, the present disclosure provides a method for ubiquitinating / transducing a target protein in a cell. In certain embodiments, the method preferably comprises decomposing a linker moiety. The method includes administering a bifunctional compound described herein that includes a CLM and a PTM linked via a In this case, CLM is linked to a PTM, and CLM binds to a ubiquitin pathway protein (e.g. For example, ubiquitin ligases, preferably E3 ubiquitin ligases such as cereblon PTMs recognize target proteins and allow them to be ubiquitin ligated to ubiquitin ligases. When placed in close proximity, degradation of the target protein occurs, and the target protein This results in a reduction / inhibition of the action of the protein, leading to the control of protein levels. Controlling the levels of the protein induced by the agonist provides a treatment for a symptom or condition, The drug targets a protein by reducing the levels of that protein in patient cells. is adjusted accordingly.

[0024] In additional embodiments, the present disclosure provides methods for evaluating (i.e., determining) the binding affinity of a CLM. In certain embodiments, the method includes, for example, a method for determining whether a Phthalimide group, phthalimide-glutarimide group, derivatized thalidomide, derivatized lena A subject, such as an agent or compound having an imide moiety, such as lidomide or a derivatized pomalidomide. providing an experimental agent or subject compound, and binding to cereblon; and / or The test drug or compound was compared to agents or compounds known to inhibit the activity of cereblon. or compounds to compare their cereblon-binding affinity and / or cereblon-inhibitory activity. This includes:

[0025] In yet another aspect, the present disclosure provides a method for the treatment of a cancer in a subject or patient, e.g., an animal, e.g., a human. The present invention provides a method for treating or ameliorating a disease, disorder, or a symptom thereof, The method includes administering to a subject an effective amount, such as a therapeutically effective amount, of a compound described herein or a salt form thereof, and a pharmaceutical and administering to a subject in need thereof a composition comprising a carrier acceptable for The composition is useful for treating or ameliorating a disease or disorder or a symptom thereof in a subject. is valid.

[0026] In another aspect, the present disclosure provides methods for the treatment of cancer in biological systems using compounds according to the present disclosure. A method for identifying the effect of degradation of a protein of interest is provided.

[0027] The foregoing general description of utility is presented for illustrative purposes only and is not intended to be limiting of the present disclosure. and are not intended to limit the scope of the appended claims. Additional objects and advantages associated with the process are set forth in the claims, detailed description, and examples. For example, various aspects and embodiments of the present invention will be apparent to those skilled in the art in light of the above. The embodiments can be used in many combinations, all of which are expressly set forth herein. These additional beneficial objects and embodiments are expressly contemplated within the scope of this disclosure. For purposes of explaining the background of the invention and, in certain cases, providing additional information regarding its implementation, Publications and other materials used to provide further information are incorporated by reference. do.

[0028] Where applicable or not specifically excluded, any of the embodiments described herein One embodiment may be combined with any other embodiment or embodiments, even if the embodiment is based on different aspects of the disclosure. Even if the invention is described in a simple manner, it is expected that combinations are possible. The foregoing general description is presented for illustrative purposes only and is not intended to be limiting of the present disclosure and the accompanying drawings. The present disclosure is not intended to limit the scope of the claims. Further related objects and advantages will become apparent from the following detailed description, examples, and appended claims. For example, various aspects and embodiments of the present disclosure may be readily apparent to those skilled in the art. and combinations thereof, all of which are expressly contemplated by this specification. These additional beneficial objects and embodiments are expressly included within the scope of this disclosure. To explain the background of the present disclosure and, in certain cases, to provide additional details regarding the implementation. Publications and other materials used in connection with the present invention are incorporated by reference.

[0029] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure. The drawings illustrate embodiments and, together with the written description, serve to explain the principles of the present disclosure. It is only for the purpose of illustrating the embodiments of the present disclosure and is not to be construed as limiting the present invention. Further objects, features and advantages of the present invention are set forth in the accompanying drawings, which illustrate exemplary embodiments of the present disclosure. This will become apparent from the following detailed description taken in conjunction with the drawings. [Brief description of the drawings]

[0030] [Figure 1A] Schematic of general principles of PROTAC function. Figure 1A: An exemplary PROTAC includes an androgen receptor targeting moiety (ABM; dark shaded rectangle), an E3 ubiquitin ligase binding moiety (CLM; light shaded triangle), such as a cereblon E3 ubiquitin ligase binding moiety, and a linker moiety (L; black line) that joins or connects the ABM and the CLM (as described herein, L can be absent, a bond, or a chemical linker moiety). [Figure 1B] FIG. 1B illustrates the functional applications of the PROTACs described herein. Briefly, the CLM recognizes and binds to the cereblon E3 ubiquitin ligase, and the ABM binds and recruits the androgen receptor, bringing it into close proximity to the cereblon E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and catalyzes the attachment of ubiquitin to lysines on target proteins via isopeptide bonds (dark circles), either alone or through the E2 protein. Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteosome machinery. [Diagram 2][Figure 2-1] to [Figure 2-36] Table 2 includes exemplary compounds 1 to 75, as well as a general scheme that can be used to make each exemplary compound. Table 2 also includes DC50, Dmax, M / Z+, and 1H NMR data for each exemplary compound. DC50 (μM) category (AR degradation ELISA in LNCaP and / or VCaP cells): A<1nM; B: 1-10nM; C: 10-100nM; D: >100nM. Dmax category (AR degradation-maximum inhibition (%) AR ELISA in LNCaP and / or VCaP cells): A>50%; B<50%. [Diagram 3] [Figure 3-1] to [Figure 3-169] Table 3 includes exemplary compounds 76 to 398, as well as a general scheme that can be used to make each exemplary compound. Table 3 also includes DC50, M / Z+, and 1H NMR data for each exemplary compound. DC50 (μM) categories (AR degradation ELISA in LNCaP and / or VCaP cells): A<1nM; B: 1-10nM; C: 10-100nM; D: >100nM. [Figure 4] [Figure 4-1] to [Figure 4-12] Table 4 includes exemplary compounds 399 to 427, as well as a general scheme that can be used to make each exemplary compound. Table 4 also includes DC50, Dmax (%), M / Z+, and 1H NMR data for each exemplary compound. DC50 (μM) categories (AR degradation ELISA in LNCaP and / or VCaP cells): A<1nM; B: 1-10nM; C: 10-100nM; D: >100nM. [Diagram 5] [Figure 5-1]~[Figure 5-11] Table 5 includes exemplary compounds 428~452. Table 5 also includes DC50, Dmax(%), M / Z+, and 1H NMR data for each exemplary compound. DC50(μM) Categories (AR Degradation ELISA in LNCaP and / or VCaP Cells): A<1nM; B: 1~10nM; C: 10~100nM; D: >100nM. [Figure 6][Figure 6-1]~[Figure 6-28] Table 6 includes exemplary compounds 453~528. Table 6 also includes DC50, Dmax, M / Z+, and 1H NMR data for each exemplary compound. DC50(μM) Categories (AR Degradation ELISA in LNCaP and / or VCaP cells): A<1nM; B: 1~10nM; C: 10~100nM; D: >100nM. Dmax Categories (AR Degradation-Maximum Inhibition (%) AR ELISA in LNCaP and / or VCaP cells): A>50%; B<50%. [Figure 7] [Figure 7-1]~[Figure 7-167] Table 7 includes exemplary compounds 529~625. Table 7 also includes DC50, M / Z+, and 1H NMR data for each exemplary compound. DC50 (μM) Categories (AR Degradation ELISA in LNCaP and / or VCaP Cells): A<1nM; B: 1~10nM; C: 10~100nM; D: >100nM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The following is a detailed description provided to aid those skilled in the art in practicing the present invention. Those skilled in the art will be able to easily implement the present invention without departing from the spirit or scope of the present disclosure. Modifications and variations of the embodiments described herein may be made. All publications, patent applications, patents, drawings and other references are incorporated by reference in their entirety. Explicitly included.

[0032] The present disclosure provides methods for the detection of E3 ubiquitin ligases by chimeric constructs (e.g., PROTACs) described herein. When the E3 ubiquitin ligase protein and the target protein are brought into close proximity, The researchers found that proteins can ubiquitinate target proteins, particularly the androgen receptor. This relates to a surprising and unexpected discovery, in which in the chimeric construct, the E3 ubiquitin The portion that binds to the ligase protein is the portion that binds to the androgen receptor target protein. The present disclosure therefore provides a method for the preparation of a method for the preparation of a selected target molecule. Compounds for the ubiquitination and degradation of proteins, such as the androgen receptor, Compositions comprising the compounds, and related methods of use thereof, are provided (see Figures 1A and 1B).

[0033] In certain embodiments, the present disclosure relates to U.S. Patent Application Publication Nos. 2014 / 0356322A1, 2015 / 0291562A1, and 2016 / 0291562A1. No. 2016 / 0214972A1, all of which are incorporated herein by reference in their entirety. is incorporated herein for the purposes of this application.

[0034] Unless otherwise defined, all technical and scientific terms used herein are It has the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains. The terminology used in the specification is for the purpose of describing particular embodiments only and is not intended to limit the present invention. It is not intended to determine

[0035] When a range of values ​​is provided, unless the context clearly dictates otherwise (e.g. a certain number For groups containing carbon atoms, the respective numbers of carbon atoms falling within the range are provided), Each intervening value between the upper and lower limits of a range and any other specified range, to one tenth of the unit of the lower limit It is understood that any value between or within the specified range is encompassed within the scope of the present invention. The upper and lower limits of the smaller ranges may independently be included in the smaller ranges, Included within the present invention are any specifically excluded limits in the specified ranges. If one or both of the boundaries are included, exclude either or both of the included boundaries. The range is also included in the present invention.

[0036] The following terms are used to describe this disclosure. If not defined, the term shall be deemed to be of a similar nature to that term in connection with its use in the description of this invention. are given their art-recognized meanings by those of ordinary skill in the art as they apply the term.

[0037] As used herein, the articles "a" and "an" shall be understood to mean any article that is clearly intended to be Unless otherwise indicated in the text, the grammatical object of the article or As an example, an "element" is used herein to refer to one or more "element" means an element or a plurality of elements.

[0038] As used herein in the specification and claims, the term "and / or" means The phrase "either or both" of the elements so combined is intended to mean "either or both" of the elements so combined. It should be understood that in some instances the elements are conjugated and in other instances they are disjointed. Multiple elements listed with "and / or" should be interpreted in the same way. That is, "one or more" of the elements are so combined. "Other elements than those specifically identified by the "Article" shall not affect those specifically identified elements. Thus, non-limiting examples include: When used in conjunction with open-ended language, such as "including," the term "A and / or B" is used interchangeably. A reference to A in one embodiment refers only to A (optionally including elements other than B) and not to another. In one embodiment, it refers to only B (optionally including elements other than A), and in another embodiment, In this case, it refers to both A and B (and optionally other elements).

[0039] As used herein in the specification and claims, "or" means any of the above. should be understood to have the same meaning as the defined "and / or." For example, When separating items within a list, "or" or "and / or" shall be deemed inclusive. i.e., any one of many elements or lists of elements. It includes one, but also includes more than one, and optionally includes additional items not listed. For example, For example, "one of," or "exactly one of," or when used in a claim. Only terms that clearly suggest the contrary, such as "consisting of" in refers to the inclusion of exactly one element of a list of elements. In this case, the term "or" is used in place of, for example, "either," "one of," or "one of An item is exclusive only if it is preceded by an exclusive term such as "only one of" or "exactly one of." Interpreted as indicating alternatives (i.e., "one or the other, but not both"). should be interpreted as follows.

[0040] As used herein, the term "about" and the like refers to a numerical value or may be limited in scope by any of the following limitations recognized in the art: practical and / or theoretical limitations. Reflects the fact that there is a certain level of variation that is tolerated. Minor variations resulting from inherent differences in the operation of the device and / or the way measurements are taken. In accordance with the above, the term "about" typically means within a standard deviation or standard error. Used to contain a value.

[0041] In the claims and the specification, the words "comprising" and "including" are used. "-ing," "carrying," "having," "containing" "involving," "holding," "composed of," etc. All transitional phrases in this section are open-ended, meaning that they include but are not limited to. It should be understood that the terms "consisting of" and "consisting essentially of" are used interchangeably. Only the transitional phrase "sisting essentially of" and the definite or semi-definite transitional phrases, respectively This is set forth in the United States Patent Examining Guidelines, Section 2111.03.

[0042] As used herein, in the specification and claims, one or more elements With respect to a list of elements, the phrase "at least one" means any one of the elements in the list, or It should be understood to mean at least one element selected from a plurality of elements. necessarily including at least one of every element specifically listed in the element list It does not exclude any combination of elements in the list of elements. This definition applies to the elements specifically identified in the list of elements referred to by the phrase "at least one." In addition to the elements, any element may be included, regardless of the relevance of those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" may be used. "and one of A or B" (or, equivalently, "at least one of A or B" or, equivalently, "A and and / or B) may, in one embodiment, be a small group containing a plurality of A. At least one A is indicated, and B is not present (optionally including elements other than B). In the case of In yet another embodiment, at least one A, optionally including a plurality of A's, and at least one B, optionally including multiple Bs (optionally including other elements).

[0043] In certain methods comprising a number of steps or actions described herein, The order of steps or actions is not to be construed as limiting the scope of the invention, unless the context indicates otherwise. The order in which they are listed is not necessarily limited to that shown.

[0044] The terms "co-administration" and "co-administering" or "combination therapy" refer to Simultaneous administration (two therapeutic agents) is acceptable, provided that the therapeutic agents are present at the same time, preferably in effective amounts. Simultaneous administration of the above therapeutic agents) and staggered administration (administration of one or more therapeutic agents at different times) (administration at a time different from that of the additional therapeutic agent). In certain embodiments, one or more of the compounds described herein are at least one of the following: In a particularly preferred embodiment, the compound is co-administered with at least one additional bioactive agent. Co-administration results in synergistic activity and / or treatment, including anti-cancer activity.

[0045] The term "effective" when used in the context of its intended use means that such a treatment or the symptom of a condition, disorder or pathology in a subject in need of administration of such treatment. to prevent, inhibit, ameliorate, delay or cure a condition, or to have a sufficient effect against the same It may refer to the amount / dosage of active pharmaceutical ingredient that is sufficient (to relieve some, preferably all, of the symptoms) to The term effective includes, but is not limited to, all other effective amounts or concentrations. Terms such as "effective amount / dose," "pharmacologically effective amount / dose," or "therapeutically effective amount / dose" are also used. "amount / dosage" and the like, which are described or used elsewhere in this application.

[0046] The effective amount will depend on the type and severity of the disease, the composition used, the route of administration, and the mammal being treated. The type of object, the physical characteristics of the specific mammal under consideration, the concomitant therapy, and the medical technology field. The exact amount can be determined using known techniques, depending on the amount of the active ingredient, the amount of the active ingredient, and other factors that one of ordinary skill in the art will recognize. This can be ascertained by one of ordinary skill in the art (see, for example, Lieberman, Pharmaceutical Dosage Form F. orms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Scie nce and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Will (see iams & wilkins).

[0047] "Pharmacological composition," "therapeutic composition," "therapeutic formulation," or "pharmaceutical acceptable The term "formulation" includes, but is not limited to, any formulation that allows for effective distribution of the agent provided by the present disclosure. These refer to compositions or formulations that are best suited to the body for the desired activity. The formulation is suitable for administration to a targeted location (eg, systemic administration).

[0048] The terms "pharmacologically acceptable" and "pharmacologically acceptable" are used interchangeably, as appropriate. Adverse reactions, allergic reactions, or other undesirable effects when administered to a substance or person It may refer to, but is not limited to, entities and compositions that do not produce a reaction.

[0049] The term "pharmacologically acceptable carrier" or "pharmacologically acceptable carrier" refers to a pharmaceutical Any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity, Suitable carriers include, but are not limited to, agents that delay absorption, and the like. The standard reference text, Remington's Pharmaceutical Sciences, is the latest edition of The preferred carriers or diluents are: Examples of suitable solutions include, but are not limited to, water, saline, finger solutions, dextrose solutions, etc. and 5% human serum albumin. Liposomes and non-aqueous, such as fixed oils. Vehicles may also be used. The use of such vehicles and agents for pharma- ceutically active substances. Except insofar as any conventional media or agent is incompatible with the active compound, it is well known in the art. Supplementary active compounds can also be incorporated into the compositions. do.

[0050] The term "systemic administration" refers to administration, such as enteral or parenteral administration, that distributes an agent throughout the body. This refers to a route of administration in which a drug is absorbed or accumulated in the bloodstream and then distributed throughout the body. Suitable forms depend in part on the use or route of entry, e.g., oral, transdermal, or by injection. Such a form inhibits the composition or formulation from reaching the target cells. (i.e., negatively charged polymers are preferred for delivery to cells). The pharmacological composition injected into the stream must be soluble. Other factors are known in the art. The toxicity and shape of the composition or formulation are known to those skilled in the art and are, for example, known to inhibit the composition or formulation from exerting its effect. Routes of administration that result in systemic absorption include, but are not limited to: These include intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary, and intramuscular. The rate of drug entry has been shown to be a function of molecular weight or size. The use of liposomes or other drug carriers containing the substances described herein may be used to treat, for example, the reticuloendothelial system (RES). Potential for localization of drugs in specific tissue types, such as tissues of the cerebrovascular (cerebrovascular) and endothelial systems It can promote the binding of drugs to the surface of cells such as lymphocytes and macrophages. Liposomal formulations are also useful.

[0051] The term "local administration" refers to administration within about 10 cm of the site of a lesion or disease. Refers to a route of administration by which an agent is delivered to an appropriate or nearby site.

[0052] As used herein, unless otherwise indicated, the term "compound" refers to any compound that is It refers to any specific chemical compound disclosed herein, including tautomers, positional isomers, geometric isomers, and the like. and, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastereoisomers). stereoisomers, including isomers, as well as, where appropriate in the context, pharma- ceutically acceptable salts thereof. and derivatives (including prodrug forms). Within its use in context, the term compound The term generally refers to a single compound, but may also refer to, for example, stereoisomers and / or optical isomers of the disclosed enantiomers (racemic mixtures) as well as mixtures enriched in a specific enantiomer or enantiomers The term may include other compounds that facilitate administration and are integrated into the active site. The term also refers to prodrug forms of compounds that have been modified to deliver the compound. Please note that many of the substituents and particularly the variables associated therewith are listed in the .

[0053] The molecules described herein are intended to be stable compounds as outlined below. It is understood by the vendor.

[0054] [ka]

[0055] When is shown, both double and single bonds are shown in the compound and valence The interactions of the various objects are represented or understood in the context of known rules regarding the interactions of the objects.

[0056] As used herein, a "derivative" refers to a compound derived directly from a natural compound, through modification, or As used herein, "analog" can refer to a composition formed by partial substitution. "Non-natural compounds" may refer to compositions that have a structure similar to, but not identical to, a naturally occurring compound. .

[0057] The term "ubiquitin ligase" refers to the enzyme that transfers ubiquitin to specific substrate proteins. This refers to a family of proteins that promote the degradation of substrate proteins. For example, cereblon acts in conjunction with E2 ubiquitin-conjugating enzymes or alone to bind to ligands on target proteins. ubiquitin is added to the ubiquitin complex, which then targets specific protein substrates for proteasomal degradation. It is an E3 ubiquitin ligase protein that targets the target of ubiquitination. Together, or alone, E3 ubiquitin ligases mediate ubiquitination of targeted proteins. In general, ubiquitin ligases are involved in polyubiquitination and A second ubiquitin is then added to the first ubiquitin, and the third ubiquitin is added to the second ubiquitin. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are restricted to monoubiquitination, in which case In this case, only one ubiquitin is added to the substrate molecule by the ubiquitin ligase. Tylated proteins are not targeted for degradation by the proteasome but are instead For example, via binding to other proteins that have domains capable of binding ubiquitin. To further complicate matters, This suggests that different lysines on ubiquitin can be targeted by E3 to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is involved in the proteasome. It is the lysine that is used to generate polyubiquitin, which is more easily recognized.

[0058] The terms "patient" or "subject" are used throughout this specification to refer to a subject who is receiving the compositions of the present disclosure. The present invention provides a method for treating, including preventing, a disease in a cell, tissue or animal, preferably a human, or livestock. A particular animal, such as a human patient. With respect to the treatment of an infection, condition or disease specific to a dog, the term patient refers to, for example, a dog or Certain animals, including domestic animals such as cats, or agricultural animals, e.g. horses, cows, sheep Generally, in this disclosure, the term patient refers to a subject, unless otherwise indicated or Unless implied from the context in which the term is used, it refers to a human patient.

[0059] Compounds and Compositions In one embodiment, the disclosure provides compounds useful for regulating protein activity. The composition is based on a defined chemical structure (preferably for E3 ubiquitin ligase alone, or complexed with E2 ubiquitin-conjugating enzymes involved in the transfer of ubiquitin to target proteins ubiquitin pathway protein binding moieties (for selected E3 ubiquitin ligases), and or a linker, wherein the ubiquitin pathway protein binding portion recognizes a ubiquitin pathway protein. The targeting moiety recognizes a target protein (e.g., the androgen receptor). The compounds may be referred to herein as PROTAC compounds or PROTACs.

[0060] In one embodiment, the present disclosure provides a method for the detection of cereblon E3 ubiquitin ligase binding moiety (CLM). The present invention provides a compound comprising an E3 ubiquitin ligase binding moiety (ULM). wherein the CLM is attached to a chemical linker group (L) according to the following structure: L-CLM (I) where L is a chemical linker group and CLM is a cereblon E3 ubiquitin ligase binding moiety. The number and / or relative positions of moieties in the compounds described herein are for illustrative purposes only. As will be appreciated by those of skill in the art, the compounds described herein may be modified in various ways, including but not limited to, by the addition of each functional group. The radical moieties can be synthesized in any desired number and / or relative positions.

[0061] The terms ULM and CLM are used in their inclusive sense unless the context indicates otherwise. For example, the term ULM is used to describe any molecule that binds to cereblon (i.e., CLM). In addition, the term CLM encompasses all possible It contains the cereblon E3 ubiquitin ligase binding portion.

[0062] In another embodiment, the present invention relates to a compound that is linked via a chemical linker moiety (L) or directly. For example, a compound having two CLMs is provided that has the following structure: It can be illustrated as follows: CLM-CLM (II) or CLM-L-CLM (III).

[0063] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are identical. In additional embodiments, a compound comprising multiple CLMs may be linked directly or via a chemical linker (L) The CLM further comprises at least one PTM linked to the CLM via, or both. In certain additional embodiments, the compound comprising multiple CLMs further comprises multiple PTMs. In yet further embodiments, the PTMs are the same or, optionally, different. In yet a further embodiment, when the PTMs are different, each PTM binds to the same protein target. The antibodies may be identical in structure or may specifically bind to different protein targets.

[0064] In additional embodiments, the present disclosure provides a method for the preparation of a medicament comprising the steps of: provides a compound comprising at least two different CLMs linked via both of the For example, such a compound with two different CLMs can be illustrated as follows: CLM-CLM' (IV) or CLM-L-CLM' (V) In the formula, CLM' represents the cereblon E3 ubiquitin ligase binding portion that is structurally distinct from CLM. In certain embodiments, the compound comprises multiple CLMs and / or multiple CLM's. In further embodiments, at least two different CLMs, a plurality of CLMs, and and / or a compound comprising multiple CLM's, either directly or via a chemical linker, It further comprises at least one PTM linked to the CLM or the CLM' via both. In any of the embodiments described herein, the compound comprising at least two different CLMs is In yet further embodiments, the PTMs are the same or or optionally different. In yet further embodiments, when the PTMs are different, each PTM may bind to the same protein target or may specifically bind to different protein targets. In yet further embodiments, the PTM itself may be a ULM or CLM (or a ULM′ or CL M').

[0065] In another aspect, the present disclosure provides a bifunctional or PROTAC compound, The compound is an E3 ubiquitin ligase binding moiety (CLM), which is a cereblon E3 ubiquitin ligase. The AR binding moiety (ABM) is a part that binds to the target protein. i.e., protein / polypeptide targeting ligands, or "PTM" groups). In the form, the structure of the bifunctional compound can be illustrated as follows: ABM-CLM (VI), The respective positions of the ABM and CLM moieties exemplified herein, and These numbers are provided for illustrative purposes only and are not intended to limit the compounds in any way. As will be appreciated by those of skill in the art, the bifunctional The compounds are synthesized such that the number and position of each functional moiety can be varied as desired. It is possible.

[0066] In certain embodiments, compounds having the following general structure: ABM-L, wherein ABM is and L is a chemical linker moiety, e.g., a linker as described herein. Car or optionally a bond.

[0067] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). The structure of the bifunctional compound can be shown as follows: ABM-L-CLM(VII) where ABM is an AR binding moiety as described herein and CLM is cereblon E3 as described herein. L is a chemical linker moiety, e.g., a linker as described herein. ABM may be a moiety or, optionally, a bond, connecting the ABM and the CLM.

[0068] Additionally, CLM binds all potential cereblon E3 ubiquitin ligase binding sites. The CLM and ABM groups may be any suitable and stable covalent linker for the linker chemistry. It may be covalently attached to the linker group via a bond.

[0069] In certain embodiments, the CLM is a ligase for cereblon E3 ubiquitin ligase (CRBN). In certain embodiments, the CLM comprises a moiety that is a ligand. In certain additional embodiments, the CLM comprises a phthalimide group or an analog thereof. or derivatives. In yet additional embodiments, the CLM is phthalimido-glutaric acid. In yet another embodiment, the CLM consists of thalidomide, lenalidomide, pomalidomide, and their analogs or derivatives. The present invention includes one of the groups:

[0070] The general structure is illustrative and the individual moieties may be in any desired order or configuration, e.g. It will be understood that the CLM-L-ABM and CLM-L-ABM, respectively, may be spatially arranged. In certain additional embodiments, the compound comprises multiple E3 ligase binding moieties and / or multiple Includes a number of ABMs.

[0071] In certain embodiments, the compounds described herein contain multiple ABMs (AbAb at the same or different positions in the AR). ubiquitin ligase (ULM) targets multiple CLMs and one or more ULMs (i.e., another E3 ubiquitin ligase) The present invention also includes moieties that specifically bind to VHL, or combinations thereof. In any of the aspects of the described embodiment, the ABM, CLM, and ULM are directly or in combination with one or more The linkers may be linked via the above chemical linkers, or combinations thereof. In embodiments, when a compound has multiple ULMs, the ULMs are linked to the same E3 ubiquitin ligator. Alternatively, each ULM may be specific for a different E3 ubiquitin ligase. In a further embodiment, when a compound has multiple ABMs, The ABMs may be the same or, optionally, different.

[0072] In certain embodiments, when a compound comprises multiple CLMs, the CLMs are either identical or In additional embodiments, a compound comprising multiple CLMs is At least one of the CLMs is attached via a bond or a chemical linker (L), or both. In certain additional embodiments, the compound comprising multiple CLMs further comprises: In yet further embodiments, the ABMs are the same or any combination of the ABMs. are different.

[0073] In certain embodiments, the ABM alone is capable of regulating protein activity without forming an ABM-L-CLM. This provides desirable characteristics in controlling

[0074] In any of the aspects or embodiments of the compounds described herein, unless otherwise indicated Insofar as the compound is a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate or Polymorphs are intended to be included.

[0075] In certain embodiments, the compounds described herein may comprise multiple PTMs (either the same or different proteins). targeting a protein target), multiple ABMs, multiple CLMs, one or more ULMs (i.e., another E3 ubiquitin a moiety that specifically binds to a tyrosine ligase, such as cereblon, or a combination thereof In any of the aspects of the embodiments described herein, the PTM, ABM, CLM, and U The LM may be attached directly, via one or more chemical linkers, or a combination thereof. In additional embodiments, when a compound has multiple ULMs, those ULMs may be may be directed to the same E3 ubiquitin ligase, or each ULM may be directed to a different E In yet a further embodiment, the compound may specifically bind to ubiquitin ligase. When an entity has multiple PTMs, the PTMs may bind to the same target protein, or Each PTM may specifically bind to a different target protein.

[0076] Exemplary CLM Neo-imide compounds In one embodiment, the present disclosure provides compounds useful for binding and / or inhibiting cereblon. In certain embodiments, the compound or CLM is selected from the group consisting of the following chemical structures: Selected from:

[0077] [ka]

[0078] During the ceremony: W is independent, CH 2 , CHR, C=O, SO 2 , NH and N-alkyl (optionally substituted straight chain, branched chain); Y is independent, CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cyclo selected from the group consisting of alkyl, N-heterocyclyl, O and S; X and Z are each independently O, S, or H. 2 but both X and Z are H 2 If Except that it won't; G and G' are independently H, alkyl (straight or branched chain optionally substituted with R'), OH, R'O COOR, R'OCONRR", CH optionally substituted with R' 2 -heterocyclyl, and optionally R' substituted benzyl; Q1-Q4 are each independently C optionally substituted with R', N, or N-oxide; A is independently alkyl (optionally substituted straight or branched chain), cycloalkyl (optionally substituted substituted), selected from the group consisting of Cl, H and F; R is -CONR'R", -OR', -NR'R", -SR', -SO 2 R', -SO 2 NR'R", -CR'R"-, -CR'N R'R"-, -aryl, -hetaryl, -alkyl (optionally substituted straight or branched chain), -cycloalkyl -alkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", -OP(O )R'R", -Cl, -F, -Br, -I, -CF 3 , -CN, -NR'SO 2 NR'R", -NR'CONR'R", -CONR'C OR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO 2 )N R'R", -SO 2 NR'COR", -NO 2 , -CO 2 R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S (C=O)(C=N-R')R", -SF 5 , -R'NR'R”, (-R'O) n R”, ​​or -OCF 3 Including, but not limited to, these Not limited to. R' and R'' are each independently a bond, H, alkyl (straight or branched chain), cycloalkyl , aryl, hetaryl, heterocyclyl, or -C(=O)R, each of which is optionally is replaced by; n is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0079] [ka]

[0080] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains 1 to 4 independent functional groups or atoms, one of which is optionally modified. and covalently bonded to an ABM, a chemical linker group (L), a ULM, a CLM (CLM'), or a combination thereof. are combined.

[0081] Exemplary CLM In any of the compounds described herein, the CLM has a chemical structure selected from the group consisting of: Construction includes:

[0082] [ka]

[0083] During the ceremony: W is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl (optionally substituted straight or branched chain). r; X and Z are each independently O, S, or H. 2 but both X and Z are H 2 If Except that it won't; Y is independent, CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cyclo Selected from the group of alkyl, N-heterocyclyl, O and S; G is H, alkyl (straight or branched), OH, R'OCOOR, R'OCONRR", CH 2 -Heterocyclyl , heterocyclic, aryl, or benzyl, each optionally substituted with R'; Q1-Q4 are each independently C optionally substituted with R', N, or N-oxide; A is independent, C 1 -C 6 Alkyl (optionally substituted straight or branched chain), cycloalkyl (optionally substituted substituted with), H, Cl or F; R is -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'N R'R"-, (-CR'O) n R”, ​​-aryl, -heteroaryl, -alkyl (optionally substituted or unsubstituted) -chain, branched chain), -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP (O)(OR')R", -OP(O)R'R", -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R", -NR' CONR'R", -CONR'COR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R ", -NR'C(=C-NO2)NR'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR' =CR'R”, -CCR', -S(C=O)(C=N-R')R”, alicyclic, heterocyclic, -SF5, or -OCF3 ; R' and R'' are each independently a bond, H, N, N-oxide, alkyl (straight chain, branched chain), Cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, or heterocycloalkyl. Ril, each of which is optionally substituted; n is an integer from 1 to 10;

[0084] [ka]

[0085] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains 1 to 4 independent functional groups or atoms, one of which is optionally modified. and covalently bonded to an ABM, a chemical linker group (L), a ULM, a CLM (CLM'), or a combination thereof. are combined.

[0086] In certain embodiments described herein, the CLM or ULM is selected from the group consisting of: Chemical structure including:

[0087] [ka]

[0088] During the ceremony: W is CH 2 , independently selected from the group consisting of C=O, NH and N-alkyl; R is H, methyl, or C1-C6 alkyl (straight or branched, optionally substituted);

[0089] [ka]

[0090] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains 1 to 4 independently selected functional groups or atoms, and optionally one of is modified to include an ABM, a chemical linker group (L), a ULM, a CLM (or CLM') or a combination thereof The resulting mixture is covalently bonded to the

[0091] As used herein, the term "independently" means that a variable that is applied independently is used to indicate that the

[0092] The term "alkyl" refers, within its context, to any fully saturated straight-chain, branched, or cyclic alkyl radical. is intended to mean a hydrocarbon radical or alkyl group, preferably 1 -C 10 , more preferably C 1 -C 6 , or C 1 -C 3 are alkyl groups of the formula: Examples of alkyl groups are in particular methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-hexane. butyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl Propyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentyl ethene In certain embodiments, aryl, cyclohexylethyl, and cyclohexyl. The alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In one embodiment, the compounds according to the present disclosure are used to covalently bind to a dehalogenase enzyme. These compounds generally have a side chain (often via a polyethylene glycol group). The side chain contains a halogen substituent (often chlorine or or bromine), thereby making it possible to distinguish compounds containing the moiety from tannic acid. Covalent bonding of proteins occurs.

[0093] The term "alkenyl" refers to straight-chain, branched or unbranched alkyl groups containing at least one C=C bond. is a cyclic C 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0094] The term "alkynyl" refers to straight, branched or alkynyl groups containing at least one C≡C bond. or cyclic C 2 -C 10 (Preferably C 2 -C 6 ) refers to a hydrocarbon radical.

[0095] The term "alkylene," when used, refers to an optionally substituted --(CH 2 ) n - Refers to the group ( (n is typically an integer from 0 to 6). When substituted, the alkylene group may be one of the methylene groups. At least one, C 1 -C 6 Substituted with an alkyl group (including a cyclopropyl group or a t-butyl group) It is preferred that the aryl group contains one or more halo groups, preferably 1 to 3 halo groups, or one or Two hydroxyl groups, O-(C 1 -C 6 alkyl) groups, or as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with an amino acid side chain. or alkoxy groups (or other groups), which may further be substituted with polyethylene. ethylene glycol chain (1 to 10, preferably 1 to 6, and often 1 to 4 ethylene glycol chains) The alkyl group is preferably, but not limited to, a chain of polyethylene units. The alkyl chain is substituted with one halogen group, preferably a chlorine atom. In yet other embodiments, the alkylene (often methylene) group is , such as natural or unnatural amino acids, such as alanine, β-alanine, arginine, Asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, Lysine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine , the side chain groups of proline, serine, threonine, valine, tryptophan or tyrosine, etc. The amino acid side chain groups may be substituted.

[0096] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. 0 of The range of carbon atoms included means that the carbon is either absent or replaced with H. Therefore, C 0 -C 6 The carbon atom range includes 1, 2, 3, 4, 5 and 6 carbon atoms, and C 0 has H instead of carbon.

[0097] The terms "substituted" or "optionally substituted" refer to any one of the following on a molecule within the context: One or more substituents at a carbon (or nitrogen) position (independent on a moiety in a compound according to the present disclosure) up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents and may include substituents which may themselves be further substituted) (i.e., when there are multiple substituents, each substituent is independent of the other substituents), and The substituents are hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO 2 ), Halogen (especially on alkyl, especially methyl groups such as trifluoromethyl) is preferred 1, 2, or 3 halogens), an alkyl group (preferably C 1 -C 10 , more preferably C 1 - 6 ), Aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), koxy group (preferably C1 -C 6 Alkyl or aryl, including phenyl and substituted phenyl. ), thioether (C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 Acyl ), ester or thioester (preferably C 1 -C 6 alkyl or aryl) alkylene esters (wherein the attachment is on the alkylene group rather than the ester functionality, preferably is C 1 -C 6 substituted with alkyl or aryl groups), preferably C 1 -C 6 Alkyl or Aryl halogen (preferably F or Cl), amine (5- or 6-membered cyclic alkyl Contains phenylamine, C 1 -C 6 Alkylamine or C 1 -C 6 The composition further comprises a dialkylamine. The alkyl group may be substituted with one or two hydroxyl groups, or optionally substituted -N(C 0 -C 6 Alkyl)C(O)(OC 1 -C 6 alkyl) group (optionally substituted with a polyethylene glycol chain which may further be bonded to an alkyl group containing one halogen, preferably chlorine, substituent. hydrazines, amides, which preferably have one or two C 1 -C 6 Alkyl group (1 or The two C's 1 -C 6 including carboxamides optionally substituted with alkyl groups), alkanols (preferably Or C 1 -C 6alkyl or aryl), or alkanoic acid (preferably C 1 -C 6 Alkyl Substituents according to the present disclosure include, for example, -SiR 1 R 2 R 3 group, where R 1 and R 2 each of which is otherwise described herein; And R 3 is H or C 1 -C 6 is an alkyl group, preferably in this context R 1 , R 2 , R 3 is C 1 -C 3 and alkyl groups (including isopropyl or t-butyl groups). The substituent may be directly attached to the substituted moiety or may be an optionally substituted (CH 2 ) m -of or optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m -or-(CH 2 CH 2 O) m -Through the group and substituted moieties (preferably in the case of aryl or heteroaryl moieties). may be bonded to, which may be substituted with any one or more of the substituents described above. -(CH 2 ) m -or-(CH 2 ) n -group or, for example, the ethylene glycol groups specified above. Other chains, such as alkylene chains, may be substituted anywhere on the chain. The substituents are halogen or C 1-C 6 (Preferably C 1 -C 3 ) alkyl groups, It optionally contains one or two hydroxyl groups, one or two ether groups (OC 1 -C 6 basis), up to three halo groups (preferably F) or at the amino acid side chain as otherwise described herein Optionally substituted amides (preferably substituted as described above) carboxamide) or urethane groups (often containing one or two C 0 -C 6 Alkyl Substituents and the like, which may also be further substituted. In certain embodiments, alkyl The aryl group (often a single methylene group) may be one or two optionally substituted C 1 -C 6 Alki C 1 -C 4 An alkyl group, most often a methyl or O-methyl group, or is replaced with an amino acid side chain as otherwise described herein. is optionally substituted with up to 5 substituents, preferably up to 3 substituents. In the present disclosure, a substituted moiety is substituted with one or two substituents.

[0098] The term "substituted," where each substituent is independent of any other substituent, means that Within the context of the use of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, amide, carbo Sulfone, keto, carboxy, including oxamide, sulfonamide, 1 -C 6 Ester (oxy ester or carbonyl ester), C1 -C 6 Keto, urethane-OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 , nitro, cyano, and amine (especially C 1 -C 6 Alkylene-NR 1 R 2 , Monoma Orji-C 1 -C 6 Alkyl-substituted amines, optionally with one or two hydroxyl groups. Each of these groups is also intended to mean the groups represented by the formula (including those which may be optionally substituted) unless otherwise indicated. Unless otherwise specified within the context, the substituents may contain from 1 to 6 carbon atoms. Examples of suitable substituents depending on the context of use are -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m - (wherein m and n are 1, 2, 3, 4, 5 or 6, depending on the context), -S-, - S(O)-, SO 2 - or -NH-C(O)-NH-, -(CH 2 ) n OH, -(CH 2 ) n SH, -(CH 2 ) n COOH, C 1 -C 6 Alki le, -(CH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n O.C.(O)-(C 1 -C 6 a Rukill), -(CH 2 )n C(O)O-(C 1 -C 6 alkyl), -(CH 2 ) n NHC(O)-R 1 , -(CH 2 ) n C(O)-NR 1 R 2 , -(OC H 2 ) n OH, -(CH 2 O) n COOH, C 1 -C 6 Alkyl, -(OCH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 O) n C(O)-(C 1 -C 6 Alkyl), -(OCH 2 ) n NHC(O)-R 1 , -(CH 2 O) n C(O)-NR 1 R 2 , -S(O) 2 -R S , -S(O)-R S (R S teeth, C 1 -C 6 Alkyl or -(CH 2 ) m -NR 1 R 2 group), NO 2 , CN or halogens (F, Cl, Br, I, Preferred are F and Cl. 1 and R 2 are H or C in the context 1 -C 6 Alkyl groups (containing one or two hydroxyl groups or up to three halogen groups, preferably The term "substituted" also refers to a group of aryl groups, which may be optionally substituted with aryl or fluorine. Within the chemical context of the compound being studied and the substituents used, optionally substituted aryl groups or or a heteroaryl group or an optionally substituted heterocycle as otherwise described herein. An alkylene group is also intended to mean a group as otherwise disclosed herein. may be substituted, preferably optionally substituted C 1 -C 6 Alkyl groups (methyl, ethyl, or hydroxymethyl or hydroxyethyl, and accordingly a chiral center is provided. provided herein), the side chains of amino acid groups as otherwise described herein, amide groups as described above, or or urethane group, OC(O)-NR 1 R 2 A group, wherein R 1 and R 2 is described elsewhere herein Although the alkyl groups may be substituted with certain groups as described above, many other groups may also be used as substituents. The optionally substituted moieties may have three or more substituents, preferably three or less, and preferably In a compound, a group may be substituted with one or two substituents at a particular position of the molecule. When a substitution is required (mainly because of valence) but the substitution is not indicated, the substitution context Note that unless otherwise indicated in the specification, the substituents are assumed or understood to be H. I want to be loved.

[0099] The term "aryl" or "aromatic" refers, in context, to a single ring (e.g., benzoyl) or a combination of both. phenyl, benzyl) or fused ring (e.g. naphthyl, anthracenylphenyl , phenanthrenyl, etc.) refers to a substituted monovalent aromatic radical and, in accordance with the present disclosure, any available stable ring or as otherwise specified in the chemical structure presented. Other examples of aryl groups, in context, include heteroaromatic ring systems, For example, imidazole, furyl, pyrrole, furanyl, thienyl, thiazole, pyridine, Imidine, pyrazine, triazole, oxazole, etc., with one or more nitrogen atoms in the ring, acid "Heteroaryl" groups containing nitrogen or sulfur atoms, or, for example, especially indole, cyclohexyl, condensed ring systems such as indolizine, azaindolizine, and benzofurazan; They may be optionally substituted as described above. Among the heteroaryl groups that may be mentioned in particular are and nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyridine ... Imidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole Indoles, indoles, isoindoles, indolizines, azaindolizines, purines, indole quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydro Isoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, Noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria azine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazolidine pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazo pyrrolopyridines, pyrrolopyrimidines, and pyridopyrimidines; sulfur-containing aromatic heterocycles rings, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan; pyran, cyclopentapyran, benzofuran, and isobenzofuran; and nitrogen, Aromatic heterocycles containing two or more heteroatoms selected from among sulfur and oxygen, e.g. For example, thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole , benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine , pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxa Examples include furopyridine, furopyrimidine, furopyrimidine, thienopyrimidine, and oxazole. all of which may be optionally substituted.

[0100] The term "substituted aryl" refers to a group consisting of at least one aromatic ring or It refers to an aromatic carbocyclic ring consisting of multiple condensed rings, at least one of which is aromatic. In the present invention, the ring is substituted with one or more substituents. For example, the aryl group is selected from the following: The substituents may include: -(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 ) alkyl, -(CH 2 ) n -O-(CH 2 ) n -(C 1 -C 6 ) alkyl, -(CH 2 ) n -C(O)(C 0 -C 6 ) alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 ) alkyl, -( CH 2 ) n -OC(O)(C 0 -C 6 ) alkyl, amine, mono- or di-(C 1 -C 6alkyl)amines The alkyl group on the amine optionally has one or two hydroxyl groups or up to three Halo (preferably F, Cl) groups, OH, COOH, C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 or CN groups (each of which is in the ortho, meta, and / or pas positions of the phenyl ring). an optionally substituted phenyl group (which may be substituted at the para-position, preferably the para-position); The group itself is preferably substituted with a linker group attached to the ABM group, which includes a ULM group. and / or F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 , or CN group (phenyl ring ortho-, meta-, and / or para-positions, preferably para-positions) of substituted with, optionally substituted naphthyl groups, optionally substituted heteroaryl groups, preferably Optionally substituted isoxazoles, preferably methyl-substituted isoxazoles. Optionally substituted oxazoles including oxazoles, optionally substituted thiazoles including methyl substituted thiazoles Substituted thiazoles, optionally substituted isothiazoles, including methyl-substituted isothiazoles pyrrole, optionally substituted pyrrole including methyl substituted pyrrole, any of the above-listed pyrroles including methylimidazole Optionally substituted imidazole, optionally substituted benzimidazole or methoxybenzene oxyimidazole, optionally substituted oxyimidazole or methyloxyimidazole aryl, optionally substituted diazole groups including methyldiazole groups, methyl-substituted triazoles Optionally substituted triazole groups, including halo- (preferably F) or methyl-substituted pyridines. an optionally substituted pyridine group, including a lysine group or an oxapyridine group, is attached to the phenyl group by an oxygen atom), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, Indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinolines, and combinations thereof.

[0101] "Carboxyl" means --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, The generic substituents of these groups have the same meaning as the corresponding group definitions defined herein.

[0102] The terms "heteroaryl" or "hetaryl" include, without limitation, optionally substituted Quinoline (attached to the pharmacophore or any carbon atom within the quinoline ring) optionally substituted on the alkyl group, optionally substituted indole (including dihydroindole), optionally substituted indolizines, optionally substituted azaindolizines (2, 3, or 4-aza indolizine), optionally substituted benzimidazole, benzodiazole, benzoxazole isofuran, optionally substituted imidazole, optionally substituted isoxazole, substituted oxazoles (preferably methyl substituted), optionally substituted diazoles, optionally substituted triazoles, tetrazoles, optionally substituted benzofurans, Substituted thiophenes, optionally substituted thiazoles (preferably methyl substituted and / or or thiol substituted), optionally substituted isothiazole, optionally substituted triazole silyl (preferably methyl, triisopropylsilyl, optionally substituted (CH 2 ) m -OC 1 -C 6 An alkyl group or an optionally substituted (CH 2 ) m -C(O)-OC 1 -C 6 1 substituted with alkyl group ,2,3-triazole), optionally substituted pyridine (2, 3, or 4-pyridine), or It may refer to a group according to the following chemical structure:

[0103] [ka]

[0104] During the ceremony, S c is CHR SS , N.R. URE , or O; R HET H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alki aryl (preferably one or two hydroxyl groups or up to three halo groups (e.g., CF 3 ) ), optionally substituted O(C 1 -C 6 Alkyl) (preferably one or two aryl groups) hydroxyl or up to three halo groups), or optionally substituted acetyl Rene group -C≡CR a wherein R a is H or C 1 -C 6 Alkyl group (preferably C 1 -C 3 Alkyl ) is an acetylene group; R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alki aryl (preferably substituted with one or two hydroxyl groups or up to three halo groups) ), optionally substituted O-(C 1 -C 6 alkyl) (preferably containing one or two hydroxyl groups or up to three halo groups), or an optionally substituted -C(O)(C 1 -C 6 Alkyl ) (preferably substituted with one or two hydroxyl groups or up to three halo groups) ) is; R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl), or -C(O)(C 1 -C 6 Al each group optionally containing one or two hydroxyl groups or up to three halo groups , preferably substituted with fluorine groups, or optionally substituted heterocycles, such as piperidines. idine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine azine, piperazine, etc., each of which is optionally substituted; and Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or may contain up to three halo groups (e.g., CF3 ), optionally substituted O(C 1 -C 6 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 H or C 1 -C 6 a alkyl group (preferably C 1 -C 3 It is an acetylene group which is an alkyl group.

[0105] The terms "aralkyl" and "heteroarylalkyl" are defined as aryl, heteroaryl, or heteroarylalkyl in accordance with the above definitions. aryl or heteroaryl, respectively, and alkyl, and / or heteroalkyl; It refers to groups containing alkyl, aryl, and / or carbocyclic and / or heterocycloalkyl ring systems.

[0106] As used herein, the term "arylalkyl" refers to any of the aryl groups defined above. An arylalkyl group refers to an aryl group as defined above appended to an alkyl group. is attached to the parent moiety through an alkyl group, where the alkyl group has 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as described above.

[0107] The term "heterocycle" refers to a ring that contains at least one heteroatom, such as N, O, or S. It refers to a cyclic group containing aryl, which may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are encompassed under the definition of heterocycle, depending on the context of its use. Suitable heteroaryl groups are described herein above.

[0108] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxolyl, Xanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothiazole enyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, Dioxolanil, Ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, iso Soxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl , oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl Dinyl, piperidinyl, phthalimido, succinimido, pyrazinyl, pyrazolinyl , pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetra Hydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolidinyl Azolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathio Ranil and Chiang are examples.

[0109] The heterocyclic group includes alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, ... Cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino , substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano No, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thio Aryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thio Alkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, hetero Aryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino , nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2- Alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl Such heterocyclic groups may be optionally substituted with a ring selected from the group consisting of a single ring, a ring structure, a ring unit, a ring structure ... Examples of nitrogen heterocycles and heteroaryls include Non-limiting examples include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyrimidine. amines, pyridazines, indolizines, isoindoles, indoles, indazoles, purines, Quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, Quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, Acridine, phenanthroline, isothiazole, phenazine, isoxazole, pheno Xanthazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, Indoline, morpholino, piperidinyl, tetrahydrofuranyl, etc., as well as N-alkoxy The term "heterocyclic" also refers to any of the heterocycles. is a benzene ring or a cyclohexane ring or another heterocyclic ring (e.g., indolyl, quinolyl Also included are bicyclic groups fused to an isoquinolyl, tetrahydroquinolyl, etc.

[0110] The term "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, 3-20 carbon atoms, including but not limited to cyclohexyl, cycloheptyl, etc. and monocyclic or polycyclic rings as defined herein, such as saturated monocyclic hydrocarbon groups having It means, but is not limited to, a monovalent group derived from an alkyl group or a cycloalkane. The term "substituted cycloalkyl" includes, for example, amino, halogen, alkyl, Substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or or sulfo, These generic substituents refer to, but are not limited to, the following groups: has the same meaning as the corresponding group definition.

[0111] "Heterocycloalkyl" means that at least one ring carbon atom in the cyclic structure is selected from the group consisting of N, O, A monocyclic or polycyclic aryl group substituted with a heteroatom selected from the group consisting of S and P. "Substituted heterocycloalkyl" refers to a group in which at least one ring of the ring structure is substituted. A monocyclic ring in which a carbon atom is replaced with a heteroatom selected from the group consisting of N, O, S, or P. or polycyclic alkyl groups, the groups being halogen, alkyl, substituted alkyl, carbaryl, The group consisting of ruoxy, carbylmercapto, aryl, nitro, mercapto, and sulfo Although these generic substituents are intended to be understood as meaning the same, they may contain one or more substituents selected from the following: has the same meaning as the corresponding group defined in

[0112] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen; They may be fully saturated, partially unsaturated, or aromatic, and may include aryl groups, alkyl groups, Includes alkenyl and alkynyl groups.

[0113] In any of the embodiments described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, A and Rn are independently a linker, and / or one or more The linker may be covalently attached to a linker that is attached to the ABM, ULM, CLM or CLM' group of the

[0114] More specifically, non-limiting examples of CLMs include the molecules shown below, as well as the molecules shown below. "Hybrid" refers to a molecule that is a product of one or more combinations of different features. In this case, Rn is 1 to 4 independently selected functional groups or atoms. The aryl group includes an ABM, a chemical linker group (L), U, and optionally one of them is modified to include an ABM, a chemical linker group (L), U, Covalently attached to the LM, CLM (or CLM') or a combination thereof.

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] [ka]

[0120] Exemplary Linkers In certain embodiments, the compounds described herein are linked via one or more chemical linkers (L). The compound comprises one or more ABMs chemically linked or attached to the ULM or CLM above. In certain embodiments, the linker group L is a group that includes one or more covalently linked structural units. (For example, -A 1.. A q -, or -A q -), in this case A 1 is a group attached to the ABM , A q is a group attached to ULM.

[0121] In certain embodiments, the linker group L is q - selected from; A q is a group linked to a ULM or ABM moiety; and q is an integer equal to or greater than 1; In the formula, A q is a bond, CR L1 R L2 , O, S, SO, SO 2 , N.R. L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 C ONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN )NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , optionally 0 to 6 R L1 and / or R L2Substituted with group C 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with group 5-13 spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with group 3-11 Haeta Rocyclyl, optionally 0 to 8 R L1 and / or R L2 C substituted with group 5-13 Spiroheterosis chloroalkyl, optionally 0 to 6 R L1 and / or R L2 aryl substituted with a group, optionally 0 ~6 R L1 and / or R L2 heteroaryl substituted with a group; Here, R L1 or R L2 each independently optionally bonded to another group, and optionally 0 to 4 R L5 Based on forming substituted cycloalkyl and / or heterocyclyl moieties; R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or 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 Sik Roalkyl, NHC 1~8 Cycloalkyl, N(C 1~8 Cycloalkyl)2 , N(C 1~8 Cycloalkane (C 1~8 alkyl), OH, NH 2 , SH, SO 2 C 1~8 Alkyl, P(O)(OC 1~8 Alkyl)(C 1~8 a Rukill), P(O)(OC 1~8 Alkyl) 2 , C.C.-C. 1~8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1 ~8 Alkyl)=CH(C 1~8 alkyl), C(C 1~8 Alkyl)=C(C 1~8 Alkyl) 2 , Si(OH) 3 , Si( C 1~8 Alkyl) 3 , Si(OH)(C 1~8 Alkyl) 2 , COC 1~8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1~8 Alkyl, SO 2 N(C 1~8 Alkyl) 2 ,SONHC 1~8 Al KILL, SON(C 1~8 Alkyl) 2 , CONH.C. 1~8 Alkyl, CON(C 1~8 Alkyl) 2 , N(C 1~8 Alki CONH(C 1~8 alkyl), N(C 1~8 Alkyl)CON(C 1~8 Alkyl) 2 , NHCONH(C1~8 Alki le), NHCON(C 1~8 Alkyl) 2 , N.H.C.O.N. 2 , N(C 1~8 Alkyl)SO 2 NH(C 1~8 alkyl), N(C 1 ~8 Alkyl)SO 2 N(C 1~8 Alkyl) 2 , NHSO 2 NH(C 1~8 alkyl), NH SO 2 N(C 1~8 Alki L) 2 , NHSO 2 NH 2 It is.

[0122] In certain embodiments, q is an integer greater than or equal to 0. In certain embodiments, q is an integer greater than or equal to 1. be.

[0123] In certain embodiments, for example, when q is greater than 2, A q is a group attached to ULM A 1 and A q are linked via a linker (L) structural unit.

[0124] In certain embodiments, for example, when q is 2, A q A 1 and, Combined with ULM It is based on

[0125] In certain embodiments, for example when q is 1, the linker group L has the structure -A 1 -And , and A 1 is a group attached to the ULM and ABM moieties.

[0126] In certain embodiments, the linker (L) has a general structure selected from the group consisting of: Contains groups represented by: -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxyl)-, -NR(CH 2 ) n -(Low-level Al COXYL)-OCH 2 -, -NR(CH 2 ) n -(lower alkoxyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -( Cycloalkyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(heterocycloalkyl)-, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heterocycloalkyl)-O-CH 2 -, -NR(C H 2 CH 2 O) n -Aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -( Cycloalkyl)-O-(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-a Reel-O-CH 2 -, -NR(CH2 CH 2 O) n -(lower alkyl)-NH-aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -( (lower alkyl)-O-aryl-CH 2 , -NR(CH 2 CH 2 O) n -Cycloalkyl-O-aryl-, -NR(CH 2 C H 2 O) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2)n-(cycloalkyl)-O-(heteroaryl) ring)-CH 2、 -NR(CH2CH2)n-(heterocycle)-(heterocycle)-CH 2 , -N(R1R2)-(heterocycle)-CH2; n may be 0 to 10; R may be H, lower alkyl; R1 and R2 may form a ring with the bond N.

[0127] In certain embodiments, the linker (L) has a general structure selected from the group consisting of: Contains groups represented by: -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-;

[0128] [ka]

[0129] During the ceremony, m, n, o, p, q, and r are each independently 0, 1, 2, 3, 4, 5, or 6; If the number is zero then there are no NO or OO bonds. R is H, methyl or ethyl; and X is H or F.

[0130] In certain embodiments, the linker (L) comprises a group represented by the following general structure:

[0131] [ka]

[0132] In the formula, m can be 2, 3, 4, or 5. In certain embodiments, the linker (L) has a general structure selected from the group consisting of: Including groups represented by:

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and X is H or F. be.

[0141] 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, 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, optionally substituted (poly) having about 2 to 4 ethylene glycol units Ethylene glycol or interspersed with optionally substituted O, N, S, P or Si atoms In certain embodiments, the linker is an aryl, fluoro, or aryl group. In certain embodiments, the alkyl group is substituted with a phenyl, benzyl, alkyl, alkylene, or heterocyclic group. The linker may be asymmetric or symmetric in configuration.

[0142] In any of the embodiments of the compounds described herein, the linker group may be any of the groups described herein. In one embodiment, the linker is from about 1 to about 12 Ethylene glycol unit, 1 to about 10 ethylene glycol units, about 2 to 6 ethylene glycol units Units, about 2 to 5 ethylene glycol units, about 2 to 4 ethylene glycol units The aryl group is a substituted or unsubstituted polyethylene glycol group.

[0143] In another embodiment, the present disclosure provides a compound comprising the ABM group described above, The group is attached to a target protein (e.g., the androgen receptor) or polypeptide and is ubiquitous. They are ubiquitinated by ubiquitin ligases and then chemically linked directly to ULM groups or ligated to the ubiquitin ligases. or ABM is alternatively a ULM' group, which is also chemically bonded via the anchor moiety L. a ubiquitin ligase binding moiety, which may be the same as or different from the ULM moiety described above. and L is linked to the ULM group via a linker moiety or directly, and L is a linker moiety as described above. may be present or absent, and may be a combination of ULM and ABM, or a pharma- ceutical acceptable salt thereof. Chemically (covalently) bound salts, enantiomers, stereoisomers, solvates, or polymorphs Combine.

[0144] In certain embodiments, ULM is 50 for E3 ubiquitin ligases with less than about 200 μM exhibit activity or bind to IC 50 have been described in the art, e.g., fluorescence polarization assays. The amount of the ion exchange reaction can be determined according to any method known in the art.

[0145] In certain additional embodiments, the bifunctional compounds described herein have a molecular weight of about 100, 50, 10, 1, Less than 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or about 100, 50, 10, 1, 0.5, 0.1, 0.05 , 0.01, 0.005, 0.001 μM or less, or about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 , IC<0.001nM 50 The activity of

[0146] The ULM and ABM groups can be linked via any group that is suitable and stable for the linker chemistry. In a preferred embodiment of the present disclosure, the linker is independently Preferably, the ULM and ABM groups are amides, esters, thioesters, keto groups, carbamers, etc. The ULM and ABM groups are covalently bonded through a urethane, carbon or ether. The ULM group is inserted on either side of the ubiquitin ligase to maximize binding of the ULM group and maximize its degradation. In certain preferred embodiments, the ABM group can be substituted with 1,2-diaminophenylamine to provide maximum binding to the target protein. In such embodiments, the linker may be an optionally substituted alkyl on the ULM and / or ABM groups, may be bonded to an alkylene, alkene or alkyne group, an aryl group or a heterocyclic group stomach.

[0147] Exemplary Androgen Binding Moieties (ABM) In another aspect, the present disclosure provides an AR binding moiety (ABM), which is In aspects and embodiments of the present invention, the linker and / or ULM is linked to will be done.

[0148] In any of the compounds described herein, the ABM binds to the androgen receptor (AR). A variety of androgen receptor binding compounds have been reported in the literature. Testosterone, dihydrotestosterone, and metribolone (methyltriethylamine) also known as noron or R1881), as well as e.g. bicalutamide, enzalutamide androgen derivatives, such as non-steroidal compounds such as acetaminophen, ... If you are a manufacturer, these androgen receptor binding compounds are ABMs in PROTAC compounds. The authors will recognize that there are a number of documents that may be of use as part of the It is not clear, but GF 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 Po utiainen et. al, J. Med. Chem. 2012, 55, 6316 - 6327 A. Pepe et. al, J. Med. Che m. 2013, 56, 8280 - 8297; ME Jung et al, J. Med. Chem. 2010, 53, 2779-2796 No. 6,393,636, which are incorporated herein by reference.

[0149] In certain embodiments, the ABM is selected from, but not limited to, the structures shown below: where the dashed line indicates the linker moiety or point of attachment of ULM:

[0150] [ka]

[0151] During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently At least one of H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (optionally substituted Linear or branched chain. For example, one or more halo, C 1~6 Optionally substituted with alkoxyl, C 1~6 Alkoxy (straight or branched chain, optionally substituted, e.g., by one or more halo) (optionally substituted), C 2~6 Alkenyl, C 2~6 Alkynyl, or CF 3 is replaced by; 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, SO 2 , Heteroa reel, or aryl; Q is a 3-6 membered ring with 0-4 heteroatoms, optionally with 0-6 R Q Each R Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally substituted; e.g., one or more halo , C 1~6 alkoxyl optionally substituted), halogen, C 1~6 Alkoxy or or two R Q The groups are 3-8 membered rings containing 0-2 heteroatoms together 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 alkoxyl optionally substituted), halogen, C 1 ~6 alkoxy, cyclic, heterocyclic or R 1 , R 2 are the atoms to which they are bonded. Forming a 3-8 membered ring system containing 0-2 heteroatoms; W 2 is a bond, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, aryl, heteroaryl, fatty cyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each of which is optionally 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 or more Optionally replaced by F above), -OR W2A , C 3-6 Cycloalkyl, C 4-6Cycloheteroalkyl , C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted), substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or is aryl, OC 1-3 Alkyl (optionally substituted), OH, NH 2 , N.R. Y1 R Y2 , CN; and Beauty R W2A , H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1~3 It is substituted by alkyl.

[0152] In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0153] In certain embodiments, W 1 teeth,

[0154] [ka]

[0155] In the formula, each R 22 are independently halo, H, optionally substituted alkyl, haloalkyl, cyano, or nitro; and Each R 23 are independently H, halo, and CF 3 , optionally substituted alkyl, alkoxy, haloalkoxy The radicals are aryl, cyano, or nitro.

[0156] In certain additional embodiments, W 1 is selected from the group consisting of:

[0157] [ka]

[0158] In certain embodiments, the ABM comprises a structure selected from the following structures shown below: During the ceremony,

[0159] [ka]

[0160] indicates the attachment point of the linker or ULM:

[0161] [ka]

[0162] During the ceremony: R Q2 is H, halogen, CH 3 or CF 3 is; R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight and branched chain) , optionally one or more halo, C 1~6 substituted with alkoxyl), C 1~6 Alkoxyl (straight chain , branched and optionally substituted with one or more halo), C 2~6 Alkenyl, C 2~6 Alkini le, or CF 3 is; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2, C.R. Y1 R Y2 , C=O, heteroaryl, or is aryl; R Y1 , R Y2 are each independently H or C 1~6 Alkyl (straight or branched, optionally with one or more Haro, C 1~6 alkoxy, cyclic or heterocyclic; and R Q are independently H, C 1 -C 6 Alkyl (straight or branched chain, optionally with one or more halo, Or C 1~6 substituted by alkoxyl) or two R Q But they are combined Together with the atom to be bonded, it forms a 3-8 membered ring system containing 0-2 heteroatoms.

[0163] In certain embodiments, each R Q are independently H or CH 3 In another embodiment, R Q3 teeth , CN.

[0164] In certain embodiments, the ABM comprises a structure selected from the following structures shown below: During the ceremony,

[0165] [ka]

[0166] indicates the attachment point of the linker or ULM:

[0167] [ka]

[0168] During the ceremony: R Q2 H, halogen, CN, CH3 or CF 3 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 with 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 CF 3 is; Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, heteroaryl, or is aryl; and R Y1 , R Y2 are each independently H or C 1~6 Alkyl (straight or branched, optionally with one or more Haro, C 1~6 alkoxy, cyclic or heterocyclic; and X is N or C.

[0169] In certain embodiments, R Q3 is CN. In certain additional embodiments, the ABM comprises the structure shown below, where the dashed line represents the linker: -Indicate the attachment point of the moiety or ULM or CLM:

[0170] [ka]

[0171] [ka]

[0172] Each R 22 are independently H or -CN; Each R 23 are independently H, halo, and C 1 -C 6 Alkyl (optionally substituted straight or branched chain), C 1 - C 6 Alkoxy, or -CF 3 is; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C 1 -C 6 Heteroaryl, or C 1 -C 6 is aryl; R 1 , R 2 are each independently H or C 1 ~ 6 Alkyl (optionally substituted straight or branched chain; e.g. If one or more halo, or C 1~6 alkoxyl optionally substituted; W 2 is a bond, C 1~6 Aryl, C 1 ~ 6 Heteroaryl, C 1~6 Alicyclic, or C 1 - 6 Heterocyclic , biheterocyclic, biaryl, or biheteroaryl, each of which is optionally 1 to 10 R W2 To is replaced by; and Each R W2 is independently H or halo; and

[0173] [ka]

[0174] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific. In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0175] In certain additional embodiments, W 1 is selected from the group consisting of:

[0176] [ka]

[0177] In any aspect or embodiment described herein, W 2 is selected from the group consisting of Selected:

[0178] [ka]

[0179] In certain embodiments, the ABM is selected from, but not limited to, the structures shown below: where the dashed line indicates the linker moiety or point of attachment of ULM:

[0180] [ka]

[0181] [ka]

[0182] Each R 22 are independently H or -CN; Each R 23are independently H, halo, or -CF 3 is; Y 1 , Y 2 each independently is 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 has one, two or three R W2 is replaced by; and Each R W2 are independently H, halo, and C 1~6 Alkyl (optionally substituted with one or more F), OC 1~ 3 Alkyl (optionally substituted with one or more -F).

[0183] In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0184] In certain additional embodiments, W 1 is selected from the group consisting of:

[0185] [ka]

[0186] In certain additional embodiments, W 2 teeth

[0187] [ka]

[0188] is selected from the group consisting of: In certain embodiments, the ABM is selected from the group consisting of:

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] [ka]

[0195] In certain embodiments, the ABM comprises the following structure:

[0196] [ka]

[0197] In the formula, W 1 are aryl or heteroaryl, each independently representing one or more of H, halo, doxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight or branched chain, optionally with one or more halides) Ro, C 1~6 substituted with alkoxyl), C 1~6 Alkoxy (linear or branched, optionally 1 (substituted with one or more halo), C 2~6 Alkenyl, C 2~6 Alkynyl, or CF 3 By 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, SO 2、 Heteroa reel, or aryl; Q is a 4-membered alicyclic ring with 0-2 heteroatoms, optionally with 0-6 R Q is replaced by Each R Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more halo, C 1~6 Arco or two R Q Groups, together with the atoms to which they are attached, are Forming a 3-8 membered ring system containing 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 aryl, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl; Each optionally contains 1, 2, or 3 R W2 is replaced by; and Each R W2 are independently H, halo, and C 1-6 Alkyl (straight or branched, optionally with one or more F) (Replaced), C 1-6Heteroalkyl (straight chain, branched, optionally substituted), -OR W2A O.C. 1-3 Alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 Sik heteroalkyl (optionally substituted), C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic Formula (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; and R W2A , H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1~3 It is substituted by alkyl.

[0198] In an additional aspect, the present disclosure provides an androgen receptor binding compound comprising the structure: Provide:

[0199] [ka]

[0200] In the formula, W 1 is aryl, heteroaryl, bicyclic or biheterocyclic; each independently being one or more of H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl ( Straight or branched chain, optionally with one or more halo, C 1~6 substituted with alkoxyl), C1~6 Al Coxyl (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 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, SO 2 , He is heteroaryl, or aryl; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally ~6 R Q Each R Q are independently H, C 1~6 Alkyl (straight or branched chain, optionally with one or more Upper halo, C 1~6 substituted with alkoxyl) or two R Q The groups are forms, together with the atom to be bonded, 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 chain, branched chain, One or more halos, C 1~6 alkoxyl), or R 1 , R 2 That together with the atom to which they are attached form a 3-8 membered ring system containing 0-2 heteroatoms); W 2 is a bond, C 1~6 Alkyl, C1~6 Heteroalkyl, O, C 1~6 Alicyclic, heterocyclic, aryl, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl; each optionally containing 1, 2, or 3 R W2 is replaced by; Each R W2 are independently H, halo, and C 1-6 Alkyl (straight or branched chain, optionally with one or more F substituted by), C 1-6 Heteroalkyl (straight chain, branched, optionally substituted), -OR W2A , O.C. 1-3 Alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4- 6 Cycloheteroalkyl, C 1-6 Alkyl (optionally substituted), C 1-6 Alicyclic (optionally substituted heterocyclic (optionally substituted), aryl (optionally substituted), or heterocyclic bicyclic heteroaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH 2 , N R Y1 R Y2 , CN; and R W2A , H, C 1~6 Alkyl (straight chain, branched chain), or C 1~6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1~3 It is substituted by alkyl.

[0201] In certain embodiments, the androgen receptor binding moiety has the structure:

[0202] [ka]

[0203] [ka]

[0204] Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF 3 is; Y 3 is a bond or O; Q is a 4-membered ring, optionally containing 0 to 4 R Q Each R Q are independently H or methyl ; Y4 is a bond or NH; Y5 is a bond, C=O, or C=S; 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 one or two heptanes. A 6-membered alicyclic ring having a hetero atom or a 5-membered ring having one, two or three hetero atoms is an aromatic ring.

[0205] In certain additional embodiments, W 2 teeth,

[0206] [ka]

[0207] In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0208] In certain additional embodiments, W 1 teeth,

[0209] [ka]

[0210] In certain embodiments, the androgen binding moiety has the structure:

[0211] [ka]

[0212] In the formula, 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 , C=O; Q is a 5-membered aromatic ring having 1 or 2 heteroatoms; R Y1 , R Y2 are independently H, C 1-6 is alkyl (straight chain, branched chain); W 2 is a bond, aryl, or heteroaryl, each of which may optionally have 1, 2, or 3 occurrences R W2 is replaced by; and Each R W2 are independently H, halo, and C 1~6 Alkyl (optionally substituted with one or more F), OC 1~ 3 Alkyl (optionally substituted with one or more -F).

[0213] In any of the embodiments described herein, W 2may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0214] In certain embodiments, W 1 teeth,

[0215] [ka]

[0216] In the formula, each R 22 is independently halo or CN; and Each R 23 are independently H or halo.

[0217] In certain additional embodiments, W 1 is selected from the group consisting of:

[0218] [ka]

[0219] In certain additional embodiments, Q is

[0220] [ka]

[0221] In certain additional embodiments, W 2 teeth

[0222] [ka]

[0223] In certain additional embodiments, (Y 3 ) 0-5 teeth

[0224] [ka]

[0225] In certain embodiments, the ABM is selected from, but not limited to, the structures shown below: where the dashed line indicates the linker moiety or point of attachment of ULM:

[0226] [ka]

[0227] [ka]

[0228] Each R 22 are independently H or -CN; Each R 23 are independently H, halo, or -CF 3 is; Y 1 , Y 2 each independently is 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 SO 2 Yes r; 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 has 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) is replaced).

[0229] In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0230] In certain additional embodiments, W 1 is selected from the group consisting of:

[0231] [ka]

[0232] In certain further embodiments, W2 is

[0233] [ka]

[0234] In certain embodiments, the ABM comprises the structure shown below, where the dashed line represents the linker moiety: Or to indicate the attachment points of ULM or CLM:

[0235] [ka]

[0236] [ka]

[0237] Each R 22 are independently H or -CN; Each R 23are independently H, halo, or -CF 3 is; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 is a bond, C=O, C 1 -C 6 Heteroaryl, or C 1 -C 6 is aryl; R 1 , R 2 are each independently H or C 1 -C 6 Alkyl (straight or branched chain with one or more halides) B or C 1-6 alkoxyl optionally substituted; W 2 is a bond, C 1~6 Aryl, C 1 - 6 Heteroaryl, C 1~6 Alicyclic, or C 1 - 6 Heterocycle Formula, each of which is an arbitrary number of 1 to 10 R W2 is replaced by; and Each R W2 is independently H or halo; and

[0238] [ka]

[0239] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific. In any of the embodiments described herein, W 2 may contain one or more ULM groups or is covalently attached to a CLM group or one or more UL groups as described herein. It is covalently attached to a linker which is attached to the M group or the CLM group.

[0240] In certain additional embodiments, W 1 is selected from the group consisting of:

[0241] [ka]

[0242] In certain additional embodiments, W 2 teeth,

[0243] [ka]

[0244] 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-tetramethylcyclohexyl tributyl]pyridazine-3-carboxamide; Trans tert-butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl]carbamate; trans 4-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl [tributyl]benzamide; Trans 5-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl tributyl]pyrazine-2-carboxamide; Trans 2-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl tributyl]pyrimidine-5-carboxamide; 4-Methoxy-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Thicyclobutyl]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-tetramethylcyclohexyl tributyl]pyridine-3-carboxamide; trans 4-[(5-hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanopheno (oxy)-2,2,4,4-tetramethylcyclobutyl]benzamide; and Trans tert-Butyl 2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran (tetramethylcyclobutyl)carbamoyl}phenyl)aminopentyl}oxy)acetate; and N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbenzene Zuamid.

[0245] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen; They may be fully saturated, partially unsaturated, or aromatic, and may include aryl groups, alkyl groups, Includes alkenyl and alkynyl groups.

[0246] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. 0 of The range of carbon atoms included means that the carbon is either absent or replaced with H. Therefore, C 0 -C 6The carbon atom range includes 1, 2, 3, 4, 5 and 6 carbon atoms, and C 0 has an H instead of a carbon. The term refers to one or more substituents (as defined in the present application) at any carbon (or nitrogen) position on the molecule within the context. Up to five independent substituents, preferably up to three substituents, on the moieties in the compounds according to the A group, often containing one or two substituents, may itself contain further substituted substituents. ) are meant to be independent (i.e., when there are multiple substituents, each substituent is a separate substituent). (independent of substituents) and the substituents are hydroxyl, thiol, carboxyl , cyano (C≡N), nitro (NO 2 ), halogen (especially alkyl, especially trifluoromethyl methyl groups such as ethyl, preferably 1, 2 or 3 halogens on the methyl group, alkyl groups (preferably C 1 -C 10 , more preferably C 1 - 6 ), aryl (especially phenyl and substituted phenyl, e.g. benzyl or benzoyl), alkoxy groups (preferably C 1 -C 6 Alkyl or Aryl phenyl and substituted phenyl), thioethers (C 1 -C 6 Alkyl or Aryl ), acyl (preferably C 1 -C 6 acyl), ester or thioester (preferably C 1 -C 6 alkyl or aryl) and an alkylene ester (the bond is not an ester functional group) , on the alkylene group, preferably C 1 -C 6 substituted with alkyl or aryl groups; Preferably C 1 -C 6 Alkyl or aryl containing, halogen (preferably F or Cl) amines (including 5- or 6-membered cyclic alkyleneamines, C 1 -C 6 Alkylamine or C 1 -C 6 Further included are dialkylamines, where the alkyl groups are substituted with one or two hydroxyl groups. ), or optionally substituted -N(C 0 -C 6 Alkyl)C(O)(OC 1 -C 6 Alkyl) group (polyethylene The ethylene glycol chain may be optionally substituted with one halogen, preferably chlorine, substituent. (an alkyl group containing an alkyl group is further bonded), hydrazine, amide, which is preferably Or two C's 1 -C 6 Alkyl group (1 or 2 C 1 -C 6 Carboxylic acid optionally substituted with alkyl groups alkanols (preferably C 1 -C 6 alkyl or aryl), or Lactic acid (preferably C 1 -C 6 alkyl or aryl). Substituents according to the present disclosure include, for example, -SiR 1 R 2 R 3 group, where R 1 and R 2 Each of is as otherwise described herein, and R 3 is H or C 1 -C 6 The alkyl group is In the vein, R is preferable. 1 , R 2 , R 3is C 1 -C 3 Alkyl group (isopropyl or t-butyl group) Each of the above groups may be directly attached to the substituted moiety, or The substituents are optionally substituted (CH 2 ) m - or optionally substituted -(OCH 2 ) m -,-( OCH 2 CH 2 ) m -or-(CH 2 CH 2 O) m A substituted moiety (preferably aryl or In the case of a heteroaryl moiety, they may be bonded to any of the above-mentioned substituents. The alkylene group may be substituted with one or more of the following: -(CH 2 ) m -or-(CH 2 ) n -Base or example Other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group are halogen or C 1 -C 6 (Preferred C 1 -C 3 ) alkyl groups, which optionally contain one or two hydroxyl groups, one or or two ether groups (OC 1 -C 6 groups), up to three halo groups (preferably F), or and optionally substituted amides, which may be substituted with amino acid side chains as otherwise described herein. (preferably a carboxamide substituted as described above) or a urethane group (often One or two C's 0 -C 6 and alkyl substituents, which may also be further substituted. In certain embodiments, an alkylene group (often a single methylene group) can have one or more is replaced by two arbitrary C 1 -C 6 Alkyl groups, preferably C 1 -C 4 Alkyl groups, in most cases and optionally substituted with a methyl or O-methyl group, or an amino acid side chain as otherwise described herein. In the present disclosure, moieties in a molecule may optionally have up to five substituents, preferably up to three. In most cases, the substituted moieties in the present disclosure may be one or more or two substituents.

[0247] The term "substituted," where each substituent is independent of any other substituent, means that Within the context of the use of C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, amide, carbo Sulfone, keto, carboxy, including oxamide, sulfonamide, 1 -C 6 Ester (oxy ester or carbonyl ester), C 1 -C 6 Keto, urethane-OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 , nitro, cyano, and amine (especially C 1 -C 6 Alkylene-NR 1 R 2 , Monoma Orji-C 1 -C 6 Alkyl-substituted amines, optionally with one or two hydroxyl groups. Each of these groups is also intended to mean the groups represented by the formula (including those which may be optionally substituted) unless otherwise indicated. Unless otherwise specified within the context, the substituents may contain from 1 to 6 carbon atoms. Depending on the context of use, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m - (wherein m and n are, in context, 1, 2, 3, 4, 5 or 6), -S- , -S(O)-, SO 2 - or -NH-C(O)-NH-, -(CH 2 ) n OH, -(CH 2 ) n SH, -(CH 2 ) n COOH, C 1 -C 6 Al Kill, -(CH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n O.C.(O)-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)O-(C 1 -C 6 alkyl), -(CH 2 ) n NHC(O)-R 1 , -(CH 2 ) n C(O)-NR 1 R 2 , -( OCH 2 ) n OH, -(CH 2 O) n COOH, C 1 -C 6 Alkyl, -(OCH 2 ) n O-(C 1 -C 6alkyl), -(CH 2 O) n C(O)-( C 1 -C 6 Alkyl), -(OCH 2 ) n NHC(O)-R 1 , -(CH 2 O) n C(O)-NR 1 R 2 , -S(O) 2 -R S , -S(O)-R S (R S teeth , C 1 -C 6 Alkyl or -(CH 2 ) m -NR 1 R 2 group), NO 2 , CN or halogens (F, Cl, Br, I , preferably F or Cl). 1 and R 2 are H or is C 1 -C 6 Alkyl groups (containing one or two hydroxyl groups or up to three halogen groups, preferably The term "substituted" also means that the substituted group is optionally substituted, preferably with fluorine. Within the chemical context of the compound being studied and the substituents used, optionally substituted aryl groups are also or heteroaryl group or an optionally substituted heteroaryl group as otherwise described herein. An alkylene group is also intended to mean a cyclic group, as otherwise disclosed herein. Preferably, optionally substituted C 1 -C 6 Alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl, and the chiral center is provided herein), the side chains of amino acid groups as otherwise described herein, amide groups as described above, or urethane groups, OC(O)-NR 1 R 2 A group, wherein R 1 and R 2 is described elsewhere herein. Although the alkyl groups may be substituted as described above, many other groups may also be used as substituents. Various optionally substituted moieties may have more than two substituents, preferably three or fewer substituents, and preferably Preferably, the compound may be substituted with one or two substituents. If a substitution is required (mainly because of valence) but no substitution is indicated, the context of the substitution Unless otherwise indicated in the specification, the substituents are assumed or understood to be H. Please be careful.

[0248] Exemplary AR-PROTAC Compounds As mentioned above, in certain embodiments, the present invention relates to a compound comprising at least one ABM group as described herein. , a linker, and at least one ULM (or CLM) group. Provided is an AC compound.

[0249] In certain embodiments, the compounds are compounds 1-625 (i.e., compounds shown in Figures 2, 3, 4, and 5, respectively). , 6, and 7 in Tables 2, 3, 4, 5, 6, and 7) and their The compound is selected from the group consisting of salts and polymorphs.

[0250] In additional embodiments, the compound is selected from the group consisting of: 4-{3-[4- ({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindole-4-yl]-4,7,10-trioxa-1-azadodecane-12-yl}oxy Phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl} -2-(trifluoromethyl)benzonitrile (1); 4-(3-{4-[2-(2-{[2-(2,6-diox Isopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl 4,4-dimethyl-5-oxo-2-sulfanilic acid 4-{3-[ 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -Isoindol-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecane-18 -yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazoline 4-[3-(4-{2-[2-(2 -{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-i soindol-4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)-4,4-dimethyl -5-Oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl )benzonitrile (4); 4-[3-(4-{3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl )-1,3-Dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)eth 4,4-dimethyl-5-oxo-2-sulfanylideneimidazo Lysin-1-yl]-2-(trifluoromethyl)benzonitrile (5); 4-{3-[4-({1-[2- (2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindo (4-yl)-4,7,10-trioxa-1-azatetradecane-14-yl)oxy)phenyl 4,4-Dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-( Trifluoromethyl)benzonitrile (6); 4-{3-[4-({1-[2-(2,6-dioxopiperidinyl 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10 -Trioxa-1-azatridecan-13-yl}oxy)phenyl]-4,4-dimethyl-5-o xo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzo Nitrile (7); 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1,3- Dioxo-2,3-dihydro-1H-isoindol-4-yl}-4,7,10-trioxa-1-a (Zadodecane-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanilide 4-(3-(phenylenediimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (8); 4-[(1-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydrazine 1H-isoindol-4-yl}-4,7,10-trioxa-1-azadodecane-12-yl Oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine-1 -yl)-2-(trifluoromethyl)benzonitrile (9); 4-[3-(4-{3-[3-(2-{[2-( 2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindo (4,4-dimethyl-5-phenyl)-4,4-dimethyl-5-phenyl-4-yl)amino)ethoxy)propoxy)propoxy)phenyl) -Oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzyl Benzonitrile (10); 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxopyridine 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]- 4,7,10-Trioxa-1-azatridecan-13-yl}oxy)phenyl]-5-oxo-2- Sulfanilideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile ( 11); 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)oxy]phenyl}furan phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]- 2-(Trifluoromethyl)benzonitrile (12); 4-{[5-(3-{[2-(2,6-dioxopiperidine Indol-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino }propoxy)pentyl]oxy}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl]benzamide (13); 4-{3-[4-({1-[2-(2,6-di Oxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl (1,4,7,10-tetraoxatridecan-13-yl)oxy)phenyl]-4,4-dimethyl -5-Oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl )benzonitrile (14); 6-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo So-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)piperazin-1-yl ]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]pyridine-3-carboxamide (15); 6-{4-[2-(3-{[2-(2,6-dioxopiperi Indol-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino }propoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyano (2,2,4,4-Tetramethylcyclobutyl)pyridine-3-carboxamide (16); 4 -(3-{4-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro 1H-isoindol-4-yl]oxy}ethyl)-1H-1,3-benzodiazole-5- 4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine-1-yl 4-{[5-(3-{[2-(2,6-dioxoyl)benzonitrile (17); Isopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl 1r,3r)-3-(3-chloro-N-[(1r,3r)-propoxy]amino}-3-fluoro-N-[(1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (18); 6-[4 -(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-i [(1r,3r)-3-(3-chloro-4-yl)oxy]ethyl)piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-yl)oxy]ethyl]piperazin-1-yl] (4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide Voxamide (19); 6-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-diox So-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl)piperazin-1-yl ]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]pyridine-3-carboxamide (20); 6-(4-{3-[2-(2,6-dioxopiperidine -3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]propyl}piperidine 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraazine-1-yl tetramethylcyclobutyl]pyridine-3-carboxamide (21); 6-{4-[2-(2-{[2-(2,6 -Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4 -yl]oxy}ethoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide 4-{4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3 -Dihydro-1H-isoindol-4-yl]oxy}ethyl)piperazin-1-yl]butyl }-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetrahydrofuran tetramethylcyclobutyl]benzamide (23); 6-{4-[2-(3-{[2-(2,6-dioxopiperidine Indol-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amino }propoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyano (2,2,4,4-tetramethylcyclobutyl)pyridine-3-carboxamide (24); 6 -{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-diox So-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)ethyl]piperazine {N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraphenyl-1-yl] Methylcyclobutyl]pyridine-3-carboxamide (25); 4-(6-{4-[2-(2,6-diox Isopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl 4-Cyano-3-(trifluoromethyl)piperazin-1-yl}hexyl)-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)piperazin-1-yl]hexyl] 4-{3-[4-(phenyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (26); -(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-4-yl]amino}propyl)piperazin-1-yl]propyl}-N-[(1r ,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyano 4-[5-(3-{[2-(2,6-dioxopiperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pe N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl cyclobutyl]benzamide (28); 6-{4-[2-(3-{[2-(2,6-dioxopiperidine-3- yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]a 3-(3-chloro-4-cyano)-N-[(1r,3r)-3-(amino}propoxy)ethyl]piperazin-1-yl] (2,2,4,4-tetramethylcyclobutyl)pyridine-3-carboxamide (29) 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3- Dihydro-1H-isoindol-5-yl}oxy)ethyl]piperazin-1-yl}butyl -N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]benzamide (30); 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine-3- yl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)ethyl]piperidine 3-(3-chloro-4-cyanophenoxy)-2,2,4-lazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-Tetramethylcyclobutyl]benzamide (31); 4-{4-[4-(2-{[2-(2,6-diox Sopiperidin-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoin N-[(1r,3r)-3-(3-(2-phenyl-4-yl)amino]ethyl)piperazin-1-yl]butyl] Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (32) 6-{4-[5-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro 1r-1H-isoindol-4-yl}oxy)pentyl]piperazin-1-yl}-N-[(1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine Zine-3-carboxamide (33); 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine -3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}oxy)e butyl]piperazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy 6-{4-[5-({2-[(3S)- 2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindole -5-yl}oxy)pentyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (35); 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo xo-2,3-dihydro-1H-isoindol-4-yl]piperazin-1-yl}butyl)-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-{4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-5- Fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl 1r,3r)piperazin-1-yl]butyl}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl]benzamide (37); 6-(4-{6-[2-(2,6-di xopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl] hexyl}piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-Tetramethylcyclobutyl]pyridine-3-carboxamide (38); 4-(4-{4- [2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxo-2,3-dihydr 1R,3R)-3-(1H-isoindol-5-yl]piperazin-1-yl}butyl)-N-[(1R,3R)-3-(3 -chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (3 9); 4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro N-[(1r,3r)-3H-isoindol-5-yl]piperazin-1-yl}hexyl -(3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide 6-{4-[5-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo -2,3-Dihydro-1H-isoindol-5-yl}oxy)pentyl]piperazin-1-yl }-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]pyridine-3-carboxamide (41); 6-[4-(5-{[2-(2,6-dioxopiperidine -3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentan 1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclo[(1r,3r)piperazin-1-yl] butyl]pyridine-3-carboxamide (42); 4-[4-(5-{[2-(2,6-dioxopiperidine -3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentan 1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclo[(1r,3r)piperazin-1-yl] butyl]benzamide (43); 4-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}pene (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl} (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl 4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)- 6-Fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl]benzamide (46); 4-(4-{[2-(2,6-dioxopiperidinyl 1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}butyrate (1r,3r)-N-[(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl] 4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo- xo-2,3-dihydro-1H-isoindol-4-yl]oxy}pentyl)-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzaldehyde 4-[3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-diamide (48); Hydro-1H-isoindol-4-yl]oxy}ethoxy)propyl]-N-[(1r,3r)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide ( 49); 4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydr 1R,3R)-3-(3-chloro-1H-isoindol-4-yl]oxy}ethoxy)butyl]-N-[(1R,3R)-3-(3-chloro-1H-isoindol-4-yl]oxy}ethoxy)butyl] (4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (50); 4-[5-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H -isoindol-4-yl]oxy}ethoxy)pentyl]-N-[(1r,3r)-3-(3-chloro -4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (51); 4-[ 6-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-i N-[(1r,3r)-3-(3-chloro-4-isoindol-4-yl]oxy}ethoxy)hexyl]- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (52); N-[(2R) -1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl 4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-diyl] Hydro-1H-isoindol-4-yl]amino}butyl)piperazin-1-yl]methyl}-1 H-Pyrazole-3-carboxamide (53); 4-(4-{6-[2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]hexyl}piperidine (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraazine-1-yl 4-(3-{[2-(2,6-dioxopiperidine-3-yl]phenyl)-2-methylcyclobutyl]benzamide (54); -yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}propyl) -N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]benzamide (55); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyridinyl] 3-[(4-[(2-(2,6-dioxopiperidine-1-yl)propan-2-yl]-5-[( ... 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine- 1-yl}propoxy)methyl]-1H-pyrazole-3-carboxamide (56); 4-[4-(3-{[ 2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo 1H-1,2,3-triazol-1-yl]-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (57); 6-[4-(6-{[2 -(2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro -1H-isoindol-5-yl]amino}hexyl)piperazin-1-yl]-N-[(1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine N-3-carboxamide (58); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H- Pyrazol-1-yl]propan-2-yl]-5-({3-[4-(2-{[2-(2,6-dioxopipene Lysine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amine (ethyl)piperazin-1-yl]propoxy}methyl)-1H-pyrazole-3-carboxamide 4-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo- ... ,3-Dihydro-1H-isoindol-4-yl]oxy}pentyl)-1H-1,2,3-triazo [(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl] amide (61); 6-{4-[2-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3 -Dioxo-2,3-dihydro-1H-isoindol-4-yl}butoxy)ethyl]piperazine {N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraphenyl-1-yl] 6-{4-[2-(4-{2-[(3R)-2, 6-Dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole -N-[(1r,3r)-3-(3-chloro-4-yl)butoxy)ethyl]piperazin-1-yl] -Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide 6-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo xo-2,3-dihydro-1H-isoindol-4-yl}pentyl)oxy]ethyl}piperazine N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraphenyl-1-yl] 6-(4-{2-[(5-{2-[(3R)-2 ,6-Dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole (1r,3r)-3-(3-chloro-4-yl)-N-[(1r,3r)-3-(phenyl-4-yl)pentyl]oxy]ethyl]piperazin-1-yl (4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide Voxamide (65); 4-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1, 3-Dioxo-2,3-dihydro-1H-isoindol-4-yl}pentyl)oxy]ethyl} Piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl]benzamide (66); 4-(4-{2-[(5-{2-[(3R)-2,6-di Oxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4 -yl}pentyl)oxy]ethyl}piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (67); 4-(4 -{6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-iso indol-5-yl]hexyl}piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4 -Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (68); 4-(3- {4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-i Soindol-5-yl]piperazin-1-yl}propyl)-N-[(1r,3r)-3-(3-chloroisoindol-5-yl]piperazin-1-yl]propyl] -4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (69); 4-[ 6-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1 H-isoindol-5-yl}piperazin-1-yl)hexyl]-N-[(1r,3r)-3-[4-cyano Ano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]ben amide (70); 4-[6-(4-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo -2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl)hexyl]-N-[ (1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethyl 6-[4-(6-{[2-(2,6-dioxopiperidine-3-yl]phenylcyclobutyl]benzamide (71); (yl)-5-fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy hexyl)piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-Tetramethylcyclobutyl]pyridine-3-carboxamide (72); 6-[4-(6- {[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydr 1R,3R-1H-isoindol-5-yl]oxy}hexyl)piperazin-1-yl]-N-[(1R,3R )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine 4-[6-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl yl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}piperazin-1-yl) Hexyl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4 ,4-tetramethylcyclobutyl]benzamide (74); and 4-[6-(4-{2-[(3R)-2,6- Dioxopiperidin-3-yl]-3-oxo-2,3-dihydro-1H-isoindole-5- 4-Cyano-3-(trifluoromethyl)piperazin-1-yl)hexyl N-((1r,3 methyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)benzamide (75); r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2 -(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)amino )hexyl)piperazin-1-yl)nicotinamide (76); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)-6-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotine Amide (78); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 2-(4-(2-((5-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(( 5-(2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl) N-((1r,3r)-3-(3-chloro-4-cyano)-2,4-dihydro-2,5-dihydro-1,6-dihydro-2,7-dihydro-1,8-dihydro-2,9-dihydro-1,9-dihydro-2,1-dihydro-1,1-dihydro-1,2-dihydro-1,3-dihydro-2,1-dihydro-1,2-dihydro-1,3-dihydro-1,4-di Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidine (1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl)benzamide (81); 4-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl)- ... N-((indolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)hexyl)benzamide (82); 1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((1R, 4R)-5-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Oxy)pentyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)nicotinamide (83); N- ((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- (5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)pentane N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)piperazin-1-yl)benzamide (84); 1-(5-((2-(2,6-dioxopiperidin-3-yl)-2,2,4,4-tetramethylcyclobutyl )-1,3-Dioxoisoindolin-5-yl)oxy)pentyl)-1,2,3,6-tetrahydropyridin N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(5-(4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo N-((1r,3r)-isoindolin-5-yl)piperazin-1-yl)pentyl)benzamide (86); 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-((R )-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl )pentyl)benzamide (87); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro- 1-Oxoisoindolin-5-yl)piperazin-1-yl)hexyl)benzamide (88); N-((1 r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4- (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-1-pyridyl)hexyl)benzamide (89); 2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2-(2,6-dioxopiperidin-3-yl )-6-Fluoro-1-oxoisoindolin-5-yl)oxy)hexyl)piperazin-1-yl)di Cotinamide (90); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (cyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin N-((1r,3r)-3-((1r,3r)-2-(propyl)-2-pyridin-5-yl)oxy)propyl)piperazin-1-yl)benzamide (91); 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4-pyrazine-1-yl)benzamide (92); ,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo Isoindolin-5-yl)piperidin-1-yl)hexyl)benzamide (93); N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6- Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)hexa N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran (94); 4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxophenyl)-4-(tetramethylcyclobutyl) soindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)pentyl)benzamide (95); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(5-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)phenyl N-((1r,3r)-3-(3-chloro-4-cyanophenyl)piperazin-1-yl)nicotinamide (96); (2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)butyl Benzamide (97); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylbenzamide (cyclobutyl)-4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole N-((1r,3r)-5-yl)-3,6-dihydropyridin-1(2H)-yl)pentyl)benzamide (98); -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(5-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl )piperidin-4-yl)benzamide (99); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1- Oxoisoindolin-5-yl)oxy)pentyl)-1H-1,2,3-triazol-1-yl)benz Amide (100); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(6-((1S,4S)-5-(2-((R)-2,6-dioxopiperidin-3-yl)-1-oxoisopropyl) 2,5-diazabicyclo[2.2.1]heptan-2-yl)hexyl)benzamide ( 101); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)) N-((1r,3r)-3-(3-oxy)pentyl)-1H-1,2,3-triazol-1-yl)nicotinamide (102); -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoyl N-isoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)butyl)benzamide (104); -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy) Piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)benzamide (105); N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3 -(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)a N-((1r zetidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)benzamide (106); ,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-( 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1H-1,2,3 -triazol-4-yl)ethyl)piperazin-1-yl)nicotinamide (107); N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-(1-(2-(2 ,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1H-1,2,3-triazolidine N-((1r,3r)-3-(3-chlorophenyl)propyl)piperazin-1-yl)nicotinamide (108); 4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)hexa N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl)nicotinamide (109); tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (110); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxa N-((1r,3r)-3-(3-chloro-4-cyano)propyl)piperazin-1-yl)nicotinamide (111); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(5-((2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl ) Nicotinamide (112); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-6-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)oxy)propyl)piperidin-4-yl)nicotinamide (113); N-((1r, 3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutene (yl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl N-((1r,3r)-3-(3-chlorophenyl)oxy)pentyl)piperazin-1-yl)nicotinamide (114); -4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-((2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperazine-1- N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran (115); 4-((3S)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-diphenyl ether Oxoisoindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)piperazine-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrachlorobenzamide (116); Methylcyclobutyl)-6-(4-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl Indolin-5-yl)oxy)azetidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (118); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)propyl)nicotinamide (120); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)nicotinamide (12 2); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pi N-((1r,3r)-3-(3-chloro-4-cyanophenyl)-2-pyridin-1-yl)butyl)nicotinamide (123); (2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butyl)nicotinamide ( 124); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin N-((1r,3r)-3-(4-cyano-3-methylphenyl)-1-pyrazine-1-yl)butyl)nicotinamide (125); (2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinic acid N-((1r,3r)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclohexyl amide (126); butyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)oxy)pentyl)piperazin-1-yl)nicotinamide (127); N-((1r,3r)-3-(3-chlorophenyl)-2-pyridyl) 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(3-((2-(2,6-dihydro- 1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotine Amide (129); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline N-((1r,3r)-3-(3-chloro-5-yl)oxy)piperidin-1-yl)butyl)nicotinamide (130); 4-(2-(4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) N-((1r,3r)-3-(3-chloro-4-cyanophenyl)piperidine-1-yl)nicotinamide (131); (2,2,4,4-tetramethylcyclobutyl)-2-(4-(5-((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)pyrimidinyl Zine-5-carboxamide (132); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo xoisoindolin-5-yl)piperazin-1-yl)propoxy)ethyl)-3,5-difluorobenzyl N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-((3S,5R)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo soindolin-5-yl)oxy)pentyl)-3,5-dimethylpiperazin-1-yl)benzamide ( 134); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) (4H)-yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)nicotinamide ( 135); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) (1H)-yl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)nicotinamide ... 136); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (yl)-6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl (4H)-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)nicotinamide ( 137); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (yl)-6-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperazin-1-yl)pentyl)nicotinamide (138); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((S)-2,6-dioxopiperidine 6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)hexyl ) Nicotinamide (139); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-6-(6-(4-(2-((S)-2,6-dioxopiperidin-3-yl)-6-fluoro-1- Oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (140); N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(9 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa- 4,9-Diazaspiro[5.5]undecan-4-yl)ethyl)benzamide (141); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyano)pyrimidine-5-carboxamide (142); Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-((2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl) Pyrimidine-5-carboxamide (143); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamide Voxamide (144); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo Phosphorin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetrafluoroethylene (145) tetramethylcyclobutyl)-6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo N-((R)-1-(3-isoindolin-5-yl)piperazin-1-yl)propyl)nicotinamide (146); -(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((4-(4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl N-((1r,3r)-3-(3-chloro- -4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(9-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[ 5.5]undecan-4-yl)propyl)benzamide (148); N-((1r,3r)-3-(4-cyano-3-methyl) (4-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidin Zine-5-carboxamide (150); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-6-(4-(5-((2-((S)-2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinamide (15 1); N-((1r,3r)-3-(4-cyano-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl) -6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperazin-1-yl)ethyl)piperidin-1-yl)nicotinamide (152); N-((1r,3r)-3-( 4-Cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-3-oxo N-((1r,3r)-3-(3-chloro-4-cyanophenyl)-1-oxopiperazin-1-yl)nicotinamide (154); (noxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)butyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyano)pyrimidine-5-carboxamide (155); Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-(3-((2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl )piperazin-1-yl)pyrimidine-5-carboxamide (156); 2-chloro-4-(3-(4-(5-(4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- 3-(4,4-dimethyl-5-oxo-2-thioxoimidazolidinyl)pentyl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzaldehyde 2-Chloro-4-(5-(4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxamide (158); Soyisoindolin-5-yl)piperazin-1-yl)pentyl)-3-fluorophenyl)-8-oxo -6-Thioxo-5,7-diazaspiro[3.4]octan-7-yl)benzonitrile (159); N-((1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2 -(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl )ethyl)piperidin-1-yl)nicotinamide (160); N-((1r,3r)-3-(3,4-dicyanopheno 2-(4-(2-(2,6-dioxopiperidine-3- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-6-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-di (oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)nicotinamide (1 62); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-6-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7 -diazaspiro[3.5]nonan-2-yl)nicotinamide (163); N-((1r,3r)-3-(3-chloro-4-phenyl)- (anhydrophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(2-(5-((2-(2,6-dioxopiperidine) Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-2,6-dihydropyridin N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(3-(2-((2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)azetidin-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)oxy)butyl)piperazin-1-yl)-2,6-difluoro Benzamide (166); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylbenzamide (cyclobutyl)-2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin 1,4-Diazepan-1-yl)pyrimidine-5-yl)methyl Voxamide (167); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)phenyl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl amide (168); 4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)benzo[5-yl]oxy[propyl] N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl amide (169); 2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoyl) N-((1r,3R)-3-(3-isoindolin-5-yl)piperazin-1-yl)ethyl)benzamide (170); Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((1R,4R)-5-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,5-diazabi Cyclo[2.2.1]heptan-2-yl)ethyl)benzamide (171); N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3,5-difluoro Fluorobenzamide (173); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrafluoroethylene 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Soyisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (174); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(4-(((1R,4R)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole (2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidin-1-yl)benzyl N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenylamide (175); 4-(4-(((1S,4S)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di xoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-3-fluoro Benzamide (177); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylbenzamide 4-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxocyclobutyl) xoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidine-1 -yl)benzamide (178); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl) tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-fluoronic Tinamide (179); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1,3-dioxobutyl) xoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (1 81); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-4-((3R)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisopropyl N-(2 ... -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3r)-3-(4-cyano-3-methyl)cyclohexyl)benzamide (183); Tyrphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclo hexyl)benzamide (184); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro -3-Oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benz Amide (185); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisopropyl) Indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (186); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5- N-((1r,3r)-3-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (187); (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2 ,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperazinium N-((1r,3r)-3-(3-chloro-4-phenyl-1-yl)ethyl)piperidin-1-yl)benzamide (188); Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(4-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)a Zetidin-1-yl)benzamide (189); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-4-(4-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-5-yl)oxy)azetidin-1-yl)ethyl)piperidin-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrachlorobenzamide (190); Methylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)piperazin-1-yl)methyl)azepan-1-yl)pyrimidine-5-carboxylate N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- 5-yl)piperazin-1-yl)cyclohexyl)benzamide (192); N-((1r,3R)-3-(3-chloro 4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((3S,5R)-4-(3-((2-(2, 6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)- 3,5-Dimethylpiperazin-1-yl)nicotinamide (193); N-((1r,3R)-3-(3-chloro-4-cyano) Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4-(3-((2-(2,6-dioxo Isopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimeth N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)phenyl)piperazin-1-yl)benzamide (194); 2-((3S,5R)-4-(3-((2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)oxypropyl)-3,5-dimethylpiperazin-3-yl N-((1r,3r)-3-(3-chloro-4-cyano)pyrimidine-5-carboxamide (195); 4-(4-((1s,3S)-3-(((2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)methyl)cyclobutyl)pyridine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)-2-fluorobenzamide (1 97); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-4-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl N-((piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)benzamide (198); 1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R) -3-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pi N-((1-pyridin-4-yl)methyl)(methyl)amino)pyrrolidin-1-yl)benzamide (199); r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)- 3-(((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine Lysin-4-yl)methyl)(methyl)amino)pyrrolidin-1-yl)benzamide (200); N-((1r, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3- (((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine N-((1r,3-diphenyl-4-yl)(methyl)amino)methyl)pyrrolidin-1-yl)benzamide (201); R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((2S,6 R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6- Dimethylpiperazin-1-yl)ethyl)benzamide (202); N-((1r,3r)-3-(3-chloro-4-phenyl) (aminophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidine 1,3'-biazetidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)- N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-4-(4-(2-(((1r,3r)-3-((2-(2,6-dioxopiperidine-3- 1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)ethyl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)piperazin-1-yl)benzamide (204); 4-(1-(2-((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)azetidin-3-yl)piperazine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)-4-(2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)ethyl)benzaldehyde N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 2-(2R,6R)-4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl N-((1r ,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3 -((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3S)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((2S,6S)-4-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethylpiperazine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl)-4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)benzene N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-(3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin N-(2 ... (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( 2-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyrazin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzamide (212); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-((4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisoindoline- 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (213); N-((1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-( 2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)piperazine N-((1r,3S)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((4aR,6R,8aS)-6-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) Octahydroisoquinolin-2(1H)-yl)nicotinamide (215); N-((1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(((1r,3r)-3-((2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutene N-((1r,3r)-3-(3-ethyl)(methyl)amino)ethyl)azetidin-1-yl)benzamide (216); -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6- Dioxopiperidin-3-yl)-4-fluoro-1,3-dioxoisoindolin-5-yl)oxy N-((1r,3R)-3-(3-chloro-4-cyano)propyl)piperazin-1-yl)benzamide (217); 4-((1r,3R)-3-((4-(2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-((1s,3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclobutyl)benzamide N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-6-((4aR,6S,8aR)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)piperazin-1-yl)octahydroisoquinolin-2(1H)-yl)nicotine Amide (220); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl)-6-((4aR,6R,8aR)-6-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)octahydroisoquinolin-2(1H)-yl)nico Tinamide (221); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo Phosphorin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide (222 ); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-((3R)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) N-((1r,3r)-3-(3-chloro)piperazin-1-yl)pyrrolidin-1-yl)benzamide (223); 4-(1-(2-(2,6-dioxa-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(1-(2-(2,6-dioxa Isopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)pipera N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-((3R)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)benz Amide (225); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl)-4-((3R)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo Xoisoindolin-5-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)benzamide (226); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisopropyl) N-(2 ... -((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(2-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl (3R)-N-(1-(4-(((1r, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl phenyl)piperidin-4-yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)-N-methylpyrrolidine-3-carboxamide (230); N-((1r,3r)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2, 6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3R)ethyl)piperidin-1-yl)pyridazine-3-carboxamide (231); N-((1r,3R)ethyl)piperidin-1-yl)pyridazine-3-carboxamide (231); )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((2S,4R,6R )-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pi Perazin-1-yl)methyl)-2,6-dimethylpiperidin-1-yl)pyrimidine-5-carboxamide N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (232); 2-((2S,4S,6R)-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl) 2,6-dimethylpiperidin-1-yl)pyrimidinyl N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl tetramethylcyclobutyl)-2-((2S,6S)-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2,6-dimethylpiperidine-1 -yl)pyrimidine-5-carboxamide (234); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) 2,2,4,4-tetramethylcyclobutyl)-4-(3-(3-((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl)propyl)azeti N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-6-(7-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperidin-1-yl)methyl)octahydro-2H-pyrido[1,2- a]pyrazin-2-yl)nicotinamide (236); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) 4-((((1r,3r)-3-((2-(2,6-dioxopiperidine) (3-indolinyl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)methyl)(methyl N-((1r,3r)-3-(3-chloro-4-cyano)amino)piperidin-1-yl)benzamide (237); Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1'-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)-[1,4'-bipiperidine]-4-yl)amino)be N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenylamide (238); (4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl)-4-(cyclobutyl) N-(2 ... -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- (yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidin-1-yl)benzaldehyde N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 2-((1S,4S,5R)-5-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxobutyl)- (isoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2.2.1]heptan-2-yl N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)pyrimidine-5-carboxamide (241); -2,2,4,4-tetramethylcyclobutyl)-2-((1S,4S,5S)-5-((4-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[1,3-dioxoisoindolin-5-yl]piperazin-1-yl Cyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide (242); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-di Oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine -1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (243); N-((1r,3R)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-((2-(( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl N-((1r,3R)-3-(3-chloro-4-phenyl)amino)pyrrolidin-1-yl)benzamide (244); -cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(3-((2-(2,6-dihydro- 1,3-dioxoisoindolin-5-yl)oxy)azetidin-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)pyrrolidin-1-yl)benzamide (245); 2,2,4,4-tetramethylcyclobutyl)-4-(5-(2-((2-(2,6-dioxopiperidin-3-yl )-1,3-Dioxoisoindolin-5-yl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrro N-((1r,3r)-3-(4-cyano-3-methylphenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidinyl Zine-5-carboxamide (247); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(4-(4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo N-((1r,3r)-isoindolin-5-yl)piperazin-1-yl)butyl)benzamide (248); 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-((R )-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl )butyl)benzamide (249); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(6-(4-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxo N-((1r,3r)isoindolin-5-yl)piperazin-1-yl)hexyl)benzamide (250); )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-( (R)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-yl N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenyl)hexyl)benzamide (251); phenyloxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)benzoate N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4 -tetramethylcyclobutyl)-4-(6-((2S,6R)-4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)-2,6-dimethylpiperazin-1-yl)hexyl)benzaldehyde N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 5-yl)-3,6-dihydropyridin-1(2H)-yl)ethyl)oxetan-3-yl)methyl)benzaldehyde N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetrafluoroethylene 4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)ethyl)piperazin-1-yl)benzamide (255); N-((1r ,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-((1S ,4S)-5-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5 -diazabicyclo[2.2.1]heptan-2-yl)hexyl)benzamide (256); N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-((2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(6-((1R,4R)-5-(2-((S)-2,6-dioxopiperidine-3- (yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl)benzamide (258); 4-(6-((1R,4R)-5-(2-((R)-2,6-dioxopiperidin-3-yl)-1,3-dimethylcyclobutyl) -Oxoisoindolin-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)hexyl Benzamide (259); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylbenzamide 3-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl) Endolin-5-yl)piperazin-1-yl)ethyl)oxetan-3-yl)methyl)benzamide ( 260); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-6-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) N-((1r,3r)-3-(3-chloro-)oxy)ethyl)piperidin-4-yl)nicotinamide (261); 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(4-((2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidine-4- N-((1r,3r)-3-((5-cyano-6-methylpyridin-2-yl)oxy)nicotinamide (262); 2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)nicotinic acid N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)oxy)pentyl)piperazin-1-yl)pyrazine-2-carboxamide (264); N-((1 r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pe N-((1r,3r)-3-(3-chlorophenyl)piperazin-1-yl)pyridazine-3-carboxamide (265); 4-(5-((2-(2,6-dioxo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxo-4-cyanophenoxy) Isopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-4- Carboxamide (267); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-1-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)oxy)pentyl)piperidin-4-yl)-1H-pyrazole-3-carboxamide N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl (1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)oxy)butyl)pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide (269); N -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2 -(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-1-phenyl-2-azinyl)ethyl)benzamide (270); )-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((R)-2,6-dioxopiperidine-3-yl) (6-fluoro-3-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotine Amide (271); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl 6-(6-(4-(2-((R)-2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxobutyl) N-((1r,3r)-isoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide (272); 3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin N-((1r,3r)-3-(3-chloro-4-cyanophenyl)-1-pyrazine (273); (2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-5-yl)-3,6-dihydropyridin-1(2H)-yl)butyl Nicotinamide (274); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-1'-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl 1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylate Ruboxamide (275); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl)-6-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl) 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl Nicotinamide (276); N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl (3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl)propan-2-yl Indolin-5-yl)piperazin-1-yl)propoxy)methyl)-1H-pyrazole-3-carboxylate N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propanamide (277); Pan-2-yl)-5-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo Phosphorus-5-yl)oxy)butyl)piperazin-1-yl)methyl)-1H-pyrazole-3-carboxamide N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (278); (2R)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole (5-phenyl)oxy)pentyl)-2-(hydroxymethyl)piperazin-1-yl)nicotinamide (2 79); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-1'-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)o (oxy)pentyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (280) ; N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6 -(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)o N-((1r,3r)-3-(3-oxy)pentyl)-2-oxopiperazin-1-yl)nicotinamide (281); Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(4-((2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)propyl)piperidin-4-yl)benzamide (283) ; N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4 -(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine N-((1r,3r)-3-(3-chloro-4-cyano)-phenylalanine (284); N-((1r,3r)-3-(3-chloro-4-cyano)-phenylalanine (284); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-((R)-2,6-dioxopyridine Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1- N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran (285); tetramethylcyclobutyl)-6-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)ethyl)azetidin-1-yl)nicotinamide (286); N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4 -((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) 4-(3-(4-(5-(4-(2-(2,6-dioxopipe Lysin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl)-3- Fluorophenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluorophenyl) Fluoromethyl)benzonitrile (288);N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridine Dazin-3-carboxamide (289); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)-5-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrazine- 2-Carboxamide (290); N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1- 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)propoxy)ethyl)-1H-pyrazole-3-carboxamide Voxamide (291); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (cyclobutyl)-5-((3S)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo soindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)piperazin-1-yl)picolin N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo Phosphorus-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-6-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl N-((1r,3r)-3-(3,9-diazaspiro[5.5]undecan-3-yl)nicotinamide (294); -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(9-(2-(2,6-dichloro 1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5] N-((1r,3R)-3-(3-chloro-4-phenylenediamine)pyrimidine-5-carboxamide (295); 2-(2,6-dioxo-2,2,4,4-tetramethylcyclobutyl)-4-(2-((1R,4R)-5-(2-(2,6-dioxo-2,2,4,4-tetramethylcyclobutyl)- Isopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-2,5-diazabiphenyl Cyclo[2.2.1]heptan-2-yl)ethyl)benzamide (296); N-((1r,3r)-3-(3-chloro-4 -cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopyrrolidinyl) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazine-1- N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,6-difluorobenzamide (297); 4-(5-((2-(2,6-dioxopiperidin-3-yl) )-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)-2,6-difluoro Fluorobenzamide (298); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrafluoroethylene 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)butyl)piperazin-1-yl)-2-fluorobenzamide (2 99); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)piperidin-1-yl)-4-(trifluoromethyl)pyrimidine-5- Carboxamide (300); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-3'-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl (5-indolyl)piperazin-1-yl)methyl)-[1,1'-biphenyl]-4-carboxamide (30 1); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)piperidin-1-yl)-3-(trifluoromethyl)benzamide ( 302); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 3'-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) N-((1r,3R)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-carboxamide (303); )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4 -(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine N-((1r,3 lysine-4-yl)ethyl)-3,5-dimethylpiperazin-1-yl)benzamide (304); r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- N-((1r,3r)-3-(3yl)methyl)piperidin-1-yl)pyrimidine-2-carboxamide (305); -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) Ethyl)piperidin-1-yl)pyrimidine-2-carboxamide (306); N-((1r,3r)-3-(3-chloro 4-(4-((1-(2-(2,6-dioxo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4- N-((1r,3r)-3-(3-chloro-4-cyano)methyl)piperazin-1-yl)benzamide (307); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl )benzamide (308); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl 4-(4-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxophenyl)cyclobutyl)- soindolin-5-yl)oxy)azetidin-1-yl)ethyl)piperazin-1-yl)benzamide N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-methylpyrimidine-5-carboxylate N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl)amide (310); 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-yl Carboxamide (311); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-4-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)ethyl)piperazin-1-yl)ethyl)benzamide (312); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3' -(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine N-((1r,3R)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4-(4-( (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyrate N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benz Amide (316); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl cyclobutyl)-6-((3S)-4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl 5-(hydroxypropyl)-3-(methyl)piperazin-1-yl)nicotinic acid N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)oxy)butyl)piperazin-1-yl)-4-fluoronicotinamide (318); N-((1r,3 r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- N-((1r,3r)-3-(3-chloro-4-cyanophenyl)ethyl)-2,6-difluorobenzamide (319); 3-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)azetidin-1-yl)benzoate N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-((3S)-3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)piperidin-4-yl)methoxy)pyrrolidin-1-yl)benzamide (321 ); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-(4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl N-((1r,3R)-3-(pyrrolidin-3-yl)methyl)piperazin-1-yl)benzamide (322); 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3- N-((1r,3r)-3-(3-chloro-4-cyano)methyl)piperazin-1-yl)benzamide (323); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-(4-(2-(2,6-dioxopiperidine Benzamide-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butyl) N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-4-((3R)-3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo N-(phosphoryl-5-yl)piperidin-4-yl)methoxy)pyrrolidin-1-yl)benzamide (325); (1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((3R ,5R)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Oxy)propyl)-3,5-dimethylpiperazin-1-yl)pyrimidine-5-carboxamide (326) ; N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4 -((3R)-3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) N-((1r,3S)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((4-(2- (2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pi N-((1r,3r)-3-(3-chlorophenyl)pyrrolidin-1-yl)benzamide (328); 4-(4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dichloro-4-cyanophenoxy)- 1-oxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)piperazin-1-yl)benzyl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenylamide (329); (cyclobutyl)-4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin N-((1r,3r)-3-(3-chloro-5-yl)azetidin-3-yl)propyl)benzamide (330); 4-(4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dichloro-4-cyanophenoxy)- 1,3-dioxoisoindolin-4-yl)butyl)piperazine-1-yl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrachlorobenzamide (331); Methylcyclobutyl)-3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)cyclobutane-1-carboxamide Voxamide (332); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (cyclobutyl)-5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin Dolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-4-((3R)-3-((((1r,3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrachlorobenzamide (334); Methylcyclobutyl)-4-(4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-diox Soyisoindolin-5-yl)pyrrolidin-3-yl)methoxy)piperidin-1-yl)benzamide N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-4-(4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo N-(phosphoryl-5-yl)pyrrolidin-3-yl)methoxy)piperidin-1-yl)benzamide (336); (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-( (((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) (methyl)oxy)cyclobutyl)amino)methyl)azetidin-1-yl)benzamide (337 ); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-((3S)-3-((((1r,3S)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin (5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidin-1-yl)benz Amide (338); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole (methyl)piperazin-1-yl)-4-fluoronicotinamide ( 339); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(4-((((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoyl soindolin-5-yl)pyrrolidin-3-yl)methyl)(methyl)amino)piperidin-1-yl)be N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenylamide (340); 4-(4-((((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3 -Dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)(methyl)amino)piperidinyl N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -tetramethylcyclobutyl)-6-((4aR,6S,8aS)-6-(4-(2-(2,6-dioxopiperidine-3-yl) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)octahydroisoquinoline -2(1H)-yl)nicotinamide (342); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro Fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1- N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-yl)-3-fluorobenzamide (343); ,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)benzamide ( 344); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisopropyl) Indolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzamide (345); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6- (4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline- 5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (34 6); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)piperidin-1-yl)-3-(2-(2-methoxyethoxy)ethoxy)benzyl N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenylamide (347); (4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole)-4-(cyclobutyl) N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4 -yl)oxy)piperidin-1-yl)benzamide (349); N-((1r,3r)-3-(3-chloro-4-cyano) Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1-(2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine N-((1r,3r)-3-(3-chloro-4-cyanophenanthrin)-4-fluoronicotinamide (350); 2,2,4,4-tetramethylcyclobutyl)-4-(3-((1-(2-(2,6-dioxopiperidine-3-yl) (1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)azetidin-1-yl )benzamide (351); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl) 3,6-dihydropyridin-1(2H)-yl)benzamide Amide (352); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl)-4-((1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)-[1,4'-bipiperidin]-4-yl)oxy)benzamide (353); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-di Oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine -1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (354); N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- N-((1r,3r)-3-(4-cyano-3-(trimethylsilyl)methyl)piperidin-1-yl)benzamide (355); Fluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-di (Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)piperidin-1-yl)benzamide (356); 2-(2,6-dioxopiperidine-3-yl)-2,2,4,4-tetramethylcyclobutyl (1,3-dioxoisoindolin-5-yl)oxy)ethyl)-2-azaspiro[3.3]heptane-2 -yl)benzamide (357); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl) tetramethylcyclobutyl)-2-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)propyl)piperazin-1-yl)-4,6-dimethylpyrimidine- 5-Carboxamide (358); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran tetramethylcyclobutyl)-5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo soyindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carboxamide (359); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene (yl)-6-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl (360); 2-Chloro)oxy)propyl)piperazin-1-yl)pyridazine-3-carboxamide -N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine) 2-Chloro-N-((1r,3r)-3-pyridinyl)methyl)piperidin-1-yl)benzamide (361); -(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2, 6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine- 1-yl)pyrimidine-2-carboxamide (363); N-((1r,3r)-3-(4-cyano-3-(trifluoro Methyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1- N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl)picolinamide (364); tetramethylcyclobutyl)-2-((3S,5S)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)pi Rimidine-5-carboxamide (365); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)ethoxy)propyl)benzamide (366); N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl)-4-(4-(4-((2-(2,6-dioxopiperidine 1-oxoisoindolin-4-yloxybutyl-1H-1,2,3-triazole 1-yl)benzamide (367); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl tetramethylcyclobutyl)-6-(4-(2-((5-(2-((R)-2,6-dioxopiperidin-3-yl)-1-oxo xoisoindolin-4-yl)pentyl)oxy)ethyl)piperazin-1-yl)nicotinamide N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl butyl)-4-(4-(2-((5-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindole (2S)-1-(4-phenyl-4-yl)pentyl)oxy)ethyl)piperazin-1-yl)benzamide (369); -(((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline)-N-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline)- Phosphorin-5-yl)piperazin-1-yl)butyl)-N-methylpyrrolidine-2-carboxamide (370); (2R)-1-(4-(((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl)carbamoyl)benzyl)-N-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxo Soyisoindolin-5-yl)piperazin-1-yl)ethyl)-N-methylpyrrolidine-2-carboxylate (2S)-1-(4-(((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrasamide (371); Methylcyclobutyl)carbamoyl)benzyl)-N-(2-(4-(2-(2,6-dioxopiperidine-3- 1-Oxoisoindolin-5-yl)piperazin-1-yl)ethyl)-N-methylpyrrolidine -2-Carboxamide (372); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxophenyl)-4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxophenyl) N-((1r,3r)-3-(3-isoindolin-5-yl)oxy)ethoxy)ethyl)benzamide (373); Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)pyrrolid Lysine-3-yl)-1H-pyrazole-4-carboxamide (374); N-((1r,3r)-3-(3-chloro-4-phenyl) 2-(3-(4-(2-(2,6-dioxopyranoside)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(3-(4-(2-(2,6-dioxopyranoside) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy) 4-(3-(4-(4-(5-((2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1- 5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluorophenyl)-4,4-dimethyl (376); 2-chloro-4-(3-(4-(4-(5-((2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl )phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile ( 377; 4-(5-(4-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole phenyl)-8-oxo-6-thioxo-5,7-diphenyl)-5-phenyl-5-yl)oxy)pentyl)piperazin-1-yl)phenyl) Azaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (378); N-(( R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((2- (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) Ethoxy)ethoxy)methyl)-1H-pyrazole-3-carboxamide (379); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenol)picolinamide (380); 2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(2,6-dioxopiperidine-3-yl) (1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propyl)picolinamide (381); 4-(3-(6-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo 5-phosphoryl)oxy)pentyl)piperazin-1-yl)pyridin-3-yl)-4,4-dimethyl-5-oxo (xo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (382) ; 4-(3-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)oxy)butyl)piperazine-1-carbonyl)-3-fluorophenyl)-4,4-dimethyl5- Oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (38 3); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(2-((1S,4S)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethyl)benzamide (384); 4-(5- (((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate bamoyl)pyridin-2-yl)-1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)pentyl)-1-methylpiperazin-1-ium (385); 4-(3-(2 -((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pi Perazin-1-yl)pentyl)oxy)phenyl)-4,4-dimethyl5-oxo-2-thioxoimida Zolidine-1-yl)-2-(trifluoromethyl)benzonitrile (386); 4-(3-(2-((6-(4-(2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl (hexyl)oxy)phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidine-1-yl N-((1r,3r)-3-(3-chloro-4-cyano) Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine -1-yl)-2-fluorobenzamide (388); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) )-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)oxy)propyl)piperazin-1-yl)benzamide (389); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) N-((1r,3r)-3-(3-chloro-4-cyano)azetidin-3-yl)ethyl)benzamide (390); Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine -1-yl)-2,6-difluorobenzamide (391); N-((1r,3r)-3-(3-chloro-4-cyanophenone) 2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidine-3-yl) 1-oxoisoindolin-4-yl)oxy)propyl)piperazin-1-yl)benzamide (392); 4-(3-(2-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoyl 5-indolyl)piperidin-4-yl)methyl)piperazin-1-yl)ethyl)phenyl)-4,4- Dimethyl 5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzodi Tolyl (393); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyano 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole) N-((1r,3r)-3-(3-chloro- 4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)methyl)pi N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2-pyridin-1-yl)benzamide (395); ,2,4,4-tetramethylcyclobutyl)-1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pi Razol-3-carboxamide (396); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-1-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)-1H-pi Razol-3-carboxamide (397); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-Tetramethylcyclobutyl)-4-(2-(dimethylamino)ethoxy)-6-(4-((4-(2-(2,6-di Oxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine -1-yl)methyl)piperidin-1-yl)nicotinamide (398); N-((1s,4s)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)nicotinic N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine N-((1r,4r)-4-(3-chloro- 4-Cyanophenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzyl N-((1s,4s)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine N-((1r,4r)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidinyl Zine-5-carboxamide (403); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexane 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide (404); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dichlorophenyl) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl N-((1r,4r)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6- Fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1 -yl)pyridazine-3-carboxamide (406); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidinyl N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl 5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoin Dolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrazine-2-carboxamide N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(4-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)-piperidin-1-yl)benzamide (409); cyclohexyl)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl) N-((1r,4 r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(1-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-yl N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)pyridazine-3-carboxamide (411); Cyclohexyl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoin (4-Dolin-5-yl)piperidin-4-yl)piperazin-1-yl)pyrimidine-5-carboxamide 12); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) Piperidin-1-yl)pyridazine-3-carboxamide (413); N-((1r,4S)-4-(3-chloro-4-phenylenediamine) 2-((3S)-3-((4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)pi Rimidine-5-carboxamide (414); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclo hexyl)-6-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)oxy)ethyl)piperazin-1-yl)pyridazine-3-carboxamide (415); N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-((2-(2,6-dioxopyridine) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazine-1-yl N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)benzamide (416); -2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Oxy)ethyl)piperazin-1-yl)pyrimidine-5-carboxamide (417); N-((1r,4r)-4- (3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pi Rimidine-5-carboxamide (418); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)-4-methyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl) Indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (419); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-((2-(2,6-dichloro-4-cyanophenoxy)cyclohexyl) 1,3-dioxoisoindolin-5-yl)oxy)ethyl)piperazine N-((1r,4r)-4-(3-chloro-4-cyanophenanthren-1-yl)pyrazine-2-carboxamide (420); 5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoyl)cyclohexyl) soindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)picolinamide (4 21); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6- Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy N-((1r,4r)-4-(3-chloro)-2,4-difluoro-2,5-difluoro-1,2 ... -4-cyanophenoxy)cyclohexyl)-5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)- 6-Fluoro-1,3-dioxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl) Pyrazine-2-carboxamide (423); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl 2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) Phosphorin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyrimidine-5-carboxamide N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-(4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- N-((1r,4r)-4-(3-chloro-4-cyano)ethyl)piperidin-1-yl)benzamide (425); Nophenoxy)cyclohexyl)-5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)propyl)piperazin-1-yl)pyrazine-2-carbo N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipera N-((1r,3r)ethyl)piperidin-1-yl)pyridazine-3-carboxamide (427); N-((1r,3r)ethyl)piperidin-1-yl)pyridazine-3-carboxamide (427); )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2- (1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ox N-((1r,3r)-3-(3-chloro-4-phenyl)piperazin-1-yl)nicotinamide (428); 2-(1-methyl-2,6-diaminophenoxy)-2,2,4,4-tetramethylcyclobutyl 1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyano)-1H-pyrazole-4-carboxamide (429); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2,6-diox 1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperidine N-((1r,3r)-3-(3-chloro-4-cyano) Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(4-((2-(1-methyl-2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)pyrrolidine-3- N-((1r,3r)-3-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carboxamide (431); (1-(5-((2-(1-methyl-2,6-dioxopiperidine) Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)pyrrolidine-3-yl N-((1r,3r)-3-(3-chloro-4-cyanophenanthracene) 2-(3-(4-(2-(1-methyl-2,6-dioxopiperidine) Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propoxy) N-((1r,3r)-3-(3-chloro-4-cyanophenyl)phenyl)-1H-pyrazole-4-carboxamide (433); (2-(1-methyl-2,6-dioxopiperidine)-2,2,4,4-tetramethylcyclobutyl Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazine-1-yl N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)picolinamide (434); )-2,2,4,4-Tetramethylcyclobutyl)-5-(4-(5-((2-(1-methyl-2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)piperazin-1-yl)pi Cholinamide (435); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl 5-(3-(4-(2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo Soyisoindolin-5-yl)piperazin-1-yl)propyl)picolinamide (436); 6-(4-(4 -((2-(1-butyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Oxy)butyl)piperazin-1-yl)-N,N-dimethylpyridazine-3-carboxamide (437); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-( 4-(4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- N-((1r,3yl)oxy)butyl)piperazin-1-yl)pyrimidine-5-carboxamide (438); r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2 -(1-Methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine N-((1r,3r)-3-(3-chlorophenyl)pyridin-1-yl)benzamide (439); 4-(2-(1-methyl-2-(1-methyl-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl (3-(5-(4-((1-(4-(( (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carba 1,3-dioxoisoin, 1,3-dioxoisoin, 1,3-dioxoisoin (2-yl)-2,6-dioxopiperidin-1-yl)methyl methyl carbonate (441); 3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl chlorobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3 -Dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl ethyl carbamide Carbonate (442); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4, 4-Tetramethylcyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)pipera (1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl) Chill isopropyl carbonate (443); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl) chlorobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3 -Dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl (tetrahydro 2H-pyran-4-yl) carbonate (444); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4 -Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidine )Methyl)piperazin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-di Oxopiperidin-1-yl)methyl (2-acetamidoethyl)carbamate (445); (3-(5-(4 -((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene phenyl) piperidin-4-yl) methyl) piperazin-1-yl)-1,3-dioxa Soyisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl (2-(2-aminoacetamide) amido)ethyl)carbamate (446); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperidine-4- 1,3-dioxoisoindolin-2-yl)-2,6-dioxopipe (peridin-1-yl)methyl (2-((S)-2-aminopropanamido)ethyl)carbamate (447); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1 ,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl (2-((S)-2 -Amino-3-methylbutanamido)ethyl)carbamate (448); (3-(5-(4-((1-(4-(((1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl) Phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindoline- 2-yl)-2,6-dioxopiperidin-1-yl)methyl (2-((S)-2-((S)-2-amino-3-methylbutyric acid (3-(5-(4-((1-(4-(((1 r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamo phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindo (2,5,8,11-tetraoxatrideca)methyl (2-yl)-2,6-dioxopiperidin-1-yl 2-Chloro-4-(3-(3-fluoro-4-(5-(4-(2-(1-methyl-2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-yl phenyl)pentyl)phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidin-1-yl)benzene Zonitrile (451); 2-chloro-4-(5-(3-fluoro-4-(5-(4-(2-(1-methyl-2,6-dioxopyridine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pentyl) (phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)benzonitrile (452); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2, 3-Dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azadodecane- 12-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazo Lysin-1-yl}-2-(trifluoromethyl)benzonitrile (453); 4-(3-{4-[2-(2 -{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-i isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-ox So-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzodi Tolyl (454); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo xo-2,3-dihydro-1H-isoindol-4-yl]-4,7,10,13,16-pentaoxa-1 -Azaoctadecan-18-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sul {phenylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (455 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]ethoxy} phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl] -2-(trifluoromethyl)benzonitrile (456); 4-[3-(4-{2-[2-(2-{[2-(2,6 -Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole -4-yl]amino}ethoxy)ethoxy]ethoxy}phenyl)-4,4-dimethyl-5-oxo -2-Sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (457); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxyl So-2,3-dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azate 4,4-dimethyl-5-oxo-2-sulfanilide 4-{3-(trifluoromethyl)-4-(imidazolidin-1-yl)}-2-(trifluoromethyl)benzonitrile (458); [4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1 H-isoindol-4-yl]-4,7,10-trioxa-1-azatridecan-13-yl} o 4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidine-1- 4-(3-{4-[(1-{2-[(3R)-2 ,6-Dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole {4,7,10-trioxa-1-azadodecane-12-yl)oxy]phenyl}-4, 4-Dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl) (fluoromethyl)benzonitrile (460); 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopipe Lysin-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-4, 7,10-trioxa-1-azadodecane-12-yl)oxy]phenyl}-4,4-dimethyl-5- Oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzene Zonitrile (461); 4-[3-(4-{3-[3-(2-{[2-(2,6-dioxopiperidin-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethoxy)pro (phenyl)-4,4-dimethyl-5-oxo-2-sulfanilideneimida Zolidine-1-yl]-2-(trifluoromethyl)benzonitrile (462); 4-{4,4-dimethyl 1-[2-(3-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxo -2,3-Dihydro-1H-isoindol-4-yl]-4,7,10-trioxa-1-azatride (can-13-yl)oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidine-1 -yl}-2-(trifluoromethyl)benzonitrile (463); 4-[3-(4-{4-[(5-{[2-( 2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindo (phenyl-4-yl)amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxy So-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzodi Tolyl (464); 4-{[5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)pentyl]oxy} -N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]benzamide (465); 4-{3-[4-({1-[2-(2,6-dioxopiperidin-3-yl )-1-Oxo-2,3-dihydro-1H-isoindol-4-yl]-1,4,7,10-tetraoxo (satridecan-13-yl)oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfani 6- lideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile (466); [4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- Isoindol-4-yl]amino}ethyl)piperazin-1-yl]-N-[(1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-ca Ruboxamide (467); 6-{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)ethyl]pi Perazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl]pyridine-3-carboxamide (468); 4-(3-{4-[1-(2-{ [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo 1H-1,3-benzodiazol-5-yl]phenyl}-4,4 -Dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2- (Trifluoromethyl)benzonitrile (469); 4-{[5-(3-{[2-(2,6-dioxopiperidine Indol-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino }propoxy)pentyl]amino}-3-fluoro-N-[(1r,3r)-3-(3-chloro-4-cyano phenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (470); 6-[4-(2-{[ 2-(2,6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindo N-[(1r,3r)-3-(3-chloro-4-yl]oxy}ethyl)piperazin-1-yl]- -Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide 6-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3 -Dihydro-1H-isoindol-4-yl]amino}ethyl)piperazin-1-yl]-N-[ (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl] Pyridine-3-carboxamide (472); 6-(4-{3-[2-(2,6-dioxopiperidine-3- yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]propyl}piperazine -1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl- 6-{4-[2-(2-{[2-(2,6-dicyclobutyl]pyridine-3-carboxamide (473); Oxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl 1r,3r)-3-(3-chloro-4-(oxy)-1-yl Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (474); 4-{4-[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- Dihydro-1H-isoindol-4-yl]oxy}ethyl)piperazin-1-yl]butyl} -N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetrahydrofuran tetramethylcyclobutyl]benzamide (475); 6-{4-[2-(3-{[2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]amine N-[(1r,3r)-3-(3-chloro-4-cyano)propoxy]ethyl]piperazin-1-yl Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (476); 6-{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxo xo-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)ethyl]pipera {N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran-1-yl] 4-(6-{4-[2-(2,6-diphenyl ether 1,3-dioxo-2,3-dihydro-1H-isoindole-5-oxopiperidin-3-yl 1-yl]piperazin-1-yl}hexyl)-N- [(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethyl 4-{3-[4-(3-{[2-(2,6-dioxopiperidine -3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}p {4-cyano-3-(trifluoropropyl)piperazin-1-yl}propyl}-N-[(1r,3r)-3-[4-cyano-3-(trifluoropropyl)]piperazin-1-yl]propyl] 4-[(trimethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (479); 5-(3-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H -isoindol-4-yl]amino}propoxy)pentyl]-N-[(1r,3r)-3-(3-chloro b-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (480); 6-{4-[2-(3-{[2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1,3-diox So-2,3-dihydro-1H-isoindol-4-yl]amino}propoxy)ethyl]piperazine {N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetraphenyl-1-yl] Methylcyclobutyl]pyridine-3-carboxamide (481); 4-(4-{4-[2-({2-[(3S)- 2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindole -5-yl}oxy)ethyl]piperazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro -4-Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (482); 4 -(4-{4-[2-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1- Oxo-2,3-dihydro-1H-isoindol-4-yl}oxy)ethyl]piperazine-1- 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl]benzamide (483); 4-{4-[4-(2-{[2-(2,6-dioxopyridine Peridine-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole 3-(3-chloro-4-yl)amino}ethyl)piperazin-1-yl]butyl}-N-[(1r,3r)-3-(3-chloro-4-yl]amino]ethyl)piperazin-1-yl]butyl] b-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (484); 6-{4-[5-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydrazine 1r,3r-1H-isoindol-4-yl}oxy)pentyl]piperazin-1-yl}-N-[(1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine -3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl}oxy)e butyl]piperazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy 6-{4-[5-({2-[(3S) -2,6-dioxopiperidin-3-yl]-1-oxo- 2,3-Dihydro-1H-isoindol-5-yl}oxy)pentyl]piperazin-1-yl} -N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl]pyridine-3-carboxamide (487); 4-(4-{4-[2-(2,6-dioxopiperidine -3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl 1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-Tetramethylcyclobutyl]benzamide (488); 4-{4-[4-(2-{[2-(2,6 -Dioxopiperidin-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H- Isoindol-4-yl]amino}ethyl)piperazin-1-yl]butyl}-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzaldehyde Mido (489); 6-(4-{6-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- Dihydro-1H-isoindol-4-yl]hexyl}piperazin-1-yl)-N-[(1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine 4-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4 -Fluoro-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine -1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl 4-(6-{4-[2-(2,6-dioxopiperidine]) 1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazine N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl]benzamide (492); 6-{4-[5-({2-[(3S)-2,6-di 1,3-dioxo-2,3-dihydro-1H-isoindole-5-oxopiperidin-3-yl 1-[(1r,3r)-3-(3-chloro-4-cyanoyl)oxy]piperazin-1-yl Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (493) 6-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]oxy}pentyl)piperazin-1-yl]-N-[(1r,3r)-3 -(3-Chloro-4-cyanophenoxy)cyclobutyl]pyridine-3-carboxamide (494) 4-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]oxy}pentyl)piperazin-1-yl]-N-[(1r,3r)-3 -(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (495); 4-(5-{4-[2 -(2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoyne (1r,3r)-3-(3-chloro-4-phenyl-5-yl)piperazin-1-yl}pentyl 4-(4-{4-(4-phenyloxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (496); -[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-iso Indol-5-yl]piperazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (497); 4-(6- {4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-di Hydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzaldehyde 4-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- N-[(1r,3r)-3-(3-chloro-4-isoindol-4-yl]oxy}butyl]-N -Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (499); 4-(5 -{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoyl N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-N-(1r,3r)-3-(3-chloro-4-cyanophenoxy)-N-(1r,3r)-3-(3-chloro-4-cyanophenoxy) 4-[3-(2-{[2-(2, 6-Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4 -yl]oxy}ethoxy)propyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy 4-[4-(2-{[2-(2,6 -Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4 -yl]oxy}ethoxy)butyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl]benzamide (502); 4-[5-(2-{[2-(2,6-di Oxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl 1r,3r)-3-(3-chloro-4-cyanophenoxy)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl]benzamide (503); 4-[6-(2-{[2-(2,6-di xopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl] oxy}ethoxy)hexyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl]benzamide (504); N-[(2R)-1-[3-(3-chloro- 4-Cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl]-5-{[4-(4-{[2 -(2,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoyne 1H-Pyrazole-3-carboxylate Ruboxamide (505); 4-(4-{6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo xo-2,3-dihydro-1H-isoindol-5-yl]hexyl}piperazin-1-yl)- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxoyl]benzamide (506); So-2,3-dihydro-1H-isoindol-4-yl]oxy}propyl)-N-[(1r,3r)-3 -(3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl] 3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propionate 4-[4-(3-{[2-(2,6-dioxy)methyl]-1H-pyrazole-3-carboxamide (508); xopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl] oxy}propyl)-1H-1,2,3-triazol-1-yl]-N-[(1r,3r)-3-(3-chloro -4-Cyanophenoxy)cyclobutyl]benzamide (509); 6-[4-(6-{[2-(2,6-dithio 1H-isopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoyl N-[(1r,3r)-3-(3-chloro-5-yl]amino}hexyl)piperazin-1-yl] (b)-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carbo N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole ‐1‐yl]propan‐2‐yl]‐5‐({3‐[4‐(2‐{[2‐(2,6‐dioxopiperidine‐3‐ yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}ethyl) Piperazin-1-yl]propoxy}methyl)-1H-pyrazole-3-carboxamide (511); 4-[4-(5-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H-isoindol-4-yl]oxy}pentyl)-1H-1,2,3-triazol-1-yl]- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (512); 4-[4-(6-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1 H-isoindol-4-yl]oxy}hexyl)-1H-1,2,3-triazol-1-yl]- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (513); 6-{4-[2-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3 -Dihydro-1H-isoindol-4-yl}butoxy)ethyl]piperazin-1-yl}-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 6-{4-[2-(4-{2-[(3R)-2,6-dioxopipe Lysine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}butanoate 3-(3-chloro-4-cyanophenoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)ethyl]piperazin-1-yl 6-(4-)-2,2,4,4-tetramethylcyclobutylpyridine-3-carboxamide (515); {2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2,3-dihydro 1H-isoindol-4-yl}pentyl)oxy]ethyl}piperazin-1-yl)-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 6-(4-{2-[(5-{2-[(3R)-2,6-dioxopyridine-3-carboxamide (516); 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}peridin-3-yl n-[(1r,3r)-3-(3-chloro-4-cyano)-N-[(1r,3r)-3-(3-chloro-4-cyano)-1-yl]- Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (517); 4-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidin-3-yl]-1,3-dioxo-2, 3-Dihydro-1H-isoindol-4-yl}pentyl)oxy]ethyl}piperazine-1- (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl 4-(4-{2-[(5-{2-[(3R)-2,6-dioxopiperidine 1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}pentyl )oxy]ethyl}piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanopheno 4-(4-{6-[2-(2,6 -Dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5 -yl]hexyl}piperazin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophen 4-(3-{4-[2-(2 ,6-Dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole (1r,3r)-3-(3-chloro-4-cyano)-N-[(1r,3r)-3-(3-chloro-4-cyano-5-yl]piperazin-1-yl}propyl] phenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (521); 4-[6-(4-{2 -[(3S)-2,6-Dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoyl N-[(1r,3r)-3-[4-cyano-3-(4-phenyl-5-yl)piperazin-1-yl]hexyl] (Trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (522); 4-[6-(4-{2-[(3R)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3- Dihydro-1H-isoindol-5-yl}piperazin-1-yl)hexyl]-N-[(1r,3r) -3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclo butyl]benzamide (523); 6-[4-(6-{[2-(2,6-dioxopiperidin-3-yl)-5 -Fluoro-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}hexyl 1r,3r)piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-Tetramethylcyclobutyl]pyridine-3-carboxamide (524); 6-[4-(6-{[2-( 2,6-Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H -isoindol-5-yl]oxy}hexyl)piperazin-1-yl]-N-[(1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3 -Carboxamide (525); 4-[6-(4-{2-[(3S)-2,6-dioxopiperidin-3-yl] (3-oxo-2,3-dihydro-1H-isoindol-5-yl)piperazin-1-yl)hexa Cyl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4- Tetramethylcyclobutyl]benzamide (526); 4-[6-(4-{2-[(3R)-2,6-dioxo Piperidin-3-yl]-3-oxo-2,3-dihydro-1H-isoindol-5-yl}piperidine 4-cyano-3-(trifluoromethyl)phenyl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenyl]-1-propanol-1-yl]hexyl] N-((1r,3r)-3-(3-phenyloxy)-2,2,4,4-tetramethylcyclobutyl)benzamide (527); -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6- Dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin rac-N-(4-methyl-1-phenyl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (528); (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( (4-(2-(2,6-dioxopiperidin-3-yl)-4-methylene-1-oxo-1,2,3,4-tetrahydrofuran Soxolin-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (529); rac-N-(1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl (2-(2,6-dioxopiperidine-3-yl)-1-(2-(2,6-dioxopiperidine-3-yl)-phenyl)azetidin-3-yl)- -yl)-1,3-dioxoisoindolin-5-yl)-N-methylpiperidine-4-carboxamide (5 30); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -6-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole phenyl)oxy)propyl)piperazin-1-yl)pyridazine-3-carboxamide (531); ac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 5-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindole 5-phenyl)oxy)propyl)piperazin-1-yl)pyrazine-2-carboxamide (532); rac -N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(3-((2-(2,6-dichloro-4-cyanophenoxy)cyclohexyl) 1,3-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy)pro rac-N-((1r,4r)-4-(3-cyclohexyl)piperazin-1-yl)pyrimidine-5-carboxamide (533); 2-(4-(2-(2,6-dioxopiperidine-3- yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin Lysine-1-yl)pyrimidine-5-carboxamide (534); rac-N-((1r,3r)-3-(3-chloro-4-phenyl) (anhydrophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine) Lysine-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) ethyl)piperidin-1-yl)-4-(2-(2-methoxyethoxy)ethoxy)nicotinamide (535); rac-N-((1r,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(2-((2R,6R)-4-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-dimethyl Piperazin-1-yl)ethyl)benzamide (536); rac-N-((1r,3r)-3-(3,4-dicyanophenanthracene) (2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3- 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl rac-N-((1r,3r)-3-(4-cyano-2-methylphenoxy)-2,2,4,4-tetramethylphenyl)benzamide (537); 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (5 38); rac-N-((1r,3r)-3-(2,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)piperidin-1-yl)benzamide (539); rac-N-((1r,3r)-3- (4-cyano-2,6-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- rac-N-((1r,3r)-3-(4-cyano-3-yl)methyl)piperidin-1-yl)benzamide (540); Methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)pi N-((1r,4r)-4-(4-cyano-3-methylphenoxy)-phenyl)-2-pyridin-1-yl benzamide (541); cyclohexyl)-5-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidine -1-yl)pyrazine-2-carboxamide (542); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo)cyclohexyl)-4-( Isoindolin-5-yl)thio)ethyl)piperazin-1-yl)benzamide (543); rac-N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3 -((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl (5-methyl)oxy)propyl)piperazin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide 44); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6,7-difluoro-1,3-dioxoisoin Dolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine -5-Carboxamide (545); rac-2-chloro-4-(((1r,4r)-4-(5-(4-((4-(2-(2,6-dioxopyridine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperazin Lysin-1-yl)-1H-benzo[d]imidazol-2-yl)cyclohexyl)oxy)benzonitrile aryl (546); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pipera rac-N-((1r,4r)-4-(3- Chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidine) Lysine-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) rac-N-((1r,4r)-4-(4-cyclohexyl)piperidin-1-yl)pyridazine-3-carboxamide (548); Anhydrous 3-methylphenoxy)cyclohexyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3-yl) (6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine rac-N-((1r,3r)-3-(4-cyano-3-methyl)pyridazine-3-carboxamide (549); 4-((4-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine rac-N-((1r,3r)-3-((5-cyano-6-methylpyridine-2-yl)benzamide (550); (oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1 -yl)benzamide (551); rac-N-((1r,3r)-3-((5-cyanopyridin-2-yl)oxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benz Amide (552); rac-N-((1r,3r)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxamide ( 553); rac-N-((1r,3r)-3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylpyridin-2-yloxy Methylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carbo rac-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyloxamide (554) (1R,4R,5S)-5-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxocyclobutyl)-2-((1R,4R,5S)- xoisoindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2.2.1]hepta rac-N-((1r,3r)-3-((5-cyano-3-methyl)pyrimidine-5-carboxamide (555); 4-((4-(2-(2,6-diphenylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-diphenylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl) (Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) rac-N-((1r,3r)-3-((5-cyanopyrimidine) -2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine rac-N-((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy) 4-((4-(2-(2,6-dioxopiperidin-3-yl) )-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl) Benzamide (558); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl )-5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (559); rac-N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(4-(2-(2,6-dioxopipe Lysin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1- rac-N-((1r,3R)-3-(3-chloro-4-cyanophenyl)pyrimidine-5-carboxamide (560); (1R,4R,5R)-5-((4-(2-(2,6-dioxopyridine) 2-( ... Azabicyclo[2.2.1]heptan-2-yl)pyrimidine-5-carboxamide (561); rac-N-((1r ,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-((2- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) rac-N-((1r,3R)-3-(3-chlorophenyl)pyrrolidin-1-yl)benzamide (562); 4-((1R,3S)-3-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclopentadiene rac-N-((1r,3r)-3-((6-cyano-5-methyl)piperazin-1-yl)benzamide (563); 4-((4-(2-(2,6-diphenylpyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-diphenylpyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl) (Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl) rac-N-((1r,3r)-3-((6-cyano-5-(trifluoromethyl)piperidin-1-yl)benzamide (564); (4-fluoromethyl)pyridin-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine- 1-yl)methyl)piperidin-1-yl)benzamide (565); rac-N-((1r,3r)-3-(3-chloro-4 -cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-((4-(2-(2,6-dioxopyrrolidinyl) Peridine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetate rac-N-((1r,4r)-4-(3-chloro-4-thiocyanide) Nophenoxy)cyclohexyl)-5-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyrazine- 2-Carboxamide (567); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylphenyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl) Indolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzamide (568); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6- Dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)oxy rac-N-((1r,4r)-4-(3-chloroethyl)piperazin-1-yl)-4-fluoronicotinamide (569); 4-(2-(2,6-dioxopiperidine-3-yl)-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-4-cyanophenoxy)cyclohexyl) (yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine rac-N-((1r,3r)-3-(3-chloro-4-cyano)pyridazine-3-carboxamide (570); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidine 7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl rac-N-((1r,3r)-3-(4-cyano)pyrimidine-5-carboxamide (571); No-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxo Isopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1- yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (572); ra cN-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6 -(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pi Perazin-1-yl)methyl)azetidin-1-yl)pyridazine-3-carboxamide (573); rac-N -((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxo isopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl Azetidin-1-yl)pyrimidine-5-carboxamide (574); rac-N-((1r,4r)-4-(4-cyano-3 -methylphenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)pyridine 5-Midine-5-carboxamide (575); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-6-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-furan (fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidine-1- rac-N-((1r,3r)-3-(3-chloro-4-cyanophenanthroline)pyridazine-3-carboxamide (576); 2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl) (yl)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine rac-N-((1r,3r)-3-(3-chloro-4-cyano)pyridazine-3-carboxamide (577); Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidine 1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1 -yl)pyrimidine-5-carboxamide (578); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) (1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl) Piperidin-1-yl)pyrazine-2-carboxamide (579); rac-N-((1r,4r)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amine (N-methyl)piperidin-1-yl)pyrimidine-5-carboxamide (580); rac-N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6 -dioxopiperidin-3-yl)-4,6-difluoro1,3-dioxoisoindolin-5-yl)piperidine Radin-1-yl)methyl)piperidin-1-yl)-4,6-dimethylpyrimidine-5-carboxamide (581); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo butyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)pyridazine-3-yl Ruboxamide (582); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran Methylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3- Dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-(2- N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)morpholino 1r,3r)-2,2,4,4-tetramethylcyclobutyl-2-(3-((((1r,3r)-3-((2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl )amino)methyl)azetidin-1-yl)pyrimidine-5-carboxamide (584); rac-N-((1r,3 r)-3-((5-cyano-6-ethylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl )-4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)piperidin-1-yl)benzamide (585); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-((((1r,3r)-3-( (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclo (isopropyl)amino)methyl)azetidin-1-yl)pyridazine-3-carboxamide rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)methyl)azetidin-1-yl)benzamide (5 87); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl rac-N-((1r,3yl)piperidin-4-yl)methyl)piperidin-4-yl)benzamide (588); r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(((1-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4 -yl)oxy)methyl)pyrrolidin-1-yl)benzamide (589); rac-N-((1r,3r)-3-(3-chlorophenyl) 4-(4-((1-(2-(2,6-dihydro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-( 6-fluoro-3-oxoisoindolin-5-yl)piperidin-4-yl rac-N-((1r,3r)-3-(3-chloro-4-methyl)piperazin-1-yl)benzamide (590); (aminophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidine) Lysin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl )piperazin-1-yl)benzamide (591); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenanthracene) 2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl) (1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperazin Peridine-1-yl)pyridazine-3-carboxamide (592); rac-2-chloro-4-(((1r,4r)-4-(5- (4'-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1- Methyl-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1-methyl-1H-imidazo rac-N-((1r,4r)-4-(3-chloro-2-yl)cyclohexyl)oxy)benzonitrile (593); -4-Cyanophenoxy)cyclohexyl)-6- (4-((4-(2-(2,6-dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxoisoindol methyl)piperidin-1-yl)pyridazine-3-carboxamide (594); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4,6-difluoro-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyrimidine-5-carboxylate Ruboxamide (595); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl) -4-(3-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) Piperazin-1-yl)methyl)azetidin-1-yl)benzamide (596); rac-N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((((1r,3r)- 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy) Cyclobutyl (isopropyl) amino) methyl) piperidin-1-yl) pyrazine-2-carboxamide Mido (597); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo Phosphorin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)pyrimidine-5-carboxamide rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisopropyl)-6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1,3-dioxoisopropyl) Indolin-5-yl)piperazin-1-yl)piperidin-1-yl)pyridazine-3-carboxamide (599); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylsilyl cyclobutyl)-6-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo isoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidine-1 -yl)pyridazine-3-carboxamide (600); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) (1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl) Piperidin-1-yl)picolinamide (601); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenanthracene) (2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidine-3- yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin-1-yl)hexyl)nicotinamide amide (602); rac-2-chloro-4-(((1r,4r)-4-(2-(4-(3-((4-(2-(2,6-dioxopiperidine 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)azetidine -1-yl)phenyl)-1H-imidazol-5-yl)cyclohexyl)oxy)benzonitrile (6 03); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene ethyl)-1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- (60)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-3-carboxamide 4); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene ethyl)-1-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )oxy)propyl)-1H-pyrazole-3-carboxamide (605); rac-N-((1r,4r)-4-(3-chloro 1-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4-cyanophenoxy)cyclohexyl) )-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)cyclohexyl)-1H- Pyrazole-3-carboxamide (606); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxopipe Lysin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidine (4-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octadiene 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxopiperidine) 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine (phenyl)-8-oxo-6-thioxo-5,7-phenyl Diazaspiro[3.4]octan-7-yl)picolinonitrile (608); rac-N-((1r,3r)-3-(3-cyclohexyl) 4-(((4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dichloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) 1-oxopiperidin-3-yl)-3-methyl-1-oxoisoindolin-5-yl)piperazin-1-yl) rac-N-((1r,3r)-3-(3-chloro-4-cyano)-2-methyl- Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine )-1-methyl-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperazin Lysin-1-yl)benzamide (610); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-4 -Fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine- 1-yl)pyridazine-3-carboxamide (611); 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxo) isopiperidine-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl Piperidin-1-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4] Octan-7-yl)picolinonitrile (612); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxo Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)pi (4-phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl 5-(4-((1-(2-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazo[3,4-dihydro-1 ... (3-yl)phenoxy)ethyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione (614); rac-N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-( (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclo (isopropyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclohexyl 4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole 1,3-dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl) Benzamide (616); rac-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrahydrofuran 1-(1r,4R)-4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-diphenyl ether)- Oxoisoindolin-5-yl)piperidin-4-yl)(methyl)amino)cyclohexyl)-1H- Pyrazole-3-carboxamide (617); 5-(4-((1-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imide 2-(2,6-diphenyl)piperazin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-diphenyl) rac-N-((1r,3r)-3-(3-chloro-1,3-dioxopiperidin-3-yl)isoindoline-1,3-dione (618); b-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-((((1r,3r)-3-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutene (61) (isopropyl) amino) methyl) azetidin-1-yl) pyrazine-2-carboxamide 9); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -1-((1R,4R)-4-((((1r,3R)-3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Indolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl)cyclohexyl )-1H-Pyrazole-3-carboxamide (620); N-((1r,3r)-3-(4-cyano-3-methoxyphenoxy) 2-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine) Lysine-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl N-((1r,3r)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (621); -3-(4-cyano-3-methylphenoxy)-2,2,4,4- Tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl N-((1r,3r)-3-(4-cyano-3-yl)pyrimidine-5-carboxamide (622); ,5-Dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-( 2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutene (isopropyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide ( 623); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutene 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin N-((1r,4r)-4-(methyl)-1-pyridin-1-yl)benzamide (624); and N-((1r,4r)-4- (3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxo Piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl (1-yl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide (625).

[0251] In another embodiment, the present disclosure provides a library of compounds. The library comprises a plurality of compounds, wherein each compound has the formula ABM-L-ULM, where ULM is a ubiquitin ubiquitin pathway protein binding moiety (preferably an E3 ubiquitin as otherwise disclosed herein) CLM is a cytokinin ligase portion, for example, CLM, and ABM is an AR protein binding portion; In this case, the ABM is linked (preferably via a linker moiety) to the ULM, and In some cases, the ubiquitin pathway protein binding moiety is a ubiquitin pathway protein, particularly an E3 Recognizes ubiquitin ligase.

[0252] The present specification refers, where applicable, to pharma- ceutically acceptable salts, particularly acid addition salts, of the compounds of the present disclosure. or compositions comprising base addition salts.

[0253] The term "pharmaceutically acceptable salt" is used throughout this specification when referring to the Used to describe one or more salt forms of the compounds described in the specification, the salts being , increasing the solubility of the compound in the gastric fluids of the patient's digestive tract, and improving the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, pharma- ceutically acceptable salts. Suitable salts include those derived from various inorganic or organic bases and acids. Among many other acids and bases known in the pharmaceutical art, potassium and sodium are alkali metals such as lithium, alkaline earth metals such as calcium and magnesium, and ammonium salts. Sodium and potassium salts include: Particularly preferred as neutralized salts of phosphates according to the present disclosure.

[0254] To prepare pharma- ceutically acceptable acid addition salts of the above-mentioned base compounds useful in the present disclosure, The acids which are used include non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, For example, hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfuric acid salts, among many other acids. Acid salts, bisulfates, phosphates, perphosphates, acetates, lactates, citrates, percitrates, Tartrate, bitartrate, succinate, maleate, fumarate, gluconate, sucrose Salts, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates , p-toluenesulfonate, and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxypropyl) Examples of acids that form 3-naphthoic acid include:

[0255] Pharmaceutically acceptable base addition salts are pharma- ceutically acceptable salts of compounds or derivatives according to the present disclosure. The present invention may also be used to produce pharma- ceutically acceptable salt forms of the present compounds which are acidic in nature. Chemical bases that can be used as reagents to prepare acceptable base salts with such compounds are Such non-toxic base salts include, but are not limited to, those which form toxic base salts. For example, alkali metal cations (e.g., potassium and sodium) and alkaline earth metals Pharmacologically acceptable cations such as metal cations (e.g., calcium, zinc, and magnesium) Base salts derived from thiones, ammonium or water-soluble amine addition salts, e.g. N-methyl Tilglucamine (meglumine), as well as lower alkanol ammonium salts, and others Examples of pharma- ceutically acceptable base salts of organic amines include:

[0256] composition In another aspect, the present disclosure relates to compounds as described herein, including salts thereof, and pharma- ceutically acceptable salts thereof. In certain embodiments, the composition comprises a composition comprising a carrier that is suitable for use in the preparation of a pharmaceutical composition as described herein. A therapeutic or pharmaceutical composition comprising an effective amount of a compound as described above and an acceptable carrier. do.

[0257] The compounds in the pharmaceutical compositions of the present disclosure can be combined with carrier materials to produce a dosage form. The amount of the compound will vary depending on the host and disease being treated, and the particular mode of administration. The daily dose of active ingredient ranges from 0.1mg / kg to 1000mg / kg of body weight, depending on the efficacy of the drug. The toxicity and therapeutic efficacy of such compounds are evaluated using standard assays in cell cultures or experimental animals. Useful pharmaceutical procedures, such as LD50 (lethal dose for 50% of the population) and ED50 (lethal dose for 50% of the population) The relationship between toxicity and therapeutic efficacy can be determined by the procedure for determining the therapeutically effective dose at The dose ratio of LD50 to ED50 is the therapeutic index and can be expressed as LD50 / ED50. Compounds that exhibit toxic side effects can be used, but are not intended to affect non-diseased cells. To minimize potential damage and side effects, such compounds are administered to the affected tissue. Consideration should be given to designing a delivery system that targets the target site. Data obtained from drug and animal studies are used to formulate a range of dosages for human use. Such compounds can be administered at a dose that provides a circulating concentration that includes the ED50 with little or no toxicity. The dosage will vary depending on the dosage form employed and the route of administration utilized. For any compound used in the disclosed method, The therapeutically effective dose can be estimated initially from cell culture assays. IC50 determined in cell culture (i.e., the concentration of the test compound that achieves 50% inhibition of symptoms) Doses that are useful in humans can be formulated in animal models. Such information can be used to refine useful doses in humans. Plasma levels can be determined more accurately, for example by high performance liquid chromatography. It may be measured.

[0258] The compositions of the present disclosure can be formulated in a conventional manner using one or more pharma- ceutical acceptable carriers. These pharmaceutical compositions may be formulated and administered in controlled release formulations. Possible pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, Aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer Binders, e.g. phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fats A mixture of partial glycerides of acids, water, salts or electrolytes, e.g. prolamin sulfate, dihydrogen phosphate Sodium, potassium hydrogen phosphate, sodium hydrochloride, zinc salts, colloidal silica, trisilicic acid Magnesium acetate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, Sodium carboxymethylcellulose, polyacrylate, wax, polyethylene- Examples include polyoxypropylene block polymers, polyethylene glycol, and wool fat. can be done.

[0259] The active compound is sufficient to deliver to the patient a therapeutically effective amount for the desired indication. , in an amount that does not cause serious toxic effects in the patient being treated, in a pharma- ceutically acceptable carrier or The diluent contains the active compound. The preferred dose of the active compound is in the range of about 10 ng / kg to 300 mg / kg, preferably about 10 mg / kg per day. In the range of 0.1-100mg / kg, more commonly 0.1 mg / kg of recipient / patient body weight per day. Typical topical doses range from 0.01 to 5% wt / wt in a suitable carrier. It is possible.

[0260] The compound contains less than 1 mg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. It may be conveniently administered in any suitable unit dosage form, including, but not limited to, about 25 to 250 mg. An oral dosage of is often convenient.

[0261] The active ingredient is administered 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 preferred to administer the active ingredient in a dosage form to achieve a desired concentration. The formulation may be administered intravenously, optionally in a saline solution or in an aqueous medium. Oral administration can be achieved by administration of a bolus of the active ingredient. It is also suitable for producing degrees.

[0262] The concentration of the active compound in the drug composition determines the absorption, distribution, inactivation, and excretion rates of the drug, As well as other factors known to those skilled in the art, dosage values ​​may be reduced. Please note that the severity of the condition may also vary depending on the individual. For a given subject, a particular dosing regimen will depend on the individual's needs and the administration of the composition. or should be adjusted over time according to the professional judgment of the person administering the drug; The concentration ranges described herein are exemplary and are not intended to limit the scope of the claimed compositions. It should be understood that this is not intended to limit the scope of the present invention or the practice of the present invention. The dose may be given in one dose, or may be divided into a number of smaller doses to be administered at various intervals of time. Good too.

[0263] If administered intravenously, preferred carriers are saline or phosphate buffered saline (PBS ).

[0264] In one embodiment, the active compound is delivered via, for example, implants and microencapsulated delivery systems. and controlled-release formulations, including delivery systems, that protect the compound from rapid elimination from the body. For example, ethylene vinyl acetate, polyanhydride, polyglycolic acid, cobalt Biodegradable and biocompatible polymers such as lagen, polyorthoesters, and polylactic acid Methods for the preparation of such formulations will be apparent to those skilled in the art.

[0265] Liposomal suspensions may also be pharma- ceutical acceptable carriers. These are described, for example, in U.S. Pat. No. 4,522,811, the entirety of which is incorporated herein by reference. For example, liposome formulations may be prepared according to methods known to those skilled in the art. A suitable lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylethanolamine, phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol The lipids are dissolved in an inorganic solvent and then evaporated to leave a thin layer of dried lipids on the surface of the container. The membrane may be left in place. An aqueous solution of the active compound is then placed in the container. Rotate the container by hand at 37°C to free lipid material from the sides of the container, disperse lipid clumps, and separate the liposomes. A suspension is formed.

[0266] Mode of administration In any of the aspects or embodiments described herein, the compounds described herein The therapeutic composition comprising the agent may be any suitable composition adapted to be delivered by any suitable route. The compound may be administered in any suitable dosage form, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or intravenously. The compositions may be administered by any suitable route, such as topically, for example as a liquid, cream, gel, or the like. or in solid form, transdermally, rectally, nasally, orally, vaginally, or via an implanted vessel; Or it can be administered in aerosol form.

[0267] As used herein, the term "parenteral" refers to any of the following: subcutaneous, intravenous, intramuscular, intraarticular, synovial, Includes intrathecal, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0268] The compounds described herein may be administered orally, parenterally or topically in a single dose or in combination with other Administration of the active compound may be continuous (intravenous drip) to several doses per day. These may range from multiple oral doses (e.g., QID) to multiple intravenous doses, among other routes of administration. Oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), oral These include intravenous, sublingual, and suppository administration. The most effective dosage form may be used to enhance the bioavailability of the compound from the oral route of administration. will depend on the pharmacokinetics of the particular agent selected, as well as the severity of the patient's disease. .

[0269] As a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration Administration of the compounds may be used. The compounds described herein may be administered in immediate release or sustained release form. The sustained release or controlled release formulations may be administered orally. is preferred, but may also be administered in suppository and transdermal or other topical forms. Intramuscular injection of may be used to control or sustain the release of the compound at the injection site.

[0270] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents, as known in the art. The sterile injectable preparation may be prepared, for example, by a solution in 1,3-butanediol. As a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, Among the acceptable vehicles and solvents that may be employed are Ringer's solution, sodium chloride solution, and the like. In addition, sterile fixed oils can be used as solvents or suspending media. For this purpose, synthetic mono- or diglycerides are used conventionally. Any bland fixed oil may be employed, for example olive oil or castor oil, particularly As are natural pharma- ceutically acceptable oils, such as their polyoxyethylated versions, e.g. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables. These oil solutions or suspensions can be diluted with a long-chain alcohol diluent or dispersant, such as Ph. Helv or may contain similar alcohols etc.

[0271] The pharmaceutical compositions described herein may be administered in the form of, but not limited to, a capsule, tablet, aqueous suspension or water. It may be orally administered in any orally acceptable dosage form, including a solution. In the case of tablets for oral administration, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Oral compositions generally include The composition may contain an inert diluent or an edible carrier. It may also be encapsulated in a gelatin capsule. For the purposes of oral therapeutic administration, the active compound or its prodrug may be administered in a dosage form, such as a tablet, tablet, or compressed into a tablet. The Rag derivative is combined with an excipient and used in the form of a tablet, troche, or capsule. Pharmaceutically compatible binding agents, and / or adjuvant materials may be added to the composition. Include as part of.

[0272] The tablets, pills, capsules, troches, etc. contain the following ingredients, or compounds of a similar nature: It may contain any of: e.g. microcrystalline cellulose, gum tragacanth or gelatin. binders such as starch or lactose; excipients such as alginic acid, Prim Dispersing agents such as ogel or cornstarch; e.g. magnesium stearate or Sterot lubricants, such as colloidal silicon dioxide; glidants, such as sucrose or or sweeteners such as peppermint, methyl salicylate or ointment; Flavoring agents, such as microwave flavorings. If the dosage unit form is a capsule, the above types of substances may be used. Additionally, liquid carriers such as fatty acids can be included. For example, various additives that modify the physical form of the dosage unit, such as sugar, shellac, or enteric agents. The composition may contain other substances such as

[0273] The active compound or a pharma- ceutically acceptable salt thereof may be administered as an elixir, suspension, syrup, wet It can be administered as a component of a syrup, chewing gum, etc. In addition to the lactic acid compounds, sucrose as a sweetener and / or certain preservatives, dyes and colorings , as well as flavoring agents.

[0274] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These are mixed with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature. It can be prepared by mixing a medicament such as a syrup with a syrup which will melt in the rectum and release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. can be.

[0275] The pharmaceutical compositions of the present disclosure may be administered topically. Suitable topical formulations are available for each of these areas. Topical application for the lower intestinal tract may be effected by rectal suppository formulations, which may be easily prepared for each area or organ. This can be achieved by administering the drug in a suitable formulation (see above) or by administering an appropriate enema. For topical application, the pharmaceutical compositions may be administered in one or more carriers. The compound of the present disclosure may also be formulated in a suitable ointment containing the active components suspended or dissolved therein. Carriers for topical administration of the compound include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, proline. Pyrene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and In certain preferred aspects of the present disclosure, the compound is surgically implanted in a patient. The present invention may be applied to a stent that is in a patient's body and is coated onto the stent to prevent blockage of the stent in the patient. The possibility of this occurring is prevented or reduced.

[0276] Alternatively, the pharmaceutical compositions may be suspended or dissolved in one or more pharma- ceutically acceptable carriers. The active ingredient may be formulated in a suitable lotion or cream. Examples include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetearyl alcohol, and the like. Chile Ester Wax, Cetearyl Alcohol, 2-Octyldodecanol, Benzyl Alcohol Coal and water.

[0277] For ophthalmic use, the pharmaceutical composition is a micronized suspension in isotonic, pH adjusted, sterile saline. As a suspension or, preferably, together with a preservative, e.g., benzylalkonium chloride It is formulated as a solution in isotonic, pH-adjusted, sterile saline with or without Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment, such as petrolatum. This may also be the case.

[0278] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. The compositions are prepared according to techniques known in the pharmaceutical formulation art and are administered as solutions in saline: Benzyl alcohol or other suitable preservative, absorption to improve bioavailability Promoters, fluorocarbons, and / or other conventional solubilizing or dispersing agents. The composition may be prepared by employing an agent.

[0279] Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical application contain the following components: Components may include: e.g., water for injection, saline solution, fixed oils, polyethylene glycols A sterile diluent such as ethanol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; or sodium bisulfite; chelators such as ethylenediaminetetraacetic acid buffers, such as acetates, citrates, or phosphates, and buffers, such as sodium chloride Tonicity adjusters such as glycerol or dextrose. Parenteral preparations are Packaged in ampoules, disposable syringes, or multiple-dose vials made from This is also fine.

[0280] The specific dosage and treatment regimen for any particular patient will depend on the particular Activity of the compound, age, body weight, general health condition, sex, diet, administration time, excretion rate, drug composition The combination of these factors, as well as the judgment of the treating physician and the weighting of the particular disease or condition being treated, It should also be understood that this will depend on a variety of factors, including the severity of the condition.

[0281] A patient or subject in need of treatment with the compounds described herein may be a patient having a pharmacologic An effective amount of the compound, including an acceptable salt, solvate or polymorph, is optionally administered in a pharma- ceutically acceptable form. The compound may be administered to a patient (subject) alone or in combination with other known agents in a suitable carrier or diluent. It can be treated by.

[0282] Coadministration Symptom conditions that may be treated using the compounds or compositions according to the present invention include, but are not limited to, Examples of cancer include, but are not limited to, cancer (e.g., prostate cancer) and Kennedy's disease. So, the therapeutic or pharmaceutical composition can contain an additional biological or bioactive agent, e.g. , including an effective amount of a co-administered agent effective in treating cancer.

[0283] The term "co-administration" or "combination therapy" refers to the administration of at least two compounds or compositions. are administered simultaneously to a patient, thereby providing an effective amount or effective doses of each of the two or more compounds. It is intended to mean that the concentration can be present in a patient for a given period of time. Although the compounds may be co-administered to a patient at the same time, the term refers to all compounds or compositions that are co-administered. The two may be administered simultaneously or at different times, so long as effective concentrations of the substances are present in the patient at a given time. In a specific preferred embodiment of the present disclosure, the above-mentioned One or more of the compounds may be administered in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In particularly preferred embodiments of the present disclosure, the co-administration of the compounds provides a method for treating cancer, including anti-cancer, This results in a synergistic treatment that

[0284] In another aspect, the present disclosure provides a method for treating a disease comprising administering to a patient a therapeutically effective amount of two or more of the PROTAC compounds described herein, and and a pharma- ceutically acceptable carrier. In certain embodiments, the composition comprises P It further includes an effective or synergistic amount of another bioactive agent that is not a ROTAC compound.

[0285] An effective amount of at least one bifunctional compound according to the present disclosure and as otherwise described herein. A combination of one or more of the described compounds in an effective amount is administered in a pharmacologic effective amount. Pharmaceutical compositions comprising the compound in combination with an agent, excipient, or vehicle represent a further aspect of the disclosure.

[0286] The term "bioactive agent" refers to an agent other than the PROTAC compounds described herein. and the treatment, inhibition, and / or control for which the compounds are used. Used in combination with the compound as a biologically active agent to aid in the prevention of disease. Preferred bioactive agents for use herein are those in which the compounds are used or administered. Examples of such agents include those having pharmacological activity similar to that of the administered agent, such as anticancer agents.

[0287] The term "additional anti-cancer agent" refers to an agent that may be administered in combination with a PROTAC compound according to the present invention to treat cancer. It is used to describe anti-cancer drugs that may be used. These drugs include, for example, everolim. everolimus, trabectedin, abraxane, TLK 2 86, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin (en zastaurin), vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, androgen receptor inhibitors, VEGFR inhibitors, EGFR TK inhibitors agents, aurora kinase inhibitors, PIK-1 inhibitors, Bcl-2 inhibitors, HDAC inhibitors, c-ME T inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase enzyme inhibitors, AKT inhibitors, JAK / STAT inhibitors, checkpoint-1 or -2 inhibitors, focal adhesion Kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed (pemetrexed), erlotinib, dasatinib, nilotinib nilotinib, decatanib, panitumumab, amrubicin (amrubicin), oregovomab, Lep-etu, nolatrexed , azd2171, batabulin, ofatumumab, zanolimumab zanolimumab, edotecarin, tetrandrine, rubite Can (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, Lucanton (lucanthone), LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311 , romidepsin, ADS-100380, sunitinib, 5-fluorouracil fluorouracil, vorinostat, etoposide, Gemcitabine, doxorubicin, liposomal doxorubicin liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine incristine, 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]benzene [zoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled iridium Irinotecan, tamoxifen, toremifene citrate emifene citrate, anastrazole, exemestane , letrozole, DES (diethylstilbestrol )), estradiol, estrogen, conjugated estrogens bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperidine) radinmethyl-indolyl-quinolone, vatalanib, AG-013736, AVE-0005 , [D- Ser(Bu t ) 6 ,Azgly 10 ] (Pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t )-Leu-Arg-Pr o-Azgly-NH 2 Acetate [C 59 H 84 N 18 Oi 4 -(C 2 H 4 O 2 ) X , where x = 1 to 2.4] acetate, Gosselery goserelin acetate, leuprolide acetate, triptorelin elin pamoate, medroxyprogesterone acetate, hydroxyprogesterone Cyprogesterone caprylate, megestrol acetate, raloxifene (raloxifene), bicalutamide, flutamide, nilutamide nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272 , erlotinib, lapatinib, canertinib , ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Lonafa Ionafarnib, BMS-214662, tipifarnib, amifostine amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid roxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib fenib, KRN951, aminoglutethimide, arnsa crine), anagrelide, L-asparaginase, Bacillus Calmette-Guerin BCG vaccine, adriamycin, bleomycin, buce Buserelin, busulfan, carboplatin, Carmustine, chlorambucil, cisplatin n), cladribine, clodronate, cyproterone roterone, cytarabine, dacarbazine, dactinomycin Dactinomycin, daunorubicin, diethylstilbestrol (diethylstilbestrol), epirubicin, fludarabine , fludrocortisone, fluoxymesterone , flutamide, Gleevec, gemcitabine, Hydroxyurea, idarubicin, ifosfamide amide), imatinib, leuprolide, levamisole isole, lomustine, mechlorethamine, melfala melphalan, 6-mercaptopurine, mesna, methotrexate methotrexate, mitomycin, mitotane, Mitoxantrone, nilutamide, octreotide eotide, oxaliplatin, pamidronate, pentose Statins (pentostatin), plicamycin, porfimer , procarbazine, raltitrexed, rituximab Rituximab, streptozocin, teniposide, tes Testosterone, thalidomide, thioguanine ne), thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard alanine mustard, uracil mustard, estramustine mustine, altretamine, floxuridine, 5-de 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine aptopurine, deoxycoformycin, calcitriol triol, valrubicin, mithramycin, vinblastine Vinblastine, vinorelbine, topotecan, razoxin Razoxin, marimastat, COL-3, neovastat ), BMS-275291, squalamine, endostatin, SU5416 , SU6668, EMD121974, interleukin-12, IM862, angiostatin , vitaxin, droloxifene, idoxyfene ene), spironolactone, finasteride, simici Cimitidine, trastuzumab, denileukin diftitox ileukin diftitox, gefitinib, bortezimib, Paclitaxel, Cremophor-free Paclitaxel litaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen oxytamoxifen, pipendoxifene, ERA-923, arzoxifene arzoxifene, fulvestrant, acolbifene, la Lasofoxifene, Idoxifene, TSE-424, HMR-3339 , ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus rolimu), AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293 684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgra Filgrastim, darbepoetin, erythropoietin, granulocyte colony Ronnie's stimulatory factor, zoledronate, prednisone, setu Cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin elin), pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon Interferon alfa-2b, interferon alfa-2b, azacitidine e), PEG-L-asparaginase, lenalidomide, gemtuzumab mab), hydrocortisone, interleukin-11, dexrazoxane (dexrazoxane), alemtuzumab, all-trans retinoic acid (all- transretinoic acid, ketoconazole, interleukin-2, meges megestrol, immunoglobulin, nitrogen mustard d), methylprednisolone, ibritumomab tiuxetan itgumomab tiuxetan, androgen, decitabine, hexamethylmelamine Hexamethylmelamine, bexarotene, tositumomab ), arsenic trioxide, cortisone, etidronate, mitotane, Cyclosporine, liposomal daunorubicin ), Edwina-asparaginase, Strontium 89, Cassopi Casopitant, netupitant, NK-1 receptor antagonist, palonosetro Palonosetron, aprepitant, diphenhydramine amine, hydroxyzine, metoclopramide, Lora Lorazepam, alprazolam, haloperidol , droperidol, dronabinol, dexamethasone xamethasone, methylprednisolone, prochlorperazine rochlorperazine, granisetron, ondansetron ), dolasetron, tropisetron, pegfilgras pegfilgrastim, erythropoietin, epoetin alfa poetin alfa, darbepoetin alfa, and mixtures thereof Examples include:

[0288] Treatment method In another aspect, the present disclosure provides a method for the detection of a marker in a subject, e.g., a cell, tissue, mammal, or human patient. A method for regulating protein ubiquitination and degradation is provided, the method comprising: , an effective amount of a PROTAC compound described herein, or an effective amount of said compound administering the composition to a subject, wherein the compound or the composition comprising the compound is The method is effective in modulating protein ubiquitination and protein degradation in the subject. In certain embodiments, the protein is the androgen receptor (AR).

[0289] In certain embodiments, the present disclosure provides a method for administering to a patient an amount of a compound described herein. androgen receptor protein activity in patients in need thereof, including administering This provides a method for

[0290] In yet further embodiments, the present disclosure provides a method for treating a symptom or condition in a patient. wherein deregulated protein activity is a symptom or condition. and the method comprises administering to the patient an effective amount of a compound described herein. and regulating the activity of the protein in the patient. In the present study, the protein is AR.

[0291] As used herein, "treat," "treating," and "treatment" The term refers to any action that provides a benefit to a patient for which the compound is The compounds may be administered to treat any condition or condition that is modulated via the protein to which they bind. Symptoms or conditions that may be treated using compounds according to the present disclosure, including cancer. is described herein above.

[0292] In another aspect, the present disclosure provides a method for the detection of a marker in a subject, e.g., a cell, tissue, mammal, or human patient. A method for regulating AR protein ubiquitination and degradation is provided, is an effective amount of a compound described herein, or wherein the compound or a composition comprising the compound is administered to a subject. The composition is effective in modulating AR protein ubiquitination and protein degradation in the subject. be.

[0293] In another aspect, the present disclosure provides a method for the detection of a marker in a subject, e.g., a cell, tissue, mammal, or human patient. A method for treating or ameliorating symptoms of a disease associated with AR activity is provided, the method comprising: The present invention relates to a method for treating a patient suffering from atopic dermatitis, comprising administering to said patient an effective amount of a compound described herein or a composition comprising an effective amount of said compound. administering to a subject in need thereof the compound, or a composition comprising the compound, The composition is effective to treat or ameliorate symptoms of a disease associated with AR activity in the subject.

[0294] In certain embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, prostate cancer, Kennedy's disease, or a combination of these. cerebrovascular disease, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders Disability, obesity, refractive errors, infertility, Angelman syndrome, Canavan syndrome, celiac disease, Charcoal-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis , hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic ovarian tumors Kidneys, (PKD1) or 4 (PDK2) Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease The cancers are squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and Turner syndrome. renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer Cancer, cervical, ovarian, pancreatic, prostate and gastric cancer; leukemia; benign and malignant lymphoma; especially Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; bone marrow Proliferative diseases; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroma, Synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, Ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, nerve fiber tumor sarcomas, including schwannomas; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer foetal cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratocarcinoma. In certain embodiments, the treatment The disease of interest is cancer, e.g., prostate cancer, or Kennedy's disease. The subject is a human.

[0295] In another aspect, the present disclosure provides a method for the detection of a marker in a subject, e.g., a cell, tissue, mammal, or human patient. A method for treating or ameliorating symptoms of a disease associated with AR activity is provided, the method comprising: an effective amount of a compound described herein, or a composition comprising an effective amount of said compound; administering to a subject in need thereof an effective or synergistic amount of another bioactive agent; wherein the composition comprising the compound is for treating a symptom of a disease associated with AR activity in the subject. In certain embodiments, the disease being treated is cancer, e.g., prostate cancer. or Kennedy's disease. In a preferred embodiment, the subject is a human. In an additional embodiment, the additional bioactive agent is an anti-cancer agent.

[0296] In another aspect, the present disclosure provides a method for treating a condition by degrading a protein or polypeptide. and a method of treating a subject with a protein or polypeptide comprising administering to said subject a therapeutic agent. The symptom or condition is modulated, and the method comprises administering to the patient or subject at least one of the above-described and optionally administering in combination with an effective amount of another compound, and optionally an additional bioactive agent. The disclosed methods are used to administer an effective amount of at least one compound described herein. By doing so, many symptoms or conditions can be treated, including cancer.

[0297] In another aspect, the present disclosure provides a method for the treatment of cancer in biological systems using compounds according to the present disclosure. The present invention provides a method for identifying the degradative effect of an elephant protein.

[0298] kit In another aspect, the present disclosure provides a kit comprising a compound or composition described herein. The kit may be advertised, distributed, or sold as a unit for performing the methods of the disclosure. Additionally, the kits of the present disclosure preferably include instructions for proper use. Such kits may be used, for example, in clinical settings, e.g., cancer, Patients exhibiting conditions such as prostate cancer or Kennedy's disease may be treated. EXAMPLES

[0299] Overall Chemistry - Analysis and Synthesis Unless otherwise stated, all materials / reagents were obtained from commercial suppliers and used without further purification. The reactions were monitored by LC-MS and / or by pre-covering with aluminum foil or Glass-reinforced silica gel 60F 254 (0.2 mm) by thin layer chromatography (TLC). The elution was monitored by flash chromatography (or "flash chromatography") and visualized with UV light. ISCO chromatography (also called "ISCO chromatography") was performed using RediSep normal phase silica gel cartridges. Preparative TLC was performed using an ISCO CombiFiash RF 75 PSI equipped with a 750 psi column or equivalent. Whatman LK6F Silica Gel 60A size 20x20cm plate with thickness of 1000μm or equivalent So I went.

[0300] 1 HNMR (300 or 400 MHz), and 13 CNMR (100.6 MHz) spectra were obtained at room temperature. The spectra were recorded on a Bruker spectrometer using TMS or the residual solvent peak as standard. The position or overlap is given by (δ), and the coupling constant (J) is given as an absolute value in Hertz (Hz). Multiplicities in 1H NMR spectra are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br or broad.

[0301] Preparative HPLC purification is performed using the 2545 Binary Gradient Module, 2767 Sample Manager and 2489 Waters equipped with a UV / Visible Detector (登録商標) On UV-Directed Purification System The experiments were performed at 37 °C and controlled by MassLynx V4.1 software. The following columns were used: The purification work was completed using: Atlantis Prep T3 OBD column, SunFire Prep C18 OBD column, and an XBridge Prep Phenyl OBD column. The mobile phase was water (0.1% TFA or 0.01% NH 4 HCO 3 of The reagents used were of HPLC grade. The flow rate was 30 ml / min. After the column, a 1:1000 LC packing flow splitter was used to separate the eluate. A small portion of the eluent was transferred to the UV detector. The electrospray source was capillary-coupled at 3.0 kV. -voltage, 30 V cone voltage, 110 °C source temperature, 350 °C desolvation temperature, 600 L / h desolvation The analyzer was set at 1000 psi, 1000 psi, and 60 L / h cone gas flow. The magnification was set at 550 for the preparative method.

[0302] Analytical LC-MS data were obtained from 0.05% TFA in acetonitrile (A) and 0.05% TFA in HPLC grey water (B). 0.1% FA in acetonitrile (A) and 0.1% FA in HPLC grade water (B) ); the mobile phase is acetonitrile (A) and 5 mM ammonium bicarbonate in HPLC grade water (B). and collected on a Shimadzu LCMS-2020.

[0303] The Shimadzu LCMS-2020 is equipped with an LC-20AD or 30AD pump, an SPD-M20A PDA, and an Alltech 3 Equipped with a 300 ELSD, the system was configured for runs of 2.0, 2.6, 3, 3.6, 5, or 5.6 minutes. The following conditions are used for the times:

[0304] 2.0 min run: Kinetex XB-C 18 100A column, 2.6 μm, 3.0 × 50 mm. Flow rate was 1.5 mL / min. The run time was 2.0 min, and the gradient profile was 0.01 min 10% A, 1.10 min 100% A, and 1.60 min 100% A. , 1.70 min 10% A, and 2.00 min 10% A.

[0305] 2.6 min run: Shim-pack VP-ODS column, 2.2 μm, 3.0 × 50 mm. Flow rate was 1.5 mL / min. The time was 2.6 min, and the gradient profile was 0.01 min 5% A, 1.20 min 100% A, 2.20 min 100% A, 2.30 min 5%A, 2.60 min 5%A.

[0306] 3.0 min run: ACE UlTracore SuperC18 column, 2.5 μm, 3.0 x 50 mm. Flow rate 1.5 mL / min. , runtime 3.0 min, gradient profile 0.01 min 10% A, 2.00 min 95% A, 2.60 min 95% A , 2.70 min 10% A, and 3.00 min 10% A.

[0307] 3.6 min run: Shim-pack VP-ODS column, 2.2 μm, 3.0 × 50 mm. Flow rate was 1.5 mL / min. The time was 3.6 min, and the gradient profile was 0.01 min 5% A, 2.20 min 100% A, 3.20 min 100% A, 3.30 min 5% A, 3.60 min 5% A.

[0308] 5.0 min run: ACE UlTracore SuperC18 column, 2.5 μm, 3.0 x 50 mm. Flow rate 1.5 mL / min. , runtime was 5.0 min, gradient profile was 0.01 min 10% A, 4.00 min 60% A, 4.70 min 60% A, 4.80 min 10% A, 5.00 min 10% A.

[0309] 5.6 min run: Shim-pack VP-ODS column, 2.2 μm, 3.0 × 50 mm. Flow rate was 1.5 mL / min. The time was 5.6 min, and the gradient profile was 0.01 min 5% A, 3.00 min 50% A, 5.00 min 50% A, and 5.20 min 5% A, 5.60 min 5% A.

[0310] or Analytical LC-MS data were obtained using an Agilent infinity 1260 LC and an Agilent 6230 TOF mass spectrometer. The analysis was performed on a Poroshell 120 EC C18 column (50 mm x 3.0 mm internal The process is carried out using a packing diameter of 2.7 μm. The solvents employed were: A = 0.1% v / v formic acid in water. B = 0.1% v / v formic acid in acetonitrile. The gradient used is:

[0311] [Table 1]

[0312] UV detection was the average signal from wavelengths of 210 nm to 350 nm, and mass spectra were obtained from the positive moieties. The ions are recorded on a mass spectrometer using electrospray ionization of the chromatographic data.

[0313] Unless otherwise stated, all compounds were prepared with LC-MS purity of >95%. chemical synthesis ABM-L-ULM PROTAC, or a pharma- ceutically acceptable salt, polymorph, or prodrug thereof; Solvated, isotope-containing derivatives can be prepared according to the general methods described below (Scheme 1 and and 2, and general schemes 1–122, 1A–22A, and 1B–25B) have been published in the field of organic chemistry. They can be prepared using known synthetic methods, as well as modification and derivatization methods known to those of skill in the art.

[0314] Scheme 1:

[0315] [ka]

[0316] Scheme 2:

[0317] [ka]

[0318] General Scheme 1:

[0319] [ka]

[0320] General Scheme 2:

[0321] [ka]

[0322] General Scheme 3:

[0323] [ka]

[0324] General Scheme 4:

[0325] [ka]

[0326] General Scheme 5:

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[0328] General Scheme 6:

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[0330] General Scheme 7:

[0331] [ka]

[0332] General Scheme 8:

[0333] [ka]

[0334] General Scheme 9:

[0335] [ka]

[0336] General Scheme 10:

[0337] [ka]

[0338] General Scheme 11:

[0339] [ka]

[0340] General Scheme 12:

[0341] [ka]

[0342] General Scheme 13:

[0343] [ka]

[0344] General Scheme 14:

[0345] [ka]

[0346] General Scheme 15:

[0347] [ka]

[0348] General Scheme 16:

[0349] [ka]

[0350] General Scheme 17:

[0351] [ka]

[0352] General Scheme 18:

[0353] [ka]

[0354] General Scheme 19:

[0355] [ka]

[0356] General Scheme 20:

[0357] [ka]

[0358] General Scheme 21:

[0359] [ka]

[0360] General Scheme 22:

[0361] [ka]

[0362] General Scheme 23:

[0363] [ka]

[0364] General Scheme 24:

[0365] [ka]

[0366] General Scheme 25:

[0367] [ka]

[0368] General Scheme 26:

[0369] [ka]

[0370] General Scheme 27:

[0371] [ka]

[0372] General Scheme 28:

[0373] [ka]

[0374] General Scheme 29:

[0375] [ka]

[0376] General Scheme 30:

[0377] [ka]

[0378] General Scheme 31:

[0379] [ka]

[0380] General Scheme 32:

[0381] [ka]

[0382] General Scheme 33:

[0383] [ka]

[0384] General Scheme 34:

[0385] [ka]

[0386] General Scheme 35:

[0387] [ka]

[0388] General Scheme 36:

[0389] [ka]

[0390] General Scheme 37:

[0391] [ka]

[0392] General Scheme 38:

[0393] [ka]

[0394] General Scheme 39:

[0395] [ka]

[0396] General Scheme 40:

[0397] [ka]

[0398] General Scheme 41:

[0399] [ka]

[0400] General Scheme 42:

[0401] [ka]

[0402] General Scheme 43:

[0403] [ka]

[0404] General Scheme 44:

[0405] [ka]

[0406] General Scheme 45:

[0407] [ka]

[0408] General Scheme 46:

[0409] [ka]

[0410] General Scheme 47:

[0411] [ka]

[0412] General Scheme 48:

[0413] [ka]

[0414] General Scheme 49:

[0415] [ka]

[0416] tert-Butyl 4-(4-(hydroxymethyl)piperidin-1-yl)benzoate 3 (15 g, 51.4 mmol) ) in DCM (100 mL), Dess-Martin periodinane (26.1 g, 61.6 mmol) was added in an ice-water bath. ) was added and the clear solution was stirred at room temperature for 2 h. The solvent was evaporated and EtoAc was added. The mixture was Pass through a pad of silica gel, wash with EtOAc, and evaporate the solvent to give the crude product. (Combined with another batch of crude product starting from 10 g of starting material for purification). The crude product was dry loaded onto an ISCO (0-10% MeOH / DCM). A pale yellow solid, 16.11 g4 (6% yield) was obtained. 5%) was obtained as the product.

[0417] tert-Butyl 4-(4-formylpiperidin-1-yl)benzoate 4 (15.79 g, 54.2 mmol) and 2-( 2,6-Dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione di A mixture of hydrochloride 5 (22.5 g, 54.2 mmol) in DCM (500 mL) was added with sodium acetate (4. The reaction mixture was stirred for 3 minutes and then poured into an ice-water bath. ) 3 (20.0 g, 94.8 mmol) was added over 10 min and removed from the vessel after an additional 10 min. After 2 h, water (500 mL) and DCM (150 mL) were added, the organic layer was removed, and the aqueous layer was extracted with DCM (150 ml). The organic matter was extracted and collected. 2 SO 4 Drying at 40° C. and evaporation gave the crude product 6, which was isolated. Silica gel was used to dry-pack an ISCO (0-10% MeOH / DCM, 750 g column) for analysis. The fractions were collected, dried, exchanged twice with DCM, and dried under high vacuum for 26 h to give 18.15 g of 6 (yield: 18.15 g). Yield: 60%) as a yellow solid.

[0418] A solution of 4N HCl in dioxane (40 mL, 29.3 mmol) was added to 4-(4-((4-(2-(2,6-dioxopiperidinyl 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine tert-Butyl (1-yl)benzoate 6 (18.15 g, 29.3 mmol) was added and the reaction mixture was stirred for 7 h, 5 Heat to 0° C. The solvent was evaporated and replaced with DCM twice and dried under high vacuum overnight. The mixture was exchanged twice with DCM and dried under high vacuum for 8 hours to give 18.77 g (101...

Claims

1. A compound having the structure: ABM-L-CLM, wherein ABM is an androgen receptor (AR) binding moiety and L is a chemical linker moiety; CLM is a cereblon E3 ubiquitin ligase binding moiety, wherein the ABM is It comprises a structure selected from the group consisting of: 【Chemistry 1】 During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently At least one of H, halo, hydroxyl, nitro, CN, C≡CH, C 1～6 Alkyl (optionally substituted Linear or branched chain. For example, one or more halo, C 1～6 optionally substituted with alkoxyl); C 1～6 Alkoxy (straight or branched chain optionally substituted, e.g., optionally substituted with one or more halo) ), C 2～6 Alkenyl, C 2～6 Alkynyl, or CF 3 is replaced by; Y 1 , Y 2 are each independently NR Ｙ1 , O, S, SO 2 , heteroaryl, or aryl; 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, SO 2 , Heteroa is aryl or aryl; Q is a 3-6 membered ring with 0-4 heteroatoms and optionally 0-6 R Q Each R Q are independently H, C 1～6 Alkyl (straight or branched chain, optionally substituted; e.g., one or more halo , C 1～6 alkoxyl optionally substituted), halogen, C 1～6 Alkoxy or is two R Q The groups are 3-8 membered ring systems that contain 0-2 heteroatoms together with the atom to which they are attached. Forming 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 alkoxyl optionally substituted), halogen, C 1 ～6 alkoxy, cyclic, heterocyclic or R 1 , R 2 are the atoms to which they are bonded. form a 3-8 membered ring system containing 0-2 heteroatoms; W 2 is a bond, C 1～6 Alkyl, C 1～6 Heteroalkyl, O, aryl, heteroaryl, fatty cyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each of which is optionally 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., 1 Optionally replaced by one or more F), -OR W2A , C 3～6 Cycloalkyl, C 4～6 Cyclohete Roalkyl, C 1～6 Alkyl (optionally substituted), heterocyclic (optionally substituted), a aryl (optionally substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl aryl or aryl, OC 1～3 Alkyl (optionally substituted, e.g., one or more -F , OH, NH 2 , N.R. Y1 R Y2 , CN; and R W2A , H, C 1～6 Alkyl (straight chain, branched chain), or C 1～6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1～3 A compound substituted with alkyl.

2. W 1 but, 【Chemistry 2】 2. The compound of claim 1, selected from the group consisting of:

3. W 2 but, 【Chemistry 3】 3. The compound of claim 2 selected from the group consisting of:

4. The CLM is an imide, thioimide, or amide that binds to cereblon E3 ubiquitin ligase. or a chemical group derived from a thioamide. Compound.

5. 5. The method of claim 4, wherein the chemical group is a phthalimide group or an analog or derivative thereof. Compound.

6. The CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isoforms thereof 4. The compound according to any one of claims 1 to 3, which is a star, or a derivative thereof.

7. The CLM: 【Chemistry 4】 having a chemical structure represented by During the ceremony, W is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; Each X is O, S, or H. 2 are independently selected from the group consisting of: Y is NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl. selected from the group consisting of ru, O and S; Z is O, S and H 2 selected from the group consisting of: G and G' are each independently H, optionally substituted straight or branched chain alkyl, OH, R'OC OOR, R'OCONRR”, CH optionally replaced by R' 2 -heterocyclyl, and R' is optionally substituted benzyl; Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from R', N, or N-oxide; a carbon C optionally substituted with a group; A is selected from the group consisting of H, alkyl, cycloalkyl, Cl and F; Rは、-CONR’R”、-OR’、-NR’R”、-SR’、-SO 2 R’、-SO 2 NR’R”、-CR’R”-、-CR’N R'R"-, -aryl, -hetaryl, -optionally substituted straight or branched chain alkyl, Cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)(OR')R", - OP(O)R’R”、-Cl、-F、-Br、-I、-CF 3 、-CN、-NR’SO 2 NR’R”、-NR’CONR’R”、-CONR 'COR”、-NR'C(=N-CN)NR'R”、-C(=N-CN)NR'R”、-NR'C(=N-CN)R”、-NR'C(=C-NO 2 )NR’R”、-SO 2 NR’COR”、-NO 2 、-CO 2 R’、-C(C=N-OR’)R”、-CR’=CR’R”、-CCR’、 -S(C=O)(C=N-R')R”, -SF 5 , -R'NR'R”, (-R'O) n R”, ​​or, and -OCF 3 Consists of Selected from the group: R' and R'' are each independently a bond, H, an optionally substituted straight or branched chain alkyl group, aryl, cycloalkyl, aryl, hetaryl, heterocyclyl, or -C(=O)R each of which is optionally substituted; 【Chemistry 5】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n is a functional group or an atom, where n is an integer from 1 to 10, and If n is 1, R n is modified to be covalently attached to a linker group (L), and If n is 2, 3, or 4, then one R n is modified to be covalently attached to a linker group (L). , and any other R n Optionally, ABM, CLM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any multiple or combination thereof. The compound according to any one of claims 1 to 3, wherein the compound is modified as follows:

8. The CLM or ULM has a chemical structure represented by: 【Chemistry 6】 During the ceremony: W is CH 2 , C═O, NH, and N-alkyl; R is independently selected from H, methyl, and alkyl; 【Chemistry 7】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains from 1 to 4 independently selected functional groups or atoms, and optionally one of is modified to include an ABM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof 10. The compound of claim 1, wherein the compound is covalently attached to the combination.

9. Chemical structure: A bifunctional compound comprising ABM-L-CLM, wherein ABM is an androgen receptor (AR) is a linking moiety, and L is absent (a bond) or a chemical linker; and CLM is the cereblon E3 ubiquitin ligase binding moiety, which is an imide, thio A chemical group derived from an imide, amide, or thioamide, where ABM is The compound includes a structure selected from the group consisting of: 【Chemistry 8】 During the ceremony: W 1 are aryl, heteroaryl, bicyclic, or biheterocyclic, each independently At least one of H, halo, hydroxyl, nitro, CN, C≡CH, C 1～6 Alkyl (optionally substituted Linear or branched chain. For example, one or more halo, C 1～6 optionally substituted with alkoxyl); C 1～6 Alkoxy (straight or branched chain optionally substituted, e.g., optionally substituted with one or more halo) ), C 2～6 Alkenyl, C 2～6 Alkynyl, or CF 3 is replaced by; 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, SO 2 , Heteroa is aryl or aryl; Q is a 3-6 membered ring with 0-4 heteroatoms and optionally 0-6 R Q Each R Q are independently H, C 1～6 Alkyl (straight or branched chain, optionally substituted; e.g., one or more halo , C 1～6 alkoxyl optionally substituted), halogen, C 1～6 Alkoxy or or two R Q The groups, together with the atom to which they are attached, may be 3-8 membered rings containing 0-2 heteroatoms. Forming 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 alkoxyl optionally substituted), halogen, C 1 ～6 alkoxy, cyclic, heterocyclic or R 1 , R 2 are the atoms to which they are bonded. form a 3-8 membered ring system containing 0-2 heteroatoms; W 2 is a bond, C 1～6 Alkyl, C 1～6 Heteroalkyl, O, aryl, heteroaryl, fatty cyclic, heterocyclic, biheterocyclic, biaryl, or biheteroaryl, each of which is optionally 1 to 10 R W2 is replaced by; 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, C 1～6 Alkyl (optionally substituted), C 1 ～6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally substituted) substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or Aryl, OC 1～3 Alkyl (optionally substituted, e.g., optionally substituted with one or more -F) ), OH, NH 2 , N.R. Y1 R Y2 , CN; and R W2A , H, C 1～6 Alkyl (straight chain, branched chain), or C 1～6 Heteroalkyl (straight chain, branched chain), each of which is optionally a cycloalkyl, cycloheteroalkyl, aryl, heterocycle, Heteroaryl, halo, or OC 1～3 Alkyl substituted, bifunctional compounds.

10. W 1 but, 【Chemistry 9】 The compound or bifunctionalized compound according to any one of claims 1 to 9 is selected from the group consisting of Compound.

11. W 2 but, 【Chemistry 10】 The compound or bifunctionalized compound according to any one of claims 1 to 10, selected from the group consisting of Compound.

12. CLM is an imide, thioimide, amide, or phosphodiesterase that binds to cereblon E3 ubiquitin ligase. The bifunctional compound according to any one of claims 9 to 11, comprising a chemical group derived from a thioamide or a thioamide. sexual compound.

13. 13. The method of claim 12, wherein the chemical group is a phthalimido group or an analog or derivative thereof. A bifunctional compound.

14. The CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isoforms thereof The bifunctional compound according to any one of claims 9 to 11, which is a star or a derivative thereof.

15. The CLM: 【Chemistry 11】 having a chemical structure represented by During the ceremony, W is CH 2 , CHR, C=O, SO 2 , NH and N-alkyl; Each X is O, S, or H. 2 are independently selected from the group consisting of: Y is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl , N-heterocyclyl, O and S; Z is O, S and H 2 selected from the group consisting of: G and G' are independently H, optionally substituted straight or branched chain alkyl (optionally substituted Straight or branched chain, optionally substituted with R', e.g., OH, R'OCOOR, R'OCONRR", CH optionally substituted with R' 2 -heterocyclyl, and benzyl optionally substituted at R' is selected from the group consisting of: Q 1 , Q 2 , Q 3 , and Q 4 are independently selected from R', N, or N-oxide. an optionally substituted carbon C; A is independently selected from the group: H, alkyl, cycloalkyl, Cl, and F; Rは、-CONR’R”、-OR’、-NR’R”、-SR’、-SO 2 R’、-SO 2 NR’R”、-CR’R”-、-CR’N R'R"-, (-CR'O) n R”, ​​-aryl, -hetaryl, -optionally substituted straight or branched chain Alkyl, -cycloalkyl, -heterocyclyl, -P(O)(OR')R", -P(O)R'R", -OP(O)( OR’)R”、-OP(O)R’R”、-Cl、-F、-Br、-I、-CF 3 、-CN、-NR’SO 2 NR’R”、-NR’CONR 'R', -CONR'COR', -NR'C(=N-CN)NR'R', -C(=N-CN)NR'R', -NR'C(=N-CN)R', - NR’C(=C-NO 2 )NR’R”、-SO 2 NR’COR”、-NO 2 、-CO 2 R’、-C(C=N-OR’)R”、-CR’=CR’R ",-CCR',-S(C=O)(C=N-R')R",-SF 5 , -R'NR'R”, (-R'O) n R”, ​​or -OCF 3 Including fruit; R' and R'' are independently a bond, H, optionally substituted straight or branched chain alkyl; Selected from the group consisting of cycloalkyl, aryl, hetaryl, heterocyclyl, -C(=O)R are selected, each of which is optionally substituted; 【Chemistry 12】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and R n contains a functional group or atom, where n is an integer from 1 to 10, and If n is 1, R n is modified to be covalently attached to a linker group (L), and If n is 2, 3, or 4, then one R n is modified to be covalently attached to a linker group (L). , and any other R n Optionally, ABM, CLM, a second CLM having the same chemical structure as CLM, CLM', a second linker, or any multiple or combination thereof. The bifunctional compound according to any one of claims 9 to 11, wherein the bifunctional compound is modified so as to

16. The CLM or ULM has a chemical structure represented by: 【Chemistry 13】 During the ceremony: W is CH 2 , C═O, NH, and N-alkyl; R is independently selected from H, methyl, and alkyl; 【Chemistry 14】 represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; and Rn contains from 1 to 4 independently selected functional groups or atoms, and optionally one of is modified to include an ABM, a chemical linker group (L), a ULM, a CLM (or CLM'), or a combination thereof 16. The compound of any one of claims 9 to 11 or 15, covalently attached to the combination.

17. The linker group L is a group comprising a chemical structural unit represented by the formula: -A q - In the formula, A q is a group attached to at least one of the CLM, ABM, or both; and q is an integer equal to or greater than 1; In the formula, Aq is a bond, CR L1 R L2 , O, S, SO, SO 2 , N.R. L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CON R L4 、NR L3 SO 2 NR L4 、CO、CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 、NR L3 C(=NCN)N R L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , 0 to 6 R L1 and / or R L2 Optionally substituted with a group C 3～11 Cycloalkyl, 0 to 9 R L1 and / or R L2 C optionally substituted with a group 5～13 Spirocycloalkyl, 0 to 6 R L1 and / or R L2 C optionally substituted with a group 3～11 Haeta Rocyclyl, 0 to 8 R L1 and / or R L2 C optionally substituted with a group 5～13 Spiroheterosis Chloroalkyl, 0 to 6 R L1 and / or R L2 aryl optionally substituted with 0 to 6 R L1 and / or R L2 and heteroaryl, optionally substituted with a group; In the formula, R L1 or R L2 each independently optionally binds to another group and is 0 to 4 R L5 Based on optional forming a substituted cycloalkyl and / or heterocyclyl moiety; R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or C 1～8 Alkyl, OC 1～8 Alki Le, S.C. 1～8 Alkyl, NHC 1～8 Alkyl, N(C 1～8 Alkyl) 2 , C 3～11 Cycloalkyl, a Aryl, Heteroaryl, C 3～11 Heterocyclyl, OC 1～8 Cycloalkyl, SC 1～8 Cyclo Alkyl, NHC 1～8 Cycloalkyl, N(C 1～8 Cycloalkyl) 2 , N(C 1～8 Cycloalkyl) (C 1～8 alkyl), OH, NH 2 , SH, SO 2 C 1～8 Alkyl, P(O)(OC 1～8 Alkyl)(C 1～8 Alki le), P(O)(OC 1～8 Alkyl) 2 , C.C.-C. 1～8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1～8 Alkyl)=CH(C 1～8 alkyl), C(C 1～8 Alkyl)=C(C 1～8 Alkyl) 2 , Si(OH) 3 , Si(C 1 ～8 Alkyl) 3 , Si(OH)(C 1～8 Alkyl) 2 , COC 1～8 Alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1～8 Alkyl, SO 2 N(C 1～8 Alkyl) 2 ,SONHC 1～8 Al KILL, SON(C 1～8 Alkyl) 2 , CONH.C. 1～8 Alkyl, CON(C 1～8 Alkyl) 2 , N(C 1～8 Alki CONH(C 1～8 alkyl), N(C 1～8 Alkyl)CON(C 1～8 Alkyl) 2 , NHCONH(C 1～8 Alki le), NHCON(C 1～8 Alkyl) 2 , N.H.C.O.N. 2 , N(C 1～8 Alkyl)SO 2 NH(C 1～8 alkyl), N(C 1 ～8 Alkyl)SO 2 N(C 1～8 Alkyl) 2 , N.H.S.O. 2 NH(C 1～8 alkyl), NHSO 2 N(C 1～8 Alkyl) 2 , N.H.S.O. 2 NH 2 The compound according to any one of claims 1 to 8 or any one of claims 9 to 16, 3. The bifunctional compound according to claim 1.

18. The linker (L) comprises a group represented by a general structure 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 15】 In the formula, m, n, o, p, q, and r are each independently 0, 1, 2, 3, 4, 5, or 6, provided that If the number is zero and there are no NO or OO bonds, R is H, methyl, or ethyl. and X is selected from the group of H and F; 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 【Chemistry 16-5】 【Chemistry 16-6】 【Chemistry 16-7】 wherein n and m are each independently 0, 1, 2, 3, 4, 5, or 6; and X is H or F. A compound or bifunctional compound according to any one of claims 1 to 17.

19. The linker (L) is 【Chemistry 17-1】 【Chemistry 17-2】 【Chemistry 17-3】 The compound or bifunctionalized compound according to any one of claims 1 to 17, selected from the group consisting of Compound.

20. The linker (L) comprises a group represented by the general structure: 【Chemistry 18】 A compound according to any one of claims 1 to 17, wherein m may be 2, 3, 4 or 5. Bifunctional compounds.

21. L is an optionally substituted aryl or phenyl containing 1 to 10 ethylene glycol units. The compound according to any one of claims 1 to 17, compound.

22. The compound may comprise a plurality of LCMs, a plurality of ABMs, a plurality of linkers, or any combination thereof.

22. The compound or bifunctional compound according to any one of claims 1 to 21, comprising a combination of

23. The compounds are Examples 1-452 and 528-625 (Tables 2-7), their salts, polymorphs, isotopically derived forms, Any one of claims 1 to 21, which is selected from the group consisting of amides, ... Item 1. A compound or bifunctional compound according to item 1.

24. The ABM is selected from the group consisting of: 【Chemistry 19-1】 【Chemistry 19-2】 During the ceremony: R Q2 is H, halogen, CH 3 or CF 3 and R Q3 is H, halo, hydroxyl, nitro, CN, C≡CH, C 1～6 Alkyl (straight or branched chain, any Optionally, one or more halo, C 1～6 substituted with alkoxyl), C 1～6 Alkoxyl (straight chain, branched branched, optionally substituted with one or more halo), C 2～6 Alkenyl, C 2～6 Alkynyl, Or CF 3 and Y 3 , Y 4 , Y 5 are each independently a bond, O, or NR Y2 , C.R. Y1 R Y2 , C=O, heteroaryl, or It is an aryl ； R Y1 , R Y2 are each independently H or C 1～6 Alkyl (straight or branched, optionally with one or more Haro, C 1～6 alkoxy, cyclic or heterocyclic; R Q are independently H, C 1 ~C 6 Alkyl (straight or branched chain, optionally with one or more halo, or is C 1～6 substituted by alkoxyl) or two R Q But they are combined together with the atom forming a 3- to 8-membered ring system containing 0-2 heteroatoms; and Compound or bifunctional compound according to any one of claims 1 to 21, wherein X is N or C. 。

25. The ABM is 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 【Chemistry 20-4】 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 The compound or bifunctionalized compound according to any one of claims 1 to 21, selected from the group consisting of Compound.

26. An effective amount of a compound or bifunctional compound according to any one of claims 1 to 25 and a pharma- ceutically acceptable A composition comprising an acceptable carrier.

27. 27. The composition of claim 26, further comprising at least one additional bioactive agent. composition.

28. 28. The composition of claim 27, wherein the bioactive agent is an anti-cancer agent.

29. A treatment comprising an effective amount of at least two different compounds according to any one of claims 1 to 25. Composition for use.

30. A method of treating a disease or disorder in a subject, comprising administering to a subject a medicament comprising a pharmacopoeia comprising a medicament ...pharmacopoeia and a compound according to claim 1. A composition comprising an effective amount of a compound or bifunctional compound according to any one of claims 1 to 25, administering to a subject in need thereof, said compound providing at least one therapeutically effective amount to treat said disease or disorder. The method is effective in treating or ameliorating one or more symptoms.

31. 31. The method of claim 30, wherein the disease or disorder is cancer or Kennedy's disease or both. method.

32. 32. The method of claim 31 , wherein the cancer is prostate cancer.

33. The composition of any one of claims 30 to 32, further comprising an effective amount of at least one additional anti-cancer agent.

2. The method according to any one of claims 1 to 11.

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