Compounds and methods for targeted degradation of androgen receptors

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 of related applications This application is based on U.S. Provisional Patent Application No. 62 / 406,888, filed on October 11, 2016, and July 2017. Claiming priority to U.S. Provisional Patent Application No. 62 / 528,385, filed on the 3rd of the month, and all of those applications By reference, it is incorporated herein in its entirety for all purposes.

[0002] Description of research funded by the federal government. This invention is based on a grant from the National Cancer Institute, grant number 1R44CA20319. This was carried out with government support under Article 9-01. The government has certain rights in this invention.

[0003] Built-in by reference U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, U.S. Patent Publication No. 2016 / 0058 Published as patent no. 872. U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published in the United States. Published as patent no. 2015 / 0291562. U.S. Patent Application No. 14 / 371,956, filed July 11, 2014. Published as Patent Application Publication No. 2014 / 0356322. U.S. Patent Application No. 15 / 074,820, March 18, 2016. The application was published as U.S. Patent Application Publication No. 2016 / 0272639. These patent applications are published in their entirety. It is incorporated into the specification. Furthermore, all references cited herein are by reference. The entirety of this is incorporated herein.

[0004] This specification provides imide compounds, and difunctional compounds containing such compounds. and related methods relating thereto. The bifunctional compound is targeted ubiquitination It is useful as a regulatory factor, and in particular, the bifunctional compound according to this disclosure degrades and / or It is useful for various polypeptides and other proteins that are inhibited by other means. In certain embodiments, the bifunctional compound is cereblon E3 ubiquitin ligase (CR The cereblon E3 ubiquitin ligase binding site that binds to BN, target protein (e.g., A A target protein binding site that binds to the endogen receptor, and optionally the cerebron binding site. These compounds include a linker portion that connects the binding portion and the target protein binding portion. The target protein / polypeptide is positioned in close proximity to the ubiquitin ligase, and its protein In a manner that affects the breakdown (and inhibition) of substances (e.g., androgen receptors) It acts. [Background technology]

[0005] Most small molecule drugs are closely attached to enzymes or receptors and have clearly defined pockets. They bind at the t. On the other hand, small molecule compounds are used to perform protein-protein interactions. It is well known that targeting is difficult, and the reason for this is the contact surface of the protein. Because the surface area is large and the interface involved is shallow groove-like or flat. E3 ubiquitin ligases (several of which are publicly known in humans) are ubiquitin ligases. It imparts substrate specificity to tinification. Therefore, it has specificity for specific protein substrates, and is general It is an even more attractive therapeutic target than conventional proteasome inhibitors. E3 ligase ligase The development of this technology inevitably involves disrupting protein-protein interactions. It has been found to be partially difficult to do so. However, these ligauzes Specific ligands that bind to these ligands have been developed in recent years. For example, the first small molecule E3 ligase inhibitors. Since the discovery of sodium, further compounds targeting E3 ligase have been reported. However, there are still many undeveloped aspects to this field.

[0006] One of the E3 ligases with potential as a therapeutic agent is transmitted in humans via the CRBN gene. The protein encoded by it is cereblon. The orthologue of CRBN is It is highly conserved from plants to humans, which clearly demonstrates its physiological importance. This is the case. Cereblon is a DNA-binding protein 1 (DDB1) that has been damaged, and karin ( E3 ubiquity of Cullin-4A (CUL4A) and Cullins1 regulator (ROC1) It forms a ligase complex. This complex ubiquitinates numerous other proteins. Through a mechanism that is not yet fully understood, the target protein cerebron ubiquitin The transformation is at the level of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then leads to an increase in numerous developmental processes, such as the formation of limbs and ear vesicles. It regulates the ubiquitin ligase complex, which is important for limb development in the embryo. The final conclusion is that, in the absence of cereblon, DDB1 will form a complex with DDB2. It forms a molecule and functions as a DNA damage-binding protein.

[0007] Thalidomide is approved for the treatment of many immunological indications, and for multiple bone disorders. It is also approved for the treatment of certain neoplasms, including multiple myeloma. Thalidomide and several of its analogues are also currently used in the treatment of various other types of cancer. Regarding its applications, investigations are underway. The precise mechanism of thalidomide's antitumor activity is still unknown. Although still under investigation, it is known to inhibit angiogenesis. The biological properties of imides are being investigated. Recent literature to consider includes Lu et al. Science 343, 305 (2014) and Kronke et al. S Science 343, 301 (2014) is cited as an example.

[0008] Significantly, thalidomide and its analogs, such as pomolinamiodo (pomo Linamiode and lenalinomide are known to bind to cereblon. These agents bind to cereblon, altering the specificity of the complex and causing multiple bone marrow infections. Ubiquitous transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are essential for tumor growth. It induces cerebrospinal fluid formation and degradation. In fact, in the treatment of multiple myeloma, the high expression of cereblon and The increased effectiveness of mid-type drugs is related.

[0009] Androgen receptors (ARs) are receptors for, for example, testosterone and dihydrotestosterone. It belongs to the family of nuclear hormone receptors that are activated by various androgens (Pharm acol. Rev. 2006, 58(4), 782-97; Vitam. Horm. 1999, 55:309-52). Androgens exist In the absence of AR, AR binds to heat shock protein 90 (Hsp90) in the cytoplasm. When androgens bind to AR, their three-dimensional structure changes, and AR is released from Hsp90. Nuclear localization signals (NLS) are exposed. The latter allows for AR. This allows AR to translocate into the nucleus, where it acts as a transcription factor to develop male sexual characteristics. It promotes the expression of genes involved in this process (Endocr. Rev.1987, 8(1):1-28; Mol. Endocrinol.20 02, 16(10), 2181-7). AR deficiency was previously called testicular feminization syndrome. It induces refractory syndrome.

[0010] AR is involved in the development of male sexual characteristics, but in certain forms of cancer, including prostate cancer, it is cancer It has also been frequently reported that it is a gene (Endocr. Rev.2004, 25(2), 276-308). Generally The target gene for the AR activity being measured is the secretory prostate-specific antigen (PSA) protein. Current treatment regimens for prostate cancer include two methods of inhibiting the androgen-AR axis. This includes the first method, which relies on androgen reduction, and the second method, which involves AR devices. The aim is to inhibit the function (Nat. Rev. Drug Discovery, 2013, 12, 823-824). Effective target Despite the development of effective treatments, many patients develop resistance, and the disease progresses. Alternative methods for treating prostate cancer include the removal of AR protein. AR is multi Since it is an important inducer of tumor formation in prostate cancer of the "K" type, its elimination is a therapeutically beneficial response. This should cause it.

[0011] Ongoing research on effective treatments for diseases, particularly cancer, prostate cancer, and Kennedy disease. There are such things in this field. However, transcription factors, for example, have nonspecific effects. Because it cannot target and regulate an entire specific type of protein, this This remains an obstacle to the development of effective anticancer drugs. Therefore, the substrate specificity of cereblon is activated. Simultaneously, a wide range of protein species can be targeted and specifically regulated by either modification or enhancement. Small molecule therapeutics that are "adjustable" in this way are extremely useful as therapeutic agents. [Overview of the project]

[0012] This disclosure describes a bifunctional compound and a method of use thereof. It functions to recruit endogenous proteins to E3 ubiquitin ligase and degrade them. In particular, this disclosure concerns bifunctional or proteolytic targeted chimeras (PROTAC: proteolysis ta This provides a compound that is a polymethyl polymer, and this compound is a polymethyl polymer that is a polymethyl polymer. It also acts as a regulator of the target ubiquitination of other proteins (e.g., androgen receptors). The usefulness of these polypeptides and other proteins has been found, and these polypeptides and other proteins are described herein. It is decomposed and / or inhibited by other means by a difunctional compound. The advantage of the compound being offered is that it may have broad pharmacological activity, and is effective against virtually all proteins. It is compatible with the degradation / inhibition of target polypeptides from a polypeptide species or family. Furthermore, this specification This book is for the treatment or improvement of disease conditions, including cancer, such as prostate cancer and Kennedy disease. This specification provides a method for using an effective amount of the compounds described herein.

[0013] Therefore, in one embodiment, this disclosure provides novel imide compounds as described herein. ru.

[0014] In further embodiments, the present disclosure provides bifunctional or PROTAC compounds, The compound has an E3 ubiquitin ligase binding moiety (i.e., it is related to E3 ubiquitin ligase). The ligand (or "ULM" group) and the part that binds to the target protein (i.e., the protein) It contains a polypeptide-targeting ligand, or a "PTM" group, thereby targeting the target The protein / polypeptide is positioned in close proximity to the ubiquitin ligase, and the protein A decongestive (and inhibitory) effect is exerted. In a preferred embodiment, ULM is Cereblon E3U This is the biquitin ligase binding site (i.e., the "CLM"). For example, in a bifunctional compound... The structure can be shown as follows: PTM-CLM.

[0015] The respective locations of the PTM portion and CLM portion as exemplified herein, and Those numbers are provided for illustrative purposes only and do not limit the compounds in any way. This is not intended. As will be understood by those skilled in the art, the bifunctionality described herein The compounds are synthesized so that the number and position of each functional part can be changed as desired. It is possible.

[0016] In certain embodiments, the bifunctional compound may further contain a chemical linker (L). In the examples, the structure of the bifunctional compound can be shown as follows: PTM - L - CLM, In the formula, PTM is the protein / polypeptide targeting moiety, and L is the chemical linker moiety. Alternatively, it is a bond that connects PTM and CLM, where CLM is a cereblon E3 ubiquitin ligase bond. This is the joining part.

[0017] In a particular preferred embodiment, the E3 ubiquitin ligase is cereblon. Therefore, In certain additional embodiments, the CLM of the bifunctional compound is, for example, an imide, an amide, or a thioa. It contains chemical parts such as mido and thioimide-derived parts. In additional embodiments, CLM is a lid The ruimide group or its analog or derivative comprises C LM contains a phthalimide-glutarimide group or its analogues or derivatives. In other embodiments, CLM is thalidomide, lenalidomide, pomalidomide, and This includes one of the group consisting of analogs or derivatives thereof.

[0018] In certain embodiments, the compounds described herein include multiple CLMs, multiple PTMs, and multiple This includes chemical linkers, or combinations thereof.

[0019] The general structure is illustrative, and each part is, for example, CLM-L-PTM and PTM-LC. It will be understood that they can be spatially arranged in any desired order or configuration, such as LM. cormorant.

[0020] In certain embodiments, the PTM is an AR binding moiety (ABM). In a particular embodiment, the ABM is selected from the following structures:

[0021] [ka]

[0022] During the ceremony: W 1 These are aryl, heteroaryl, bicyclic, or biheterocyclic compounds, each independently of the other. one or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (optionally substituted) A straight chain, branched chain. For example, one or more halos, C1~6 optionally substituted with alkoxyl), C 1~6 alkoxyl (optionally substituted linear or branched chain; for example, optionally substituted by one or more halo groups), C 2~6 alkenyl, C 2~6 alkynyl, or substituted with CF3; Y 1 , Y 2 are each independently NR Y1 , O or S; Y 3 , Y 4 , Y 5 are each independently a bond, O, NR Y2 , CR Y1 R Y2 , C=O, C=S, SO, SO 2、 heteroar yl or aryl; Q is a 3- to 6-membered alicyclic or aromatic ring containing 0 to 4 heteroatoms, optionally substituted with 0 to 6 of R Q groups, and each R Q is independently H, C 1~6 alkyl (optionally substituted linear or branched chain; for ex ample, optionally substituted with one or more halo, C 1~6 alkoxyl groups), halogen, C 1~6 alk oxy, or two R Q groups together with the atoms to which they are bonded form a 3- to 8-membered ring system containing 0 to 2 heteroat oms); R 1 , R 2 , R a , R b , R Y1 , R Y2 are each independently H, C 1~6 alkyl (optionally substituted linear or branched chain; for example, optionally substituted with one or more halo, C 1~6 alkoxyl groups), halogen, C1 ~6 alkoxy, cyclic, heterocyclic, or R1 , R 2 The atoms to which they are bonded They also form a 3-8 member ring system containing 0-2 heteroatoms; W 2 is a combination, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, C 1~6 Alicyclic, heterocyclic, Ally These are heteroaryl, biheterocyclic, biaryl, or biheteroaryl compounds, each of which is Optionally 1 to 10 R W2 Replaced by; Each R W2 These are independently H, Halo, and C. 1~6 Alkyl (a linear or branched chain that can be optionally substituted. For example, one or more alkyl groups.) (Optionally replaced by F above), C 1~6 Heteroalkyl (linear or branched chains that can be optionally substituted) , -OR W2A , C 3~6 Cycloalkyl, C 4~6 Cycloheteroalkyl, OC 1~3 Alkyl (optional) It is replaced. For example, it is optionally replaced by one or more -Fs), C 1~6 Alicyclic (optional substitution) (is performed), complex rings (arbitrarily substituted), aryls (arbitrarily substituted), or heterogeneous rings. Loaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH2, NR Y1 R Y2 , is CN; R W2A H, C 1~6 Alkyl (linear, branched), or C 1~6 Heteroalkyl (linear, branched) The chain consists of, and each of the elements can be optionally cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, Heteroaryl, halo, or OC 1~3 A compound that is substituted with an alkyl group.

[0023] In additional embodiments, this specification may provide for effective amounts of the compounds or salt forms thereof described herein. The present invention provides a therapeutic composition comprising a pharmaceutically acceptable carrier. The therapeutic composition is used by patients and This regulates the breakdown of proteins in animals such as humans, and the breakdown of the proteins It can be used to treat or improve symptoms or conditions that are regulated via protein. In certain embodiments, the therapeutic compositions described herein are for the treatment of diseases, such as cancer or It is used to degrade and / or inhibit the target protein for the purpose of improvement. This disclosure may also describe ubiquitinating a target protein in a cell. A method for disassembling is provided. In a particular embodiment, this method preferably involves disassembling the linker portion. The method includes administering a bifunctional compound as described herein, comprising CLM and PTM linked via a mediated linkage. In this case, CLM is bound to PTM, and CLM is a ubiquitin pathway protein (e.g. For example, recognizing ubiquitin ligases (preferably E3 ubiquitin ligases such as Cereblon). PTM recognizes the target protein, thereby enabling the target protein to be converted into ubiquitin ligase. When positioned in close proximity, degradation of the target protein occurs, and consequently, the target protein This results in a decrease / inhibition of the action, leading to regulation at the protein level. Controlling the protein levels that are affected provides treatment for symptoms or conditions, and this This works by reducing the level of that protein in patient cells, thereby targeting the protein. It is adjusted.

[0024] In an additional embodiment, this specification evaluates (i.e., determines) the binding affinity of CLMs. The method provides a method for measuring (and / or) certain embodiments. Thalidomide group, phthalimide-glutarimide group, derivatized thalidomide, derivatized lena Agents or compounds having an imide moiety, such as lidomide or its derivatized form, pomalidomide, etc. To provide an investigational drug or target compound, and which binds to cereblon, and / or Compared to agents or compounds known to inhibit the activity of cereblon, the investigational drug... Alternatively, compare the cereblon-binding affinity and / or cereblon-inhibiting activity of the compounds. This includes the act of doing something.

[0025] In yet another embodiment, this specification applies to subjects such as animals, including humans, or patients. This involves providing methods to treat or improve diseases, disorders, or their symptoms. The method involves using an effective amount, such as a therapeutically effective amount of the compound or a salt form described herein, and pharmaceutical This includes administering a composition containing an acceptable carrier to a subject in need, in this case In this context, the composition is used to treat or improve a disease or disorder or its symptoms in the subject. It is effective.

[0026] In another embodiment, this specification describes the use of the compounds of the present disclosure in biological systems. This invention provides a method for identifying the degradation effect of target proteins.

[0027] The above general statements regarding usefulness are provided for illustrative purposes only and are not included in this disclosure. And it is not intended to limit the scope of the attached claims. The compositions, methods, and Any additional objectives and benefits related to the process are described in the claims, detailed description, and examples. This will be obvious to those skilled in the art in view. For example, various aspects and practical applications of the present invention The application method can be used in many combinations, all of which are explicitly stated herein. These are expected. These additional beneficial purposes and embodiments are expressly contained within the scope of this disclosure. It is included in the following. To explain the background of the present invention, and in specific cases, additional information regarding implementation is provided. The published literature and other materials used to provide further details are incorporated by reference. ru.

[0028] If applicable, or unless specifically excluded, any embodiment of the embodiments described herein One is any other embodiment, even if such embodiment is based on a different aspect of the present disclosure. Even if it is described as such, it is expected that combinations are possible. Therefore, usefulness The above general statements relating thereto are provided for illustrative purposes only and are not included in this disclosure or attached. No limitation is intended to the scope of the claims. The compositions, methods, and processes of this disclosure are not intended to limit the scope of the claims. Relevant additional objectives and benefits should be considered in light of the claims, detailed description, and examples. This will be obvious to those skilled in the art. For example, many aspects and embodiments of this disclosure are They can be used in combination, and all of them are expressly expected herein. These additional beneficial purposes and embodiments are expressly included within the scope of this disclosure. This disclosure is intended to explain the background to this disclosure and, in specific cases, to provide additional details regarding implementation. The published literature and other materials used are incorporated by reference.

[0029] The attached drawings incorporated in part and forming part of this specification are some of the practical aspects of this disclosure. The drawings illustrate the implementation form and serve to explain the principles of this disclosure together with the description in the specification. This is solely for illustrative purposes of the embodiments of the present disclosure and should not be construed as limiting the present invention. There are none. Further objects, features and advantages of the present invention are described in the appendices illustrating exemplary embodiments of the present disclosure. This will become clear from the following detailed explanation, along with the drawings. [Brief explanation of the drawing]

[0030] [Figure 1A] An illustration illustrating the 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 binds or links the ABM and CLM (wherein described herein, L may be absent, a binding, or a chemical linker moiety). [Figure 1B] Figure 1B illustrates the functional uses of the PROTACs described herein. Briefly, CLM recognizes and binds to cereblon E3 ubiquitin ligase, while ABM binds to and recruits the androgen receptor, bringing it close to the cereblon E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein and, either alone or via the E2 protein, catalyzes ubiquitination via isopeptide bonds to lysine on target proteins (dark circles). The polyubiquitinated protein (far right) is then targeted for degradation by the cellular proteasomal mechanism. [Figure 2] [Figures 2-1] to [Figures 2-36] Table 2 includes exemplary compounds 1 to 75, as well as general schemes that may be used to prepare 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. Dmax category (AR degradation - maximum inhibition (%) AR ELISA in LNCaP and / or VCaP cells): A > 50%; B < 50%. [Figure 3] [Figures 3-1] to [Figures 3-169] Table 3 includes 76 to 398 exemplary compounds, as well as general schemes that may be used to prepare 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. [Figure 4] [Figures 4-1] to [Figures 4-12] Table 4 includes exemplary compounds 399 to 427, as well as general schemes that may be used to prepare 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. [Figure 5] [Figures 5-1] to [Figures 5-11] Table 5 contains exemplary compounds 428 to 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. [Figure 6] [Figure 6-1] to [Figure 6-28] Table 6 contains exemplary compounds 453 to 528. Table 6 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. Dmax category (AR degradation - maximum inhibition (%) AR ELISA in LNCaP and / or VCaP cells): A > 50%; B < 50%. [Figure 7][Figure 7-1] to [Figure 7-167] Table 7 contains exemplary compounds 529 to 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 < 1 nM; B: 1 to 10 nM; C: 10 to 100 nM; D: > 100 nM. [Modes for carrying out the invention]

[0031] The following is a detailed explanation provided to assist those skilled in the art in carrying out the present invention. It is clear. A person skilled in the art will be able to understand this without departing from the intent or scope of this disclosure. The embodiments described in this specification may be modified and altered. All published documents, patent applications, patents, drawings, and other references are referenced in their entirety. It will be explicitly incorporated.

[0032] This specification describes how the E3 ubiquitin ligator can be formed using the chimeric constructs described herein (e.g., PROTAC). When the ligase protein and the target protein are positioned in close proximity, the E3 ubiquitin ligase protein The substance can ubiquitinate target proteins, particularly androgen receptors. This relates to a surprising and unexpected discovery, where in the chimeric construct, E3 ubiquitin The part that binds to ligase proteins is the part that binds to androgen receptor target proteins. They are bonded together, for example, by covalent bonds. Therefore, this specification refers to the selected target A compound intended for the ubiquitination and degradation of proteins, such as androgen receptors, The present invention provides compositions containing the compound and related methods of use thereof (see Figures 1A and 1B).

[0033] This specification, in certain embodiments, refers to U.S. Patent Application Publications 2014 / 0356322A1 and 2015 / 0291562A1. This relates to patent number 2016 / 0214972A1. All of those patent applications are by reference. This specification is incorporated herein for the purpose of [the specified purpose].

[0034] Unless otherwise defined, all technical and scientific terms used herein are: This disclosure has the same meaning as that generally understood by those skilled in the art. The technical terms used in this document are for the sole purpose of explaining specific embodiments and do not limit the present invention. It is not intended to be fixed.

[0035] If a range of values ​​is provided, unless otherwise clearly specified by the context (for example, a certain number In the case of a group containing carbon atoms, the number of carbon atoms within that range is provided. Each intermediate value between the upper and lower limits of the range and any other specified range, up to one-tenth of the lower limit unit. It should be understood that values ​​between these specified ranges are included within the scope of the present invention. The upper and lower limits of a smaller range may be independently included within an even smaller range, and this also The specified range is encompassed within the present invention and becomes any specifically excluded boundary value within the specified range. If one or both of the boundary values ​​are included, exclude either or both of the boundary values ​​that contain them. The scope is also included in this invention.

[0036] The following terms are used to describe this disclosure. Unless otherwise defined, the term is used in relation to its use in this description of the invention. The meaning is given as it is recognized in the art by those skilled in the art to apply it.

[0037] Where used herein, the articles "a" and "an" are used as more descriptively than the context would indicate. Unless otherwise indicated, one or more of the grammatical objects of the article in question (i.e., a small number of) In this specification, "element" is used to refer to at least one. For example, "element" refers to one It means one or more elements.

[0038] When used herein in this specification and in the claims, “and / or” The phrase means "either or both" of the elements that are combined in that way. Please understand that in some cases the elements exist combined, while in other cases they exist separately. They exist. Multiple elements listed using "and / or" should be interpreted in the same way. It is the case that "one or more" elements are joined in that way. Other elements other than those specifically identified by the clause are not considered to be the same as those specifically identified elements. It can exist arbitrarily, regardless of whether or not it is related to an element. Therefore, as an unrestricted example, For example, when used in conjunction with non-restrictive phrases such as "including," it can mean "A and / or B." In one embodiment, the reference refers only to A (optionally including elements other than B), and another In this embodiment, only B is referred to (optionally including elements other than A), and in yet another embodiment... This refers to both A and B (and optionally other elements).

[0039] As used herein and in the claims, “or” means the same as above. It should be understood to have the same meaning as the defined "and / or". For example, When separating items within a list, use "or" or "and / or" as inclusive and It shall be interpreted as follows: that is, many elements, or a small portion of a list of elements This includes one item, but also multiple items, and optionally additional items not listed. For example "only one of ~" or "exactly one of ~" or used in a claim In such cases, only terms that clearly suggest the opposite, such as "consisting of ~", are used, and many other elements, This refers to the inclusion of exactly one element from the list of elements. Generally, in the context used herein The terms "or" and "either" are used, for example, "either," "one of," or "one of." The term "exclusive" is only used when preceded by an exclusive term such as "exactly one of the..." or "one of the...". Interpretations indicate alternative options (i.e., "one or the other, but not both"). It should be explained.

[0040] Where used herein, the term "about" and similar terms refer to numerical values ​​or In relation to its scope, and due to practical and / or theoretical limitations, it is recognized in the art. This reflects the fact that there is a certain level of variation that is acceptable. For example, a certain data Minor variations resulting from inherent differences in how the vise is operated and / or the measurement is performed. Movement is permitted. Accordingly, the phrase "about" usually refers to within the standard deviation or standard error. It is used to enclose a value.

[0041] In the claims and the specification, the terms "comprising" and "containing" "ing)", "carrying", "having", "containing" "Involving," "holding," "composed of," etc. All transitional clauses are non-restrictive, meaning they include them but are not limited to them. It should be understood as "consisting of" and "essentially consisting of". Only the transitional phrase "sisting essentially of" is a restrictive or semi-restrictive transitional phrase. This is assumed to be the case, and this is stated in Section 2111.03 of the U.S. Patent Examination Guidelines.

[0042] When used herein, one or more elements in the specification and claims Regarding the list, the phrase "at least one" means that any one of the elements in the list, or It should be understood to mean at least one element selected from multiple elements, It does not necessarily contain at least one of all the elements specifically listed in the element list. It does not exclude any combination of elements in the element list. This definition refers to the elements specifically identified within the list of elements that the phrase "at least one" refers to. In addition to the elements, any element can be arbitrarily selected regardless of whether or not those elements are specifically identified as related. It allows for the possibility of existence. Therefore, as an unrestricted example, "at least one of A and B" "One of the following" (or equivalently, "at least one of A or B", or equivalently, "A and / or at least one of B) is, in one embodiment, a small number of A's which optionally include multiple A's. It refers to at least one A, and B does not exist (optionally includes elements other than B). In another embodiment... In this case, it refers to at least one B which may include multiple Bs, and A does not exist (optionally, other than A). (including elements). In yet another embodiment, at least one A including optionally multiple A This refers to at least one B that optionally contains multiple Bs (and optionally contains other elements).

[0043] In a particular method comprising multiple steps or operations described herein, the process of the method Unless otherwise indicated by the context, the order of the steps or actions in the method is as follows: The order in which they are listed is not necessarily limited.

[0044] The terms "co-administration" and "co-administration" or "combination therapy" are used in patients. If, to some extent, two therapeutic agents are present simultaneously in a preferably effective amount, then simultaneous administration ( Administering the above therapeutic agents simultaneously, and administering them at different times (one or more therapeutic agents, This refers to both (administering at a time different from when additional therapeutic agents are administered). In one embodiment, one or more of the compounds described herein include, in particular, anticancer agents, and It is co-administered in combination with another additional bioactive agent. In a particularly preferred embodiment, the compound Co-administration results in synergistic activity and / or therapeutic effects, including anticancer activity.

[0045] The term "effective" when used in the context of its intended use refers to such treatment. In a person requiring medical treatment or administration of such treatment, the symptoms of a condition, disorder, or pathology To prevent, inhibit, improve, delay, or treat a condition, or to treat them adequately. This can mean the amount / dosage of the active drug component (to some extent, preferably alleviating all symptoms). However, it is not limited to this. The term effective includes all other effective amounts or effective concentrations. Terms such as "effective dose / amount," "pharmaceutically effective dose / amount," or "therapeutably effective" This includes terms such as "quantity / dosage," which are described or used separately in this application.

[0046] The effective dose depends on the type and severity of the disease, the composition used, the route of administration, and the feeding behavior being treated. The type of object, the physical characteristics of the specific mammal under consideration, concurrent therapies, and medical technology fields. It depends on other factors that a person skilled in the art would recognize. The exact amount can be determined using known techniques. This can be verified by those skilled in the art (e.g., Lieberman, Pharmaceutical Dosage 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 "pharmaceutically acceptable" The term "formulation" is not limited to enabling the effective distribution of the formulation provided herein. This refers to compositions or formulations that are best suited to the body for the desired activity. This form is suitable for administration to a specific location (e.g., systemic administration).

[0048] The terms "pharmaceutically acceptable" or "pharmacologically acceptable" may be used as appropriate. When administered to an object or person, it may cause an adverse reaction, allergic reaction, or other undesirable reaction. This may mean, but is not limited to, entities and compositions that do not produce a reaction.

[0049] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" is used in the context of pharmaceuticals. Any solvent, dispersion medium, coating, antimicrobial and antifungal agent, isotonic, suitable for administration of [the substance]. This may mean, but is not limited to, absorbable retarders, etc. Suitable carriers are in this field. This is described in the latest edition of Remington's Pharmaceutical Sciences, a standard reference book. The relevant literature is incorporated herein by reference. The preferred carrier or diluent is Examples include, but are not limited to, water, physiological saline, Finger's solution, and dextrose solution. Examples include liquids and 5% human serum albumin. Liposomes and non-aqueous solutions such as fixative oils. Vehicles may also be used. Such vehicles and agents are used for pharmaceutically active substances. This is common knowledge in the field. Except when conventional media or agents are incompatible with the active compound. Their use in the composition is anticipated. Auxiliary active compounds may also be incorporated into the composition. ru.

[0050] The term "systemic administration" refers to methods such as enteral or parenteral administration, where the drug is distributed throughout the body. This refers to a route of administration in which the drug is absorbed or accumulated throughout the body in the bloodstream and then distributed throughout the body. The appropriate form depends in part on the application, or on the route of entry, such as oral, transdermal, or injection. It depends on the composition or formulation, which inhibits the composition or formulation from reaching the target cells. This is not the case (i.e., negatively charged polymers are desirable for delivery to cells). For example, blood The pharmacological composition injected into the fluid must be soluble. Other factors in this field Toxicity and form that are publicly known, for example, inhibit the effectiveness of a composition or formulation Factors to consider include the state of the body. The administration route that results in systemic absorption is not limited to a specific route. These include intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary, and intramuscular administration. The rate of drug penetration has been shown to be a function of molecular weight or size. The use of liposomes or other drug carriers containing substances is, for example, related to the reticular endothelial system (RES). The drug may be localized in specific tissue types, such as tissues in the ulnar endothelial system. It can promote the binding of drugs to the surface of cells such as lymphocytes and macrophages. Liposome formulations are also useful.

[0051] The term "local administration" refers to, for example, administration to the lesion or affected area within approximately 10 cm. This refers to the route of administration through which the drug is delivered to an appropriate or nearby site.

[0052] As used herein, unless otherwise indicated, the term “compound” refers to the same compound as used in this specification. This refers to any specific chemical compound disclosed in this book, including tautomers, positional isomers, and geometric isomers. , and, where appropriate, optical isomers (enantiomers) and other stereoisomers (diastes). Stereoisomers including the leomer, and, where appropriate in context, their pharmaceutically acceptable salts. and derivatives (including prodrugs). In its use in context, the compound The term generally refers to a single compound, but for example, stereoisomers and / or optical isomers as described herein. Enantiomers (racemic mixtures) and specific enantiomers or mixtures enriched with enantiomers, etc. It may also contain other compounds. In this context, the term means promoting administration and conversion to the active site. This also refers to the prodrug form of the compound, which has been modified to deliver the compound. Please note that many substituents, and especially the variables associated with them, are listed. .

[0053] The molecules described herein are stable compounds, as outlined below. The contractors will understand.

[0054] [ka]

[0055] If indicated, both double and single bonds, the compound shown, and the valency The interactions between them are expressed or understood against the backdrop of known rules.

[0056] As used herein, “derivative” means derived directly from a natural compound, through modification, and This may mean a composition formed by partial substitution. When used herein, "analog" may mean a composition formed by partial substitution. "G" can refer to a composition that has a structure similar to, but not identical to, a natural compound. .

[0057] The term "ubiquitin ligase" refers to the transport of ubiquitin to specific substrate proteins. This refers to a family of proteins that promote the degradation of substrate proteins, making them targets for degradation. Cerebron, when used in combination with E2 ubiquitin-conjugating enzyme, or alone, acts on target proteins. By attaching ubiquitin to the synth, a specific protein substrate is then targeted for proteasomal degradation. It is an E3 ubiquitin ligase protein that targets [the target]. Therefore, it is complex with E2 ubiquitin-conjugating enzyme. In combination or individually, E3 ubiquitin ligases ubiquitinate the target protein. It is involved in the transport of ubiquitin. Generally, ubiquitin ligases are involved in polyubiquitination and The second ubiquitin is added to the first ubiquitin, and the third ubiquitin is added to the second ubiquitin Polyubiquitination is attached to the cyndromycin. Polyubiquitination is the process of marking proteins against proteasome degradation. However, there are some ubiquitination events that are limited to monoubiquitination, and in those cases... In monoubiquitin ligase, only one ubiquitin molecule is attached to the substrate molecule by ubiquitin ligase. Chininated proteins are not targets for proteasome degradation, but instead, for example... For example, through binding with other proteins that have a domain capable of binding ubiquitin. This can alter the location and function of the cells, further complicating the problem. This means that different lysines on ubiquitin can be targeted by E3 and form chains. Yes, there is. The most common lysine is Lys48 on the ubiquitin chain. This is on the proteasome. This is lysine used to produce more recognizable polyubiquitin.

[0058] The terms “patient” or “subject” throughout this specification refer to the use of the compositions described herein. Treatment is provided that includes preventive therapy, for cells, tissues, or animals, preferably for example, human. Alternatively, it is used to describe mammals such as livestock. For example, specific animals such as human patients. In relation to the treatment of infections, conditions, or diseases specific to a particular animal, the term "patient" is used, for example, for dogs or Certain animals, including domestic animals such as cats, or agricultural animals such as horses, cows, and sheep. Refers to an object. Generally, in this disclosure, the term "patient" means, unless otherwise suggested, or in the same manner. Unless otherwise implied by the context in which the term is used, it refers to a human patient.

[0059] Compounds and compositions In one embodiment, the present disclosure provides compounds useful for regulating protein activity. The product conforms to a defined chemical structure (preferably E3 ubiquitin ligase alone), Alternatively, it can complex with E2 ubiquitin-conjugating enzymes involved in the transport of ubiquitin to target proteins. The ubiquitin pathway protein binding site (for E3 ubiquitin ligase), and preferred The part includes a protein targeting moiety that is linked or bound together via a linker, in this case In this case, the ubiquitin pathway protein binding site recognizes the ubiquitin pathway protein. The targeting portion recognizes the target protein (e.g., androgen receptor). The compound may be referred to as a PROTAC compound or PROTAC in this specification.

[0060] In one embodiment, this specification relates to the cereblon E3 ubiquitin ligase binding moiety (CLM) The present invention provides a compound containing a certain E3 ubiquitin ligase binding moiety (ULM). In one embodiment, CLM is then bonded to the chemical linker group (L) according to the following structure: L-CLM (I) In the formula, L is a chemical linker group, and CLM is the cereblon E3 ubiquitin ligase binding site. The number of parts in the compounds described herein, and / or their relative positions, are illustrative examples. Provided only for the purposes of this document. As will be understood by those skilled in the art, the compounds described herein are each functional. The base parts can be combined in any desired number and / or relative positions.

[0061] The terms ULM and CLM are used in their comprehensive sense unless otherwise indicated by the context. It is used. For example, the term ULM is used in combination with cereblon (i.e., CLM). It includes all ULMs, including those mentioned above. Furthermore, the term CLM encompasses all possible... It contains the ubiquitin ligase binding portion of Cerebron E3.

[0062] In another embodiment, this specification refers to linking via or directly via a chemical linker portion (L). The present invention provides compounds containing multiple CLMs. For example, a compound having two CLMs is as follows: It can be illustrated as follows: CLM-CLM (II) or CLM-L-CLM (III).

[0063] In certain embodiments, if a compound contains multiple CLMs, those CLMs are identical. In additional embodiments, compounds comprising multiple CLMs are either directly or chemically linked (L) It further includes at least one PTM coupled to the CLM via or both. In certain additional embodiments, a compound comprising multiple CLMs further comprises multiple PTMs. In further embodiments, the PTMs are identical or optionally different. In a further embodiment, if the PTMs are different, each PTM binds to the same protein target. Alternatively, it may bind specifically to different protein targets.

[0064] In additional embodiments, this specification describes how to directly or via a chemical linker (L), This provides a compound comprising at least two different CLMs bonded via both of them. A compound having two different CLMs can be illustrated as follows: CLM-CLM' (IV) or CLM-L-CLM' (V) In the formula, CLM' represents a cereblon E3 ubiquitin ligase binding site that is structurally different from CLM. In certain embodiments, the compound contains multiple CLMs and / or multiple CLM's. It may include. In further embodiments, at least two different CLMs, a plurality of CLMs, and / or compounds containing multiple CLMs, either directly or via a chemical linker, This further includes at least one PTM coupled to a CLM or CLM' via both. In any of the embodiments described in this document, a compound comprising at least two different CLMs is multiple It may further include a number of PTMs. In further additional embodiments, the PTMs are identical or Or they may be different. In further embodiments, if the PTMs are different, each PTM It may bind to the same protein target, or it may bind specifically to different protein targets. In further embodiments, the PTM itself may be ULM or CLM (or ULM' or CL It is M').

[0065] In another embodiment, this specification provides bifunctional or PROTAC compounds, The compound is the E3 ubiquitin ligase binding site (CLM) of cereblon E3 ubiquitin ligase. The gauze binding portion (ULM) and the AR binding portion (ABM) are the parts that bind to the target protein. In other words, it contains a protein / polypeptide-targeting ligand, or a "PTM" group. One implementation Morphologically, the structure of a bifunctional compound can be illustrated as follows: ABM - CLM (VI), The respective locations of the ABM portion and CLM portion as exemplified herein, and These numbers are provided for illustrative purposes only and do not in any way limit the compounds in question. This is not intended. As will be understood by those skilled in the art, the bifunctionality described herein The compounds are synthesized so that the number and position of each functional part can be changed as desired. It is possible.

[0066] In a particular embodiment, the compound has the following general structure:ABM-L, where ABM is the same as in the formula. The AR linkage portion is as described in the specification, where L is the chemical linker portion, for example, the phosphorus as described herein. It is either a car or optionally a combination.

[0067] In certain embodiments, the bifunctional compound further comprises a chemical linker (L). The structure of a bifunctional compound can be shown as follows: ABM - L - CLM (VII) In the formula, ABM is the AR bond portion as described herein, and CLM is Cereblon E3 as described herein. This is a ligase binding portion, where L is a chemical linker portion such as the linker described herein. It is either a segment or optionally a combination, linking ABM and CLM.

[0068] Furthermore, CLM has identified all possible cereblon E3 ubiquitin ligase binding sites. It includes. The CLM group and ABM group are suitable and stable for any combination of linkers with respect to the chemical properties of the linker. The linker group may be covalently bonded via a bonded structure.

[0069] In certain embodiments, CLM is a ligase of Cereblon E3 ubiquitin ligase (CRBN). It includes a portion that is a Gand. In certain embodiments, the CLM is a chemical species derived from an "imide" species molecule. Includes. In certain additional embodiments, CLM is a phthalimide group or an analogue thereof. Or it includes derivatives. In a further additional embodiment, CLM is phthalimide-glutal The imide group comprises an analog or derivative thereof. In yet another embodiment, CLM These are derived from thalidomide, lenalidomide, pomalidomide, and their analogs or derivatives. It includes one of the groups.

[0070] The general structure is illustrative, and each part can be in any desired order or configuration, for example, It will be understood that these can be spatially arranged as CLM-L-ABM, and CLM-L-ABM, respectively. In certain additional embodiments, the compound has multiple E3 ligase binding sites and / or multiple Includes the number ABM.

[0071] In certain embodiments, the compounds described herein are multiple ABMs (at the same position or different positions in AR). (Targeting the location of), multiple CLMs, one or more ULMs (i.e., another E3 ubiquitin ligase) This specification includes moieties that specifically bind to (e.g., VHL), or combinations thereof. In any aspect of the embodiments described, ABM, CLM, and ULM are directly or one or more They may be bonded via the above chemical linkers, or in combination thereof. In the application form, if a compound has multiple ULMs, those ULMs are the same E3 ubiquitin ligator. It may be for ze, or each ULM may be specific to another E3 ubiquitin ligase. They may be bonded heteromorphically. In a further embodiment, if the compound has multiple ABMs, Those ABMs are either the same or, at will, different.

[0072] In certain embodiments, if the compound contains multiple CLMs, are those CLMs identical or , or optionally different. In additional embodiments, a compound comprising multiple CLMs is directly At least CLM is bonded via a linker (L) or a chemical linker (L), or both. It further includes another ABM. In certain additional embodiments, a compound comprising multiple CLMs is Further includes multiple ABMs. In additional embodiments, the ABMs may be identical or optional. They are different.

[0073] In certain embodiments, ABM alone can suppress protein activity without forming ABM-L-CLM. To provide desirable characteristics in your case.

[0074] In any aspect or embodiment of the compounds described herein, there is no other suggestion. To the extent that a compound is a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or The intention is to include polymorphisms.

[0075] In certain embodiments, the compounds described herein include multiple PTMs (same or different proteins) (targeting a chemical target), multiple ABMs, multiple CLMs, one or more ULMs (i.e., another E3 ubiquitous A portion that specifically binds to tin ligase (e.g., cereblon), or a combination thereof. Includes. In any of the embodiments described herein, PTM, ABM, CLM, and U LMs are bonded directly, via one or more chemical linkers, or in combination thereof. This may also be done. In an additional embodiment, if the compound has multiple ULMs, those ULMs The ULMs may be for the same E3 ubiquitin ligase, or each ULM may be for a different E 3. It may bind specifically to ubiquitin ligase. In further embodiments, If an object has multiple PTMs, those 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, this specification relates to a compound useful for binding and / or inhibiting cereblon. Provides a substance. In a particular embodiment, the compound or CLM is from the group consisting of the following chemical structures. Selected from:

[0077] [ka]

[0078] During the ceremony: W can independently be CH2, CHR, C=O, SO2, NH, and N-alkyl (optionally substituted, linear, branched). Selected from a group consisting of chains; Y is independently CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetalil, N-cyclo Selected from the group consisting of alkyl, N-heterocyclyl, O, and S; X and Z are each independently O, S, or H2, but not both X and Z are H2. Except for things that cannot be done; G and G' independently consist of H, alkyl (linear or branched, optionally substituted with R'), OH, and R'O. COOR, R'OCONRR'', CH2-heterocyclyl optionally substituted with R', and optionally substituted with R' Selected from the group consisting of benzyl to be replaced; Q1 to Q4 are each independent carbon atoms that can be optionally substituted with R', N, or N-oxide; A can independently be alkyl (optionally substituted linear or branched), cycloalkyl (optionally substituted). Selected from the group consisting of (which will be replaced), Cl, H, and F; R is -CONR'R", -OR', -NR'R", -SR', -SO2R', -SO2NR'R", -CR'R"-, -CR'N R'R"-, -aryl, -hetalil, -alkyl (optionally substituted linear, branched, -alkyl) Roalkyl, -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'C OR", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-NO2)N R'R", -SO2NR'COR", -NO2, -CO2R', -C(C=N-OR')R", -CR'=CR'R", -CCR', -S (C=O)(C=N-R')R'', -SF5, -R'NR'R”, (-R'O) n R'' or -OCF3, but these Not limited to this. R' and R'' are independently linked, H, alkyl (linear, branched), and cycloalkyl, respectively. aryl, hetalyl, heterocyclyl, or -C(=O)R, each of which is arbitrary Replaced by; n is an integer between 1 and 10 (for example, 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0079] [ka]

[0080] represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific; and R n It contains 1 to 4 independent functional groups or atoms, and optionally one of them is modified. Covalent bonds are formed in ABM, chemical linker group (L), ULM, CLM (CLM'), or combinations thereof. They are combined.

[0081] Exemplary CLM In any of the compounds described herein, CLM is a chemical composition selected from the following group. Including construction:

[0082] [ka]

[0083] During the ceremony: W is CH2, CHR, C=O, SO2, NH, and N-alkyl (optionally substituted linear or branched chains). ru; X and Z are each independently O, S, or H2, but not both X and Z are H2. Except for things that cannot be done; Y is independently CH2, -C=CR', NH, N-alkyl, N-aryl, N-hetalil, N-cyclo Selected from the group consisting of alkyl, N-heterocyclyl, O, and S; G is H, alkyl (linear, branched), OH, R'OCOOR, R'OCONRR'', CH2-heterocycline , heterocyclic, aryl, or benzyl, each optionally substituted with R'; Q1 to Q4 are each independent carbon atoms that can be optionally substituted with R', N, or N-oxide; A is independently a C1-C6 alkyl (optionally substituted linear or branched), or a cycloalkyl (optional). (Substituted by), 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) 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 independently of each other: bond, H, N, N-oxide, alkyl (linear, branched), Cycloalkyl, aryl, heteroaryl, heterocyclic, -C(=O)R, or heterocyclic They are Lil, and each of them can be optionally replaced; n is an integer between 1 and 10;

[0084] [ka]

[0085] represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific; and R n It contains 1 to 4 independent functional groups or atoms, and optionally one of them is modified. Covalent bonds are formed in ABM, chemical linker group (L), ULM, CLM (CLM'), or combinations thereof. They are combined.

[0086] In the specific embodiments described herein, the CLM or ULM is selected from the following group. Includes chemical structure:

[0087] [ka]

[0088] During the ceremony: W is independently selected from the group consisting of CH2, C=O, NH, and N-alkyl groups; R is H, methyl, or C1-C6 alkyl (optionally substituted, linear or branched);

[0089] [ka]

[0090] represents a binding that 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 them This is modified to include ABM, chemical linker group (L), ULM, CLM (or CLM'), or combinations thereof. They are covalently bonded together.

[0091] In this specification, the term “independently” means that the variables applied independently are not affected by each application. It is used to show that it changes independently.

[0092] The term "alkyl" in this context refers to a linear, branched, or cyclic perfect saturation chain. This should mean a hydrocarbon radical or alkyl group, preferably C1-C 10 , more preferably C1-C6 or C1-C3 alkyl groups, which may be optionally substituted. Examples of alkyl groups include, in particular, methyl, ethyl, n-butyl, sec-butyl, n-hexyl, and n-hexyl. Butyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclo Propyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentyl These are chlorohexylethyl, cyclohexylethyl, and cyclohexyl. In certain embodiments, The kill group is terminally capped with a halogen group (At, Br, Cl, F, or I). In one embodiment, the compound according to the present disclosure is used to covalently bind to a dehalogenase enzyme. These compounds generally have side chains (often via polyethylene glycol groups). The side chain contains (and is bonded), and the distal end of the side chain has a halogen substituent (often chlorine) The compound is terminated with an alkyl group having bromine, thereby separating the compound containing that portion from the tan compound. Covalent bonds are formed in the proteins.

[0093] The term "alkenyl" refers to a linear, branched, or otherwise containing at least one C=C bond. is a ring C2-C 10 This refers to (preferably C2-C6) hydrocarbon radicals.

[0094] The term "alkynyl" refers to a linear, branched chain containing at least one C≡C bond. Or is a ring-shaped C2-C 10 This refers to (preferably C2-C6) hydrocarbon radicals.

[0095] The term "alkylene" may be optionally substituted when used - (CH2) n - refers to the base ( n is generally an integer between 0 and 6). When substituted, the alkylene group is one of the methylene groups. One or more C1-C6 alkyl groups (including cyclopropyl or t-butyl groups) are substituted. It is preferable to have one or more halo groups, preferably 1 to 3 halo groups, or one or Two hydroxyl groups, an O-(C1-C6 alkyl) group, or as otherwise disclosed herein. It may be substituted with an amino acid side chain. In certain embodiments, the alkylene group is urethane Alternatively, they may be substituted with an alkoxy group (or other group), which may further be polyethylene Ethylene glycol chain (1 to 10 units, preferably 1 to 6 units, often 1 to 4 units) A chain of 3 units is substituted, and an alkyl group is added to it (not limited to, but preferably polyethylene). The alkyl chain is substituted (at the distal end of the glycol chain), and the alkyl chain has one halogen group, preferably a salt It is substituted with an elementary group. In yet another embodiment, the alkylene (often methylene) group is , for example, natural or unnatural amino acids, for example, alanine, β-alanine, arginine, Asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, Lysine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine side chain groups such as proline, serine, threonine, valine, tryptophan, or tyrosine. It may also be substituted with an amino acid side chain group.

[0096] The term "unsubstituted" shall mean that it is substituted only with hydrogen atoms. The range of carbon atoms included means that carbon is either absent or replaced by hydrogen. Therefore, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5 and 6 carbon atoms, and C For 0, there is H instead of carbon.

[0097] The terms "substituted" or "optionally substituted" refer to either of the molecules in the context. One or more substituents at the carbon (or nitrogen) position (on a portion of the compound according to this disclosure, independently and up to 5 substituents, preferably up to 3 substituents, often 1 or 2 substituents. (and may include substituents that can be further substituted) is meant to mean independently ( That is, if there are multiple substituents, each substituent is independent of the other substituents), and As conversion groups, hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO2), Halogens (especially alkyl groups, particularly trifluoromethyl, preferably on the methyl group) 1, 2, or 3 halogens), alkyl group (preferably C1-C) 10 , more C1-6), Aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), aryl Coxy groups (preferably C1-C6 alkyl or aryl; phenyl and substituted phenyl) (mu), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl) ), ester or thioester (preferably C1-C6 alkyl or aryl), Cheline ester (the bond is on an alkylene group, not an ester functional group, and preferably) (The group is substituted with a C1-C6 alkyl or aryl group), preferably a C1-C6 alkyl or aryl group. Contains ions, halogens (preferably F or Cl), amines (5 or 6-membered cyclic alkyl groups) It contains lenamine, and further contains C1-C6 alkylamine or C1-C6 dialkylamine, The alkyl group may be substituted with one or two hydroxyl groups, or optionally substituted. -N(C0-C6alkyl)C(O)(O-C1-C6alkyl) group (optionally substituted with polyethylene glycol chain) Furthermore, an alkyl group containing one halogen, preferably a chlorine substituent, may be bonded to it. ), hydrazine, amide, which is preferably 1 or 2 C1-C6 alkyl groups (1 or (Containing carboxamides optionally substituted with two C1-C6 alkyl groups), alkanols (preferably) (or C1-C6 alkyl or aryl), or alkanic acid (preferably C1-C6 alkyl or aryl) Examples of substituents according to this disclosure include those substituted with aryls. It may also contain a 2R3 group, where each of R1 and R2 is as otherwise described herein. R3 is H or a C1-C6 alkyl group, and in this context, preferably R1, R2, and R3 are C1 -C3 alkyl group (including isopropyl or t-butyl group). Each of the above groups is The substituted portion may be directly bonded, or the substituent may be optionally substituted (CH2) m -of via, or optionally substituted, -(OCH2) m -,-(OCH2CH2) m -or-(CH2CH2O) m - via the basis and the substituted portion (preferably in the case of an aryl or heteroaryl portion) They may be bonded to and may be substituted with one or more of the substituents described above. Lukilen group -(CH2) m -or-(CH2) n - A group or, for example, the ethylene glyco specified above Other chains, such as the alkylene chain, may be substituted on any of the chains. Examples of substituents include halogens or C1-C6 (preferably C1-C3) alkyl groups. This may optionally consist of one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), Up to three halo groups (preferably F), or amino acid side chains as otherwise described herein. Optionally substituted amides (preferably substituted as described above) Carboxamide) or urethane group (often one or two C0-C6 alkyl substituents) Examples include (and this group may also be further substituted). In certain embodiments, alkyl The C1-C6 alkyl group (often a single methylene group) is substituted with one or two optional C1-C6 alkyl groups. A C1-C4 alkyl group, preferably a methyl or O-methyl group, The part in the molecule is substituted with an amino acid side chain as otherwise described herein. It may be optionally substituted with up to 5 substituents, preferably up to 3 substituents. In this case, the portion to be substituted in this disclosure is substituted with one or two substituents.

[0098] The term "substitutable" (where each substituent is independent of any other substituent) is used to mean that In the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, and carb Xamide, sulfonamide, sulfone, keto, carboxy, C1-C6 ester (oxy Esters or carbonyl esters), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R 1)-C(O)-O-R1, nitro, cyano, and amines (especially C1-C6 alkylene-NR1R2, mono or di-C1-C6 alkyl-substituted amines, with one or two hydroxyl groups as This also means (including those that can be substituted by meaning). Each of these bases is used unless otherwise suggested. Insofar as it is used, it contains 1 to 6 carbon atoms in the context. In certain embodiments, substituents are used. Depending on the context in which it is used, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, and -(CH2). m - (In this specification, m and n are 1, 2, 3, 4, 5 or 6 in the context), -S-, - S(O)-, SO2-, or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 Alky Ru, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl),-(CH2) n OC(O)-(C1-C6A Lukil), -(CH2) nC(O)O-(C1-C6 alkyl),-(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2,-(OC H2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1 -C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S ,-S(O)-R S (R S teeth, C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogen (F, Cl, Br, I, Preferably, F or Cl) would be mentioned. R1 and R2 are H or C in the context respectively. 1-C6 alkyl group (one or two hydroxyl groups, or up to three halogen groups, preferably) (or optionally substituted with fluorine). The term "substituted" is also defined as Within the chemical background of the compound and the substituents used, any substituted aryl group may also or a heteroaryl group or an optionally substituted heterocycle as otherwise described herein. It shall mean a group. The alkylene group is also as otherwise disclosed herein. It may be substituted with, preferably optionally, a C1-C6 alkyl group (methyl, ethyl...). Hydroxymethyl or hydroxyethyl is preferred, and consequently the chiral center is provided. (provided), side chains of amino acid groups as otherwise described herein, the amide groups described above, and or a urethane group, OC(O)-NR1R2 group, where R1 and R2 are as otherwise described herein. While substitution with a certain group is possible, many other groups can also be used as substituents. The optionally substituted portion consists of three or more substituents, preferably three or fewer substituents, and preferably Alternatively, it may be substituted with one or two substituents. In a compound, at a specific position on the molecule If a substitution is required (mainly due to valency) but the substitution is not shown, then in the context of the substitution... Note that unless otherwise indicated, substituents are considered or understood to be H. Please be mindful of this.

[0099] The terms "aryl" or "aromatic" in context refer to a single ring (e.g., a ben). (e.g., phenyl, benzyl) or fused ring (e.g., naphthyl, anthracenylphenyl) Substituted (as otherwise described herein) or non-(e.g., phenantrenyl) This refers to a substituted monovalent aromatic radical, and in accordance with this disclosure, any available stable on the ring The compound is bonded at a specific position, or as otherwise specified in the presented chemical structure. It is possible. Other examples of aryl groups include, in context, heterocyclic aromatic ring systems. For example, imidazole, furyl, pyrrole, furanil, thiene, thiazole, pyridine, pi Limidine, pyrazine, triazole, oxazole, etc., with one or more nitrogen atoms in the ring, acid A "heteroaryl" group having an elementary atom or a sulfur atom, or for example, indole, cyanoacrylate, etc. Examples of condensed ring systems include noline, indoridine, azaindolidine, and benzofurazan. These can be optionally substituted as described above. Among the heteroaryl groups that can be mentioned, in addition, nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, py Limidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazo Indole, isoindole, indoridine, azaindoridine, purine, ind Zole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydro Isoquinoline, tetrahydroisoquinoline, quinoridine, phthalazine, naphthyridine, ki Noxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotria Zin, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoli Pyrimidine, phenanthroline, phenacene, oxadiazole, benzimidazole Pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine; sulfur-containing aromatic complex Rings, e.g., thiophene and benzothiophene; oxygen-containing aromatic heterocycles, e.g., furan, Pyran, cyclopentapyran, benzofuran, and isobenzofuran; as well as nitrogen, Aromatic heterocycles containing two or more heteroatoms selected from sulfur and oxygen, e.g. For example, thiazole, thiadizol, isothiazole, benzoxazole, benzothiazole benzothiadiazole, phenothiazine, isoxazole, furazan, fenoxazine Pyrazoloxazole, imidazothiazole, thienofran, phlopyrrole, pyridoxa Examples include dins, phlopyridines, phlopyrimidines, thienopyrimidines, and oxazoles. And all of them can be replaced as desired.

[0100] The term "substituted aryl" refers to a compound consisting of at least one aromatic ring, or fewer than one. It refers to an aromatic carbon ring composed of multiple fused rings, at least one of which is aromatic, and in this case In this ring, one or more substituents are substituted. For example, the aryl group is selected from the following: It may contain substituents:-(CH2) n OH, -(CH2)n -O-(C1-C6)alkyl, -(CH2) n -O-(CH2) n -(C1-C6)alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n -C(O)O(C0-C6)alkyl, -( CH2) n -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, wherein , the alkyl groups on said amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted at the ortho, meta, and / or pa ra position, preferably the para position of the phenyl ring), an optionally substituted phenyl group (preferably, said phenyl group itself is substituted with a linker group attached to an ABM group comprising a ULM group) and / or substituted with at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN groups (at the ortho, meta, and / or para position of the phenyl ring, preferably the para position), optionally substituted naphthyl, optionally substituted heteroaryl, prefer ably optionally substituted isoxazole including methyl-substituted isoxazole, methyl-substituted optionally substituted oxazole including methyl-substituted oxazole, optionally substituted including methyl-substituted thiazole substituted thiazole, optionally substituted isothiazole including methyl-substituted isothiazole , optionally substituted pyrrole including methyl-substituted pyrrole, optionally substituted including methylimidazole optionally substituted imidazole, optionally substituted benzimidazole or methoxyben zene Zilimidazole, optionally substituted with oxyimidazole or methyloxyimidazole A methyl diazole group, an optionally substituted diazole group, or a methyl-substituted triazole. A triazole group that is optionally substituted with a group, a halo-(preferably F) or methyl-substituted pyramidal group. A pyridine group that is optionally substituted with a lysine group or an oxapyridine group (wherein the formula, pyridine group (is bonded to the phenyl group by oxygen), optionally substituted furan, optionally substituted Benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, Indolindine or azaindolidine (2, 3, or 4-azandolidine), optionally Quinolines that are replaced, and combinations thereof.

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

[0102] The terms "heteroaryl" or "hetalil" are, but are not limited to, optional substitutions. Quinoline (which is added to the pharmacophore or any carbon atom within the quinoline ring) Indole (including dihydroindole) which can be replaced on the child, optionally replaced Indridines are substituted by choice, and azaindridines are substituted optionally (2, 3, or 4-azalindridines). Indolinidine), optionally substituted with benzimidazole, benzodiazole, or benzoxy Sofran, optionally substituted imidazole, optionally substituted isoxazole, optionally placed Substitutable oxazole (preferably methyl-substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl-substituted and / or thiol-substituted), optionally substituted isothiazole, optionally substituted tria zole (preferably 1,2,3-triazole substituted with a methyl group, a triisopropylsilyl group, optionally substituted (CH2) m -O-C 1-C6 alkyl group, or optionally substituted (CH2) m -C(O)-O-C1-C6 alkyl group), optionally substituted pyridine (2-, 3-, or 4-pyridine), or may represent a group having the following chemical structure: [[Chemical formula]]

[0103] ## STR ##

[0104] wherein, S c is CHR SS , NR URE , or O; R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alky l (preferably substituted with 1 or 2 hydroxyl groups or up to 3 halo groups (e.g., CF3)) , optionally substituted O(C1-C6 alkyl) (preferably substituted with 1 or 2 hydr oxyl groups or up to 3 halo groups), or an optionally substituted acety lene group -C≡C-R a , wherein R a is H or a C1-C6 alkyl group (preferably C1-C3 alkyl ), which is an acetylene group; R SSThis consists of H, CN, NO2, halo (preferably F or Cl), and optionally substituted C1-C6 alkyl groups. (preferably substituted with one or two hydroxyl groups or up to three halo groups) ), optionally substituted O-(C1-C6 alkyl) (preferably one or two hydroxyl groups) (or substituted with up to 3 halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (Preferably substituted with one or two hydroxyl groups or up to three halo groups) ) is; R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or -C(O)(C1-C6 alkyl (Kil) and each group can optionally consist of one or two hydroxyl groups or up to three halo groups Preferably a heterocycle substituted with a fluorine group, or optionally substituted, such as piperi Zin, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperi These include dins, piperazines, and each of them can be optionally substituted, and Y C is N or CR YC And in the formula, R YC is H, OH, CN, NO2, halo (preferably Cl or F) Optionally substituted C1-C6 alkyl (preferably one or two hydroxyl groups) O(C1-C6 alkyl) can be substituted with up to three halo groups (e.g., CF3), and optionally substituted with three halo groups (C1-C6 alkyl). (Preferably substituted with one or two hydroxyl groups or up to three halo groups) , or optionally substituted acetylene group -C≡CR a And in the formula, R a is H or C1-C6A It is an acetylene group that is a lucyl group (preferably a C1-C3 alkyl group).

[0105] The terms "aralkyl" and "heteroarylalkyl" are defined according to the above definitions. Reels or heteroaryls, respectively, as well as alkyls and / or heteroalkyls This refers to groups containing a carbon ring and / or a heterocycloalkyl ring system.

[0106] As used herein, the term "arylalkyl" means the A This refers to the aryl group defined above that is added to the aryl group. The alkyl group is attached to the parent part via a kill group, in this case consisting of 1 to 6 carbon atoms. It is an atom. The aryl group in the arylalkyl group may be substituted as described above.

[0107] The term "heterocyclic ring" includes at least one heteroatom, such as N, O, or S. It refers to a cyclic group, which may be aromatic (heteroaryl) or non-aromatic. The heteroaryl portion is included under the definition of a heteroalge, depending on its usage. Typical heteroaryl groups are described herein as described above.

[0108] Exemplary heterocycles include azetididine, benzimidazolyl, and 1,4-benzodione. Xanil, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothi Enyl, dihydroimidazolyl, dihydropyranil, dihydrofuranil, dioxanil, Dioxolanil, ethylene urea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane n, frill, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, Indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, i Soxazolidinil, isoxazolyl, morpholinil, naphthilidinil, oxazolidinil Oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiper Dinyl, piperidinyl, phthalimide, scriimide, pyrazinyl, pyrazolinyl Pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetra Hydrofuranil, tetrahydropyranil, tetrahydroquinoline, thiazolidinyl, thi Azolyl, thienyl, tetrahydrothiophene, oxane, oxetanil, oxathio Ranil and Chiang are examples.

[0109] Heterocyclic groups include alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, and cycloalkyl groups. Chloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, shea No, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thio Aryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thio Alkyl, substituted thioalkoxy, aryl, aryloxy, heteroaryl, hetero Aryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino , nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2- Alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo(=O), and -SO2-heteroaryl It may be optionally substituted with one selected from the group consisting of . Such heterocyclic groups are single It may have a ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include Not limited to pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidi N, pyridazine, indidine, isoindole, indole, indazole, purine, Quinolidine, Isoquinoline, Quinoline, Phthalazine, Naphthylpyridine, Quinoxaline, Quinazoline, cinnoline, pteridine, carbazole, carborin, phenanthidine, Acridine, phenanthroline, isothiazole, phenazine, isoxazole, pheno Xazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, Indoline, morpholino, piperidinyl, tetrahydrofuranil, and N-alcohols, etc. Examples include xy-nitrogen-containing heterocycles. The term "heterocyclic formula" also refers to any of the heterocycles. is a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolyl). This also includes bicyclic groups that are condensed with isoquinolyl, tetrahydroquinolyl, etc.

[0110] The term "cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, Includes, but is not limited to, cyclohexyl and cycloheptyl, and consists of 3 to 20 carbon atoms. A saturated monocyclic hydrocarbon group having a ring, such as a monocyclic or polycyclic group as defined herein. This refers to, but is not limited to, a monovalent group derived from an alkyl group or cycloalkane. It cannot be. The term "substituted cycloalkyl" is used, for example, amino, halogen, alkyl, Substituting alkyl, carbyloxy, carbyl mercapto, aryl, nitro, mercapto Monocyclic or polycyclic alkyls substituted with one or more substituents such as sulfo. This refers to a group, but is not limited to this; these generic substituents are the counterparts defined in this explanation. It has the same meaning as the definition of the corresponding base.

[0111] A "heterocycloalkyl" is defined as a ring carbon atom in which at least one of the cyclic structures is N, O monocyclic or polycyclic aluminum substituted with heteroatoms selected from the group consisting of S or P. This refers to the kill group. "Substituted heterocycloalkyl" means at least one ring in its cyclic structure. A monoring in which a carbon atom is replaced by a heteroatom selected from the group consisting of N, O, S, or P. Alternatively, it refers to a polycyclic alkyl group, where the group is a halogen, alkyl, substituted alkyl, or carboxymethyl group. A group consisting of luoxy, carbil mercapto, aryl, nitro, mercapto, or sulfo. It contains one or more substituents selected from, but these generic substituents are described in this description. It has the same meaning as the definition of the corresponding base as defined in [the relevant section].

[0112] The term "hydrocarbyl" refers to a compound containing carbon and hydrogen. They may be fully saturated, partially unsaturated, or aromatic, and may contain aryl groups, alkyl groups, Contains 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 independent linkers, and / or one or more It can be covalently bonded to a linker that is bonded to an ABM, ULM, CLM, or CLM' base.

[0114] More specifically, non-limiting examples of CLMs include the molecules shown below, as well as the following: A "hybrid" arises from a combination of one or more different characteristics exhibited in the molecule. Examples of molecules include Rn, in which case Rn is a functional group or protogroup selected from 1 to 4 independently chosen groups. It includes the children, and optionally one of them is modified to include ABM, chemical linker group (L), U It is covalently bonded to LM, CLM (or CLM'), or a combination thereof.

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] [ka]

[0120] Exemplary linker In certain embodiments, the compounds described herein are linked via a chemical linker (L) to one or more It contains one or more ABMs chemically linked to or bonded to the above ULM or CLM. In certain embodiments, the linker group L is a group comprising one or more covalently bonded structural units. (For example, -A 1.. A q -, or -A q -), in this case A1 is a group bonded to ABM. , A q This is a group bonded to ULM.

[0121] In a particular embodiment, the linker group L is A q - Selected from; A q is a base that is linked to the ULM portion or the ABM portion; and q is an integer greater than or equal to 1, In the formula, A q , combine, CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 , SONR L3 CONR L3 , NR L3 C Major League L4 , NR L3 SO2NR L4 CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 P(O)R L1 , P(O)OR L1 , NR L3 C(=NCN )NR L4 , NR L3 C (=NCN), NR L3 C(=CNO2)NR L4 , optionally 0 to 6 R L1 and / or R L2 Substitute with base C 3-11 Cycloalkyl, optionally 0 to 9 R L1 and / or R L2 C substituted with the base 5-13 Spirocycloalkyl, optionally 0 to 6 R L1 and / or R L2 C substituted with the base 3-11 Hete Rosicrill, optionally 0 to 8 R L1 and / or R L2 C that is substituted with the group 5-13 Spiroheterosi Chloalkyl, optionally 0 to 6 R L1 and / or R L2 The aryl that is substituted with the base, optionally 0 ~6 R L1 and / or R L2Selected from the group consisting of heteroaryls substituted with a group, Here R L1 or R L2 Each of these can be independently and arbitrarily bonded to other groups, and can optionally contain 0 to 4 R groups. L5 Place at base Forms a cycloalkyl and / or heterocyclyl moiety to be replaced; R L1 , R L2 , R L3 , R L4 and R L5 These are H, Haro, and C, each independent of the others. 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 Heterocycline, OC 1~8 Cycloalkyl, SC 1~8 Shik Roalkyl, NHC 1~8 Cycloalkyl, N(C 1~8 Cycloalkyl)2, N(C 1~8 Cycloalkyl (C) 1~8 Alkyl), OH, NH2, SH, SO2C 1~8 alkyl, P(O)(OC 1~8 Alkyl)(C 1~8 a Lukil), P(O)(OC 1~8 Alkyl)2, CC-C 1~8 Alkyl, CCH, CH=CH(C 1-8 Alkyl), C(C1 ~8 Alkyl)=CH(C 1~8 Alkyl), C(C 1~8 Alkyl) = C(C 1~8 Alkyl)2, Si(OH)3, Si( C 1~8 Alkyl)3,Si(OH)(C 1~8 Alkyl)2, COC 1~8 Alkyl, CO2H, Halogen, CN, CF 3, CHF2, CH2F, NO2, SF5, SO2NHC 1~8 Alkyl, SO2N(C 1~8 Alkyl) 2, SONHC 1~8 Al Kill, SON(C 1~8 Alkyl)2, CONHC 1~8 Alkyl, CON(C 1~8 Alkyl)2, N(C 1~8 Alki (C)CONH(C 1~8 Alkyl), N(C 1~8 Alkyl)CON(C 1~8 Alkyl)2, NHCONH(C 1~8 Alki Ru), NHCON(C 1~8 Alkyl)2, NHCONH2, N(C 1~8 Alkyl)SO2NH(C 1~8 Alkyl), N(C1 ~8 Alkyl) SO2N(C 1~8 Alkyl)2,NH₃SO₂NH₃(C 1~8 Alkyl), NH₃SO₂N(C 1~8 Alki It is 2, NH₃SO₂NH₂.

[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, if q is greater than 2, A q This is a group that is bound to ULM. A1 and A q These are linked via linker (L) structural units.

[0124] In a particular embodiment, for example, when q is 2, A q A1 and Combined with ULM It is the basis.

[0125] In certain embodiments, for example, when q is 1, the structure of the linker group L is -A1-. A1 is a group that is bonded to the ULM and ABM portions, respectively.

[0126] In certain embodiments, the linker (L) is a general structure selected from the group consisting of the following: Includes the base represented by: -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(low-grade Al Coxyl)-OCH2-,-NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-,-NR(CH2) n -( Cycloalkyl)-(lower alkyl)-OCH2-,-NR(CH2) n -(heterocycloalkyl)-, -NR(CH2 CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-,-NR(C H2CH2O) n -aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -( Cycloalkyl)-O-(heteroaryl)-O-CH2-,-NR(CH2CH2O) n -(cycloalkyl)-O-a Reel-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-,-NR(CH2CH2O) n -( Lower alkyl)-O-aryl-CH2,-NR(CH2CH2O) n -Cycloalkyl-O-aryl-,-NR(CH2C H2O) n-Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2)n-(cycloalkyl)-O-(complex ring)-CH 2、 -NR(CH2CH2)n-(heterogenetic ring)-(heterogenetic ring)-CH2, -N(R1R2)-(heterogenetic ring)-CH2; where n can be anywhere from 0 to 10; R may be H, or a low alkyl group; R1 and R2 may form rings having a bonded nitrogen.

[0127] In certain embodiments, the linker (L) is a general structure selected from the group consisting of the following: Includes the base 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 independently 0, 1, 2, 3, 4, 5, and 6, respectively; If the number is zero, no NO or OO joins exist. R is H, methyl, or ethyl; and X is either H or F.

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

[0131] [ka]

[0132] In the formula, m may be 2, 3, 4, or 5. In certain embodiments, the linker (L) is provided by a general structure selected from the group consisting of the following: Includes the base represented:

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138] [ka]

[0139] [ka]

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

[0141] In an additional embodiment, the linker group has about 1 to about 100 ethylene glycol units, about 1 to Approximately 50 ethylene glycol units, approximately 1 to approximately 25 ethylene glycol units, approximately 1 to 10 units Ethylene glycol units, 1 to approximately 8 ethylene glycol units, and 1 to 6 ethylene Glycol units, optionally substituted (poly) having approximately 2-4 ethylene glycol units. Ethylene glycol, or optionally substituted O, N, S, P, or Si atoms scattered therein It is an optionally substituted alkyl group. In certain embodiments, the linker is an aryl, f Substituted with an phenyl, benzyl, alkyl, alkylene, or heterocyclic group. Specific implementations Morphologically, the linker may be asymmetrical or symmetrical.

[0142] In any embodiment of the compounds described herein, the linker group is as described herein. It may be any suitable part that is mounted. In one embodiment, the linker is about 1 to about 12 Ethylene glycol units: 1 to approximately 10 ethylene glycol units, approximately 2 to 6 ethylene glycol units The units are approximately 2-5 ethylene glycol units, and the size range is approximately 2-4 ethylene glycol units. It is a substituted or unsubstituted polyethylene glycol group.

[0143] In another embodiment, the present disclosure presents compounds containing the above-described ABM group, The group binds to a target protein (e.g., androgen receptor) or polypeptide, and ubiquitous It is ubiquitinated by tin ligase and then chemically bonded directly to the ULM group, or Chemical bonding occurs via the L group. Alternatively, ABM is an ULM' group, and the ULM' group is also This is the ubiquitin ligase binding site, and it may be the same as or different from the ULM group mentioned above. L is bonded to the ULM group either via the linker portion or directly. It is a minute, and may or may not be present, ULM and ABM, or its pharmaceutically acceptable Salts, enantiomers, stereoisomers, solvates, or polymorphs are chemically (covalently) bonded together. Combine them.

[0144] In certain embodiments, ULM is IC 50 For E3 ubiquitin ligase with a concentration of less than approximately 200 μM It exhibits activity or binds to it. 50 For example, in this field, such as fluorescence polarization assays. This can be determined according to any publicly known method.

[0145] In certain additional embodiments, the bifunctional compounds described herein are approximately 100, 50, 10, 1. Less than 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or approximately 100, 50, 10, 1, 0.5, 0.1, 0.05 Less than 0.01, 0.005, 0.001 μM, or approximately 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005 ICs with a minimum impedance of 0.001 nM 50 It exhibits activity.

[0146] The ULM and ABM groups are suitable for the chemical properties of the linker and can be connected via any stable group. The linker group may be covalently bonded, and in a preferred embodiment of this disclosure, the linker is independent The ULM group and ABM group are preferably an amide, ester, thioester, keto group, or carbamate. Covalently bonded via urethane, carbon, or ether, each of these groups is a ULM group and an ABM group. It is inserted into one of the groups, and the maximum binding of the ULM group to the ubiquitin ligase and decomposition It can provide maximum binding of ABM groups to the target protein. In this case, the linker is an optionally substituted alkyl group on the ULM group and / or ABM group. It may be bonded to an alkylene, alkene or alkyne group, aryl group or heterocyclic group. stomach.

[0147] Exemplary androgen binding moiety (ABM) In another aspect, this specification provides an AR coupling portion (ABM), which is specific In the embodiments and aspects thereof, coupled to the linker and / or ULM described herein. It will be done.

[0148] In any of the compounds described herein, ABM binds to androgen receptors (ARs). It contains a binding chemical part. Various androgen receptor binding compounds have been reported in the literature. It contains testosterone, dihydrotestosterone, and metriborone (methyltriester). (also known as nolon or R1881), as well as, for example, bicalutamide, enzalutamide Examples include various androgen derivatives such as nonsteroidal compounds. If you're a supplier, these androgen receptor binding compounds are ABM in PROTAC compounds. They will recognize that it may be possible to use it as a part. Such literature is limited Although not definitively established, 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 These are listed below. They are incorporated herein by reference.

[0149] In certain embodiments, the ABM is selected from, but is not limited to, the structures shown below. The structure includes the following, with dashed lines indicating linker sections or ULM joints:

[0150] [ka]

[0151] During the ceremony: W 1 These are aryl, heteroaryl, bicyclic, or biheterocyclic compounds, each independently of the other. one or more H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (optionally substituted) A straight chain, branched chain. For example, one or more halos, C 1~6 (Optionally substituted with alkoxyl), C 1~6 Alkoxyls (linear or branched chains that can be optionally substituted. For example, by one or more halos) (to be replaced by meaning), C 2~6 Alkenil, C 2~6 Substituted with alkynyl or CF3; Y 1 , Y 2 Each is independently NR Y1 , O, S; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 C=O, C=S, SO, SO2, heterogeneous It is a reel, or aryl; Q is a 3-6 member ring with 0-4 heteroatoms and optionally 0-6 R Q Replaced by each R Q H and C are independent of each other. 1~6 Alkyl (a linear or branched chain that can be optionally substituted. For example, one or more halos , C 1~6 (Optionally substituted with alkoxyl), halogen, C 1~6 Is it an alkoxy or or two R Q The group is a 3-8 member ring containing 0-2 heteroatoms along with the atom to which they are bonded. Forming a system; R 1 , R 2 , Ra , R b , R Y1 , R Y2 H and C are independent of each other. 1~6 Alkyl (a linear chain which can be optionally substituted) Branched chain. For example, one or more halos, C 1~6 (Optionally substituted with alkoxyl), halogen, C1 ~6 It is an alkoxy, cyclic, heterocyclic, or R 1 , R 2 The atoms to which they are bonded They also form a 3-8 member ring system containing 0-2 heteroatoms; W 2 is a bond, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, aryl, heteroaryl, lipid It can be a cyclic, heterocyclic, diheterocyclic, biaryl, or biheteroaryl compound, each of which is arbitrary. 1 to 10 R W2 Replaced by; Each R W2 These are independently H, Halo, and C. 1~6 Alkyl (a linear or branched chain that can be optionally substituted. For example, one or more alkyl groups.) (Optionally replaced by F above), -OR W2A , C 3-6 Cycloalkyl, C 4-6 Cycloheteroalkyl , C 1-6 Alicyclic (optionally substituted), heterocyclic (optionally substituted), aryl (optionally (Substituted), or heteroaryl (optionally substituted), bicyclic heteroaryl or is Ariel, OC 1-3 Alkyl (optionally substituted), OH, NH2, NR Y1 R Y2 , CN; oyo Beauty R W2A H, C 1~6 Alkyl (linear, branched), or C 1~6 Heteroalkyl (linear, branched) The chain consists of, and each of the elements can be optionally cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, Heteroaryl, halo, or OC 1~3 It is substituted with alkyl.

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

[0153] In a particular embodiment, W 1 teeth,

[0154] [ka]

[0155] In the formula, each R 22 These are independently halo, H, optionally substituted alkyl, haloalkyl, cyano, or nitro; and Each R 23 These are independently H, halo, CF3, optionally substituted alkyl, alkoxy, and haloalkyl It is ru, cyano, or nitro.

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

[0157] [ka]

[0158] In a particular embodiment, the ABM includes a structure selected from the following structures shown below: During the ceremony,

[0159] [ka]

[0160] This indicates the linker or ULM connection point:

[0161] [ka]

[0162] During the ceremony: R Q2 This is H, halogen, CH3, or CF3; R Q3 H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight-chain, branched-chain) , optionally one or more halos, C 1~6 (substituted with alkoxy), C 1~6 Alkoxyl (linear chain) (A branched chain, optionally replaced by one or more halos), C 2~6 Alkenil, C 2~6 Alkini It is either 'Lu' or CF3; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 , C=O, heteroaryl, or It is an allele; R Y1 , R Y2 Each is independently H or C 1~6 Alkyl (linear or branched, optionally one or more) Hello, C 1~6 (Substituted by alkoxyl, cyclic, or heterocyclic compounds); and R Q Each is independently H, C1-C6 alkyl (straight-chain, branched-chain, optionally one or more halos, Taha C 1~6 (substituted with alkoxyl) or two R Q However, they are combined Together with the atoms present, it forms a 3-8 member ring system containing 0-2 heteroatoms.

[0163] In a specific method of operation, each R Q In another embodiment, R Q3 teeth , CN.

[0164] In a particular embodiment, the ABM includes a structure selected from the following structures shown below: During the ceremony,

[0165] [ka]

[0166] This indicates the linker or ULM connection point:

[0167] [ka]

[0168] During the ceremony: R Q2 is H, halogen, CN, CH3 or CF3; and R Q3 H, halo, hydroxyl, nitro, CN, C≡CH, C 1~6 Alkyl (straight-chain, branched-chain, Optionally, one or more halos, C 1~6 (substituted with alkoxy), C 1~6 Alkoxyl (linear, (A branched chain, optionally replaced by one or more halos), C 2~6 Alkenil, C 2~6 Alkinyl , or CF3; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 , C=O, heteroaryl, or It is aryl; and R Y1 , R Y2 Each is independently H or C 1~6 Alkyl (linear or branched, optionally one or more) Hello, C 1~6 (Substituted by alkoxyl, cyclic, or heterocyclic compounds); and X is either N or C.

[0169] In a particular embodiment, R Q3 This is CN. In certain additional embodiments, the ABM includes the structure shown below, where dashed lines represent linkers. — Indicates a joint point of a portion, ULM, or CLM:

[0170] [ka]

[0171] [ka]

[0172] Each R 22 These are independently H or -CN; Each R 23 These are independently H, halo, C1-C6 alkyl (optionally substituted linear or branched chain), C1- It is a C6 alkoxy or -CF3; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 This is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 Each of these is independently H or C1-6 alkyl (a linear or branched chain which can be optionally substituted). If one or more halos, or C 1~6 (Optionally substituted with alkoxyl); W 2 is a bond, C 1~6 Aryl, C1-6 heteroaryl, C 1~6 Alicyclic or C1-6 heterocyclic They are biheterocyclic, biaryl, or biheteroaryl compounds, each with an optional 1 to 10 R compounds. W2 to Replaced by; and Each R W2 H or halo is independent of H; and

[0173] [ka]

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

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

[0176] [ka]

[0177] In any aspect or embodiment described herein, W 2 The group consists of the following: Selected:

[0178] [ka]

[0179] In certain embodiments, the ABM is selected from, but is not limited to, the structures shown below. The structure includes the following, with dashed lines indicating linker sections or ULM joints:

[0180] [ka]

[0181] [ka]

[0182] Each R 22 These are independently H or -CN; Each R 23 These are independently H, halo, or -CF3; Y 1 , Y 2 Each is independently either O or S; R 1 , R 2 Each of these is independently either a hydrogen atom or a methyl group; W 2 is a bond, C 1~6 They are aryl or heteroaryl, each consisting of 1, 2, or 3 individuals. R W2 Replaced by; and Each R W2 These are independently H, Halo, and C. 1~6 Alkyl (optionally substituted with one or more F), OC 1~ It is a 3-alkyl group (which can be optionally substituted with one or more -F groups).

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

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

[0185] [ka]

[0186] In certain additional embodiments, W 2 teeth

[0187] [ka]

[0188] It is selected from the group consisting of the following. In a particular embodiment, the ABM is selected from the group consisting of:

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193] [ka]

[0194] [ka]

[0195] In a particular embodiment, the ABM includes the following structure:

[0196] [ka]

[0197] In the formula, W 1 is an aryl or heteroaryl, each independently containing one or more H, halo, and hi Droxyl, Nitro, CN, C≡CH, C 1~6 Alkyl (linear or branched chain, optionally containing one or more alkyl groups) Ro, C 1~6 (substituted with alkoxy), C 1~6 Alkoxyl (straight-chain, branched-chain, any 1 (replaced by one or more halos), C 2~6 Alkenil, C 2~6 Alkinyl, or CF3 Replaced; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 C=O, C=S, SO, SO 2、 Hetero It is a reel or a reel; Q is a four-membered alicyclic ring with 0 to 2 heteroatoms, and optionally 0 to 6 R Q Replaced by, Each R Q H and C are independent of each other. 1~6 Alkyl (straight-chain or branched-chain, optionally containing one or more halos, C) 1~6 Arco (substituted with xyl) or two R Q The groups, along with the atoms to which they are bonded, are 0~ It forms a 3- to 8-membered ring system containing two heteroatoms. R Y1 , R Y2 H and C are independent of each other. 1~6 Alkyl (linear, branched, and optionally containing one or more halos) , C1~6 (Substituted with alkoxyl); W 2 is a combination, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, C 1~6 Alicyclic, heterocyclic, Ally It is a bicyclic, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl. Each can have 1, 2, or 3 R's. W2 Replaced by; and Each R W2 These are H, Halo, and C, which are independent of each other. 1-6 Alkyl (straight-chain, branched-chain, optionally with one or more fluorine atoms) (to be replaced), C 1-6 Heteroalkyl (linear, branched, optionally substituted), -OR W2A OC 1-3 Alkyl (optionally substituted with one or more -F), C 3-6 Cycloalkyl, C 4-6 Shik Roheteroalkyl (optionally substituted), C 1-6 Alkyl (optionally substituted), C 1-6 Alienic ring Formulas (can be substituted as desired), complex algebras (can be substituted as desired), aryls (can be substituted as desired) ), heteroaryl (optionally substituted), bicyclic heteroaryl (optionally substituted) , bicyclic aryl, OH, NH2, NR Y1 R Y2 , or CN; and R W2A H, C 1~6 Alkyl (linear, branched), or C 1~6 Heteroalkyl (linear, branched) The chain consists of, and each of the elements can be optionally cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, Heteroaryl, halo, or OC 1~3 It is substituted with alkyl.

[0198] In additional embodiments, this specification provides androgen receptor-binding compounds comprising the following structures. To provide:

[0199] [ka]

[0200] In the formula, W 1 These are aryl, heteroaryl, bicyclic, or biheterocyclic compounds. Each independently contains one or more H, halo, hydroxyl, nitro, CN, C≡CH, and C 1~6 Alkyl ( Linear or branched chains, with optionally one or more halos and C 1~6 (substituted with alkoxy), C 1~6 Al Coxyl (straight-chain, branched-chain, optionally substituted with one or more halos), C 2~6 Alkenil, C 2~6 Substituted with alkynyl or CF3; Y 1 , Y 2 Each is independently NR Y1 It is O, or S; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 C=O, C=S, SO, SO2, H Terroraryl, or aryl; Q is a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, and optionally 0 ~6 R Q Replaced by each R Q H and C are independent of each other. 1~6 Alkyl (linear or branched chain, one or more of any kind) The halo above, C 1~6 (substituted with alkoxyl) or two R Q The base is formed by the combination of these elements. It forms a 3-8 member ring system containing 0-2 heteroatoms along with the atom being subjected to it. R 1 , R 2 , R a , R b , R Y1 , R Y2 H and C are independent of each other. 1~6 Alkyl (straight-chain, branched-chain, One or more halos, C 1~6 (Optionally substituted with an alkoxyl) or R 1 , R 2 That These atoms, along with the atoms to which they are bonded, form a 3-8 member ring system containing 0-2 heteroatoms. W 2 is a combination, C 1~6 Alkyl, C 1~6 Heteroalkyl, O, C 1~6 Alicyclic, heterocyclic, In aryl, biheterocyclic, biaryl, or biheteroaryl, or heteroaryl Yes, each can have 1, 2, or 3 R's. W2 Replaced by; Each R W2 These are H, Halo, and C, which are independent of each other. 1-6 Alkyl (straight-chain or branched-chain, optionally containing one or more F (replaced by), C 1-6 Heteroalkyl (linear, branched, optionally substituted), -OR W2A , OC 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 (optional substitution) (is performed), complex rings (arbitrarily substituted), aryls (arbitrarily substituted), or heterogeneous rings. Loaryl (optionally substituted), bicyclic heteroaryl or aryl, OH, NH2, N R Y1 R Y2, is CN; and R W2A H, C 1~6 Alkyl (linear, branched), or C 1~6 Heteroalkyl (linear, branched) The chain consists of, and each of the elements can be optionally cycloalkyl, cycloheteroalkyl, aryl, heterocyclic, Heteroaryl, halo, or OC 1~3 It is substituted with alkyl.

[0201] In a particular embodiment, the androgen receptor binding moiety has the following structure:

[0202] [ka]

[0203] [ka]

[0204] Each R 22 These are independently H or -CN; Each R 23 These are independently H, halo, or -CF3; Y 3 is a bond or O; Q is a 4-member ring, and can have 0 to 4 R's. Q Replaced by each R Q is independently H or methyl. ; Y4 is either a bond or an NH group; Y5 is a bond, C=O, or C=S; Each W 2 These are independently bonded, C1-6 aryl or heteroaryl groups, each consisting of 1, 2, or 3 atoms. of W2 It is optionally replaced by each R W2 Independently, H, halo, or one or two hete A 6-membered alicyclic ring having a heteroatom, or a 5-membered ring having one, two, or three heteroatoms. It is an aromatic ring.

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

[0206] [ka]

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

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

[0209] [ka]

[0210] In a particular embodiment, the androgen binding moiety has the following structure:

[0211] [ka]

[0212] In the formula, W 1 is an aryl and can be independently replaced by one or more halos, CN; Y 3 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 , C=O; Q is a five-membered aromatic ring having one or two heteroatoms; R Y1 , R Y2 H and C are independent of each other. 1-6 Alkyl (straight-chain, branched-chain); W 2 These are bonded, aryl, or heteroaryl compounds, each of which can be one, two, or three in number. R W2 Replaced by; and Each R W2 These are independently H, Halo, and C. 1~6 Alkyl (optionally substituted with one or more F), OC 1~ It is a 3-alkyl group (which can be optionally substituted with one or more -F groups).

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

[0214] In a particular embodiment, W 1 teeth,

[0215] [ka]

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

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

[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 is not limited to, the structures shown below. The structure includes the following, with dashed lines indicating linker sections or ULM joints:

[0226] [ka]

[0227] [ka]

[0228] Each R 22 These are independently H or -CN; Each R 23 These are independently H, halo, or -CF3; Y 1 , Y 2 Each is independently either O or S; Y 3 , Y 4 , Y 5 Each is independently bonded, O, NR Y2 , CR Y1 R Y2 C=O, C=S, SO, or SO2 ru; R 1 , R 2 Each of these is independently either a hydrogen atom or a methyl group; W 2 is a bond, C 1~6 They are aryl or heteroaryl, each consisting of 1, 2, or 3 individuals. R W2 Replaced by; and Each R W2 These 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 by one or more -F (It will be replaced.)

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

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

[0231] [ka]

[0232] In certain additional embodiments, W2 is

[0233] [ka]

[0234] In certain embodiments, the ABM includes the structure shown below, where the dashed line represents the linker portion. Alternatively, it indicates the junction of ULM or CLM:

[0235] [ka]

[0236] [ka]

[0237] Each R 22 These are independently H or -CN; Each R 23 These are independently H, halo, or -CF3; Y 3 is a bond or O; Y 4 is a bond or NH; Y 5 This is a bond, C=O, C1-C6 heteroaryl, or C1-C6 aryl; R 1 , R 2 Each is independently H or C1-C6 alkyl (straight-chain or branched-chain, with one or more H Ro or C 1-6 (Optionally substituted with alkoxyl); W 2 is a bond, C 1~6 Aryl, C1-6 heteroaryl, C 1~6 Alicyclic, or C1-6 heterocyclic This is an equation, and each can have 1 to 10 R's. W2 Replaced by; and Each R W2 H or halo is independent of H; and

[0238] [ka]

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

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

[0241] [ka]

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

[0243] [ka]

[0244] In a particular embodiment, the androgen receptor binding compound of ABM is selected from the group consisting of the following: 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-tetramethylcycline Robylpyridazine-3-carboxamide; Trans tert-butyl N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl butyl [Clobutyl]carbamate; trans 4-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline [butyl]benzamide; trans 5-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robylpyrazine-2-carboxamide; trans 2-amino-N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline [Robutyl]pyrimidine-5-carboxamide; 4-Methoxy-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl [Tylcyclobutyl]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-tetramethylcycline [Robutyl]pyridine-3-carboxamide; trans 4-[(5-hydroxypentyl)amino]-N-[3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl]benzamide; and trans tert-butyl 2-({5-[(4-{[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto [Lamethylcyclobutyl]carbamoyl}phenyl)aminopentyl}oxy)acetate; and N-((1r,3r)-3-(4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-methylbene Zuamido.

[0245] The term "hydrocarbyl" refers to a compound containing carbon and hydrogen. They may be fully saturated, partially unsaturated, or aromatic, and may contain aryl groups, alkyl groups, Contains alkenyl and alkynyl groups.

[0246] The term "unsubstituted" shall mean that it is substituted only with hydrogen atoms. The range of carbon atoms included means that carbon is either absent or replaced by hydrogen. Therefore, the range of carbon atoms C0-C6 includes 1, 2, 3, 4, 5 and 6 carbon atoms, and C For 0, there is H instead of carbon. This is called "substituted" or "optionally substituted". The term refers to one or more substituents at the position of any carbon (or nitrogen) on a molecule in context. A portion of the compound shown may have up to five independent substituents, preferably up to three substitutions. The group is often one or two substituents, and may include substituents that can be further substituted. ) are meant to be independent (i.e., if there are multiple substituents, each substituent is a separate entity) (Independent of the substitution group), and as substituents, hydroxyl, thiol, carboxyl , cyano(C≡N), nitro(NO2), halogen (especially alkyl, especially trifluoromethyl Preferably one, two, or three halogens on a methyl group such as tyl, alkyl group (preferably Kuha C1-C 10 , more preferably C1-6), aryl (especially phenyl and substituted phenyl, e.g. (e.g., benzyl or benzoyl), alkoxy group (preferably C1-C6 alkyl or alkoxy group) Phenyl and substituted phenyls, thioethers (C1-C6 alkyl or aryl). ), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 Alkyl or aryl alkylene esters (the bond is not an ester functional group) (The alkylene group is preferably substituted with a C1-C6 alkyl or aryl group.) Preferably containing C1-C6 alkyl or aryl compounds, and halogens (preferably F or Cl). , amine (containing a 5 or 6-membered cyclic alkyleneamine, C1-C6 alkylamine or C1-C6 The compound further comprises a dialkylamine, wherein the alkyl group is substituted with one or two hydroxyl groups. (Polyethylene) or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (polyethylene) It may be optionally substituted with a ethylene glycol chain, to which one halogen, preferably a chlorine substituent, may be added. A alkyl group containing is further bonded), hydrazine, amide, which is preferably 1 or two C1-C6 alkyl groups (a carboxyl group optionally substituted with one or two C1-C6 alkyl groups) (containing samide), alkanol (preferably C1-C6 alkyl or aryl), or Examples include those substituted with rukanic acid (preferably C1-C6 alkyl or aryl). The substituents according to this disclosure may include, for example, a -SiR1R2R3 group, wherein the formula, each of R1 and R2 This is described otherwise in this specification, and R3 is H or a C1-C6 alkyl group, as stated in the text. In the pulse, R1, R2, and R3 are preferably C1-C3 alkyl groups (isopropyl or t-butyl group) (including) Each of the above groups may be directly bonded to the substituted part, or The substituents are optionally substituted (CH2) m - via, or optionally substituted by -(OCH2) m -,-( OCH2CH2) m -or-(CH2CH2O) m - Via the group, the substituted portion (preferably aryl or In the case of the heteroaryl moiety, they may be bonded to any of the substituents mentioned above. It may be substituted with one or more of the alkylene groups -(CH2) m -or-(CH2) n -Base or example If other chains, such as the ethylene glycol chain specified above, are substituted on any of the said chains It may also be used. Preferred substituents on the alkylene group are halogens or C1-C6 (preferably) Examples include C1-C3 alkyl groups, which optionally consist of one or two hydroxyl groups, one or more or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the present specification The amino acid side chain may be substituted with an amino acid side chain as otherwise described in the book, and optionally substituted amides. (preferably a carboxamide substituted as described above) or a urethane group (often, Examples include one or two C0-C6 alkyl substituents, and this group may also be further substituted. In certain embodiments, the alkylene group (often a single methylene group) is one or These are two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, in most cases Substituting a methyl or O-methyl group, or an amino acid side chain as otherwise described herein. In this disclosure, the molecular portion can have up to 5 substituents, preferably up to 3 substituents. It may be substituted with substituents. In most cases, the substituted portion in this disclosure is one It is substituted with two substituents.

[0247] The term "substitutable" (where each substituent is independent of any other substituent) is used to mean that In the context of its use, C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, and carb Xamide, sulfonamide, sulfone, keto, carboxy, C1-C6 ester (oxy Esters or carbonyl esters), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R 1)-C(O)-O-R1, nitro, cyano, and amines (especially C1-C6 alkylene-NR1R2, mono or di-C1-C6 alkyl-substituted amines, with one or two hydroxyl groups as This also means (including those that can be substituted by meaning). Each of these bases is used unless otherwise suggested. Insofar as it is used, it contains 1 to 6 carbon atoms in the context. In certain embodiments, substituents are used. Depending on the context in which it is used, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, and -(CH2 ) m - (In this specification, m and n are 1, 2, 3, 4, 5 or 6 in the context), -S- -S(O)-,SO2- or -NH-C(O)-NH-,-(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 A Kill, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl),-(CH2) n OC(O)-(C1-C6 Alkyl), -(CH2) n C(O)O-(C1-C6 alkyl),-(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2,-( OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-( C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S ,-S(O)-R S (R S teeth , C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halogen (F, Cl, Br, I , preferably F or Cl) would be examples. R1 and R2 are each H or C1-C6 alkyl groups (one or two hydroxyl groups, or up to three halogen groups, preferred (or it can be optionally substituted with fluorine). The term "substituted" is also defined as Within the chemical background of the compounds being worked on and the substituents being used, the optionally substituted aryl groups are also or heteroaryl group or any substituted complex as otherwise described herein It shall mean a ring group. The alkylene group is also disclosed otherwise herein. It may be substituted with, preferably optionally, a C1-C6 alkyl group (methyl, ethyl). Alternatively, hydroxymethyl or hydroxyethyl is preferred, and thereafter the chiral center (Provided), side chains of amino acid groups as otherwise described herein, the amide groups described above, Alternatively, a urethane group, an OC(O)-NR1R2 group, where R1 and R2 are as otherwise described herein. As described above, substitution may be made with the specified group, but many other groups can also be used as substituents. The various optionally substituted portions consist of three or more substituents, preferably three or fewer substituents, and preferred The substituent may be substituted with one or two substituents in the compound at a specific position in the molecule. A substitution is required (mainly due to valence), but if the substitution is not shown, the context of the substitution... Unless otherwise indicated, substituents are considered or understood to be H. Please be careful.

[0248] Exemplary AR-PROTAC compounds As described above, in certain embodiments, this specification refers to at least one ABM group described herein. , linker, and a bifunctional PROT containing at least one ULM (or CLM) group AC compounds are provided.

[0249] In certain embodiments, this compound is compound 1 to 625 (i.e., Figures 2, 3, 4, and 5, respectively). , 6 and 7 (the chemical structures described in Tables 2, 3, 4, 5, 6 and 7) and their 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-dioxopiperidine-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-dioxy Sopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl [Amino]ethoxy)ethoxy]phenyl]-4,4-dimethyl-5-oxo-2-sulfanyl Denimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile(2); 4-{3-[ 4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H -Isoindole-4-yl]-4,7,10,13,16-pentaoxa-1-azaoctadecane-18 -yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazoly Zin-1-yl}-2-(trifluoromethyl)benzonitrile(3); 4-[3-(4-{2-[2-(2 -{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-yl Soindole-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-Dioxopiperidine-3-yl )-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}ethoxy)eth [Xy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazo Lysine-1-yl]-2-(trifluoromethyl)benzonitrile (5); 4-{3-[4-({1-[2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxo-2,3-Dihydro-1H-Isoindo [4-yl]-4,7,10-trioxa-1-azatetradecane-14-yl}oxy)phen [L]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-( Trifluoromethyl)benzonitrile(6); 4-{3-[4-({1-[2-(2,6-dioxopiperid [n-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10 -Trioxa-1-azatridecane-13-yl}oxy)phenyl]-4,4-dimethyl-5- Xo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzo Nitrile (7); 4-(3-{4-[(1-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1,3- Dioxo-2,3-dihydro-1H-isoindole-4-yl}-4,7,10-trioxa-1-a Zadodecane-12-yl)oxy]phenyl}-4,4-dimethyl-5-oxo-2-sulfanyl Denimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile(8); 4-(3-{ 4-[(1-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihydr (Ro-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(9); 4-[3-(4-{3-[3-(2-{[2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxo-2,3-dihydro-1H-isoindo [4-yl]amino}ethoxy)propoxy]propoxy}phenyl)-4,4-dimethyl-5 -Oxo-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl) Nzonitrile (10); 4-{4,4-dimethyl-3-[4-({1-[2-(3-methyl-2,6-dioxop [Peridine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]- 4,7,10-trioxa-1-azatridecane-13-yl}oxy)phenyl]-5-oxo-2- Sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl)benzonitrile( 11); 4-[3-(4-{4-[(5-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)oxy]phenyl}f [(enyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl]- 2-(trifluoromethyl)benzonitrile(12); 4-{[5-(3-{[2-(2,6-dioxopiper [zin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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 Oxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl [L]-1,4,7,10-tetraoxatridecane-13-yl]oxy)phenyl]-4,4-dimethyl {-5-oxo-2-sulfanylideneimidazolidin-1-yl}-2-(trifluoromethyl ) Benzonitrile (14); 6-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxy So-2,3-dihydro-1H-isoindole-4-yl]aminoethyl)piperazine-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-dioxopiperine [zin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino }Propoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyanoph Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (16); 4 -(3-{4-[1-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihy (Dro-1H-isoindole-4-yl]oxyethyl)-1H-1,3-benzodiazole-5- Il]phenyl}-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1- (Iyl)-2-(trifluoromethyl)benzonitrile(17); 4-{[5-(3-{[2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl [Lu]amino}propoxy)pentyl]amino}-3-fluoro-N-[(1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl]benzamide (18); 6-[4 -(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-yl) Soindole-4-yl]oxyethyl)piperazine-1-yl]-N-[(1r,3r)-3-(3-C [Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-cal Boxamide (19); 6-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-diox So-2,3-dihydro-1H-isoindole-4-yl]aminoethyl)piperazine-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-isoindole-4-yl]propyl}pipette Radin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl]pyridine-3-carboxamide (21); 6-{4-[2-(2-{[2-(2,6 (-Dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4 -yl]oxy}ethoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl]pyridine-3-carboxa Mido(22); 4-{4-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3 [Dihydro-1H-isoindole-4-yl]oxyethyl)piperazine-1-yl]butyl }‐N‐[(1r,3r)‐3‐[4-cyano-3-(trifluoromethyl)phenoxy]‐2,2,4,4-teto [Lamethylcyclobutyl]benzamide (23); 6-{4-[2-(3-{[2-(2,6-dioxopiperyl [zin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]amino }Propoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyanoph [Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (24); 6 -{4-[2-(3-{[2-(2,6-dioxopiperidine-3-yl)-7-fluoro-1,3-diox So-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)ethyl]piperazi 1-yl-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl]pyridine-3-carboxamide (25); 4-(6-{4-[2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl [piperazine-1-yl}hexyl)-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl] [Tyl(phenoxy)]-2,2,4,4-tetramethylcyclobutyl]benzamide(26); 4-{3-[4 -(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H -Isoindole-4-yl]aminopropyl)piperazine-1-yl]propyl}-N-[(1r ,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethyl Clobutyl]benzamide (27); 4-[5-(3-{[2-(2,6-dioxopiperidine-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminopropoxy) [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- [Iyl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl] Minopropoxy)ethyl]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-shya Nophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (29) ; 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3- Dihydro-1H-isoindole-5-yl}oxy)ethyl]piperazine-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-isoindole-4-yl}oxy)ethyl]pipette Radin-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-dioxy Sopiperidine-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoin Dol-4-yl]aminoethyl)piperazin-1-yl]butyl}-N-[(1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (32) ; 6-{4-[5-({2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihy Diro-1H-isoindole-4-yl}oxy)pentyl]piperazine-1-yl}-N-[(1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyri Din-3-carboxamide (33); 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine [-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}oxy) [Tyl]piperazine-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl]benzamide (34); 6-{4-[5-({2-[(3S)- 2,6-Dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole [-5-yl}oxy)pentyl]piperazine-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-dioxopiperidine-3-yl)-5-fluoro-1,3-dioxopiperidine-3-yl)-5-fluoro-1,3-dioxopiperidine-3-yl) Xo-2,3-dihydro-1H-isoindole-4-yl]piperazine-1-yl}butyl)-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty Lu]benzamide (36); 4-{4-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-5- Fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminoeth Piperazine-1-yl]butyl}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl]benzamide (37); 6-(4-{6-[2-(2,6-diode Xopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl] Hexyl piperazine-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-dioxopiperidine-3-yl)-4-fluoro-1,3-dioxo-2,3-dihyde Ro-1H-isoindole-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-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihy [Dro-1H-isoindole-5-yl]piperazine-1-yl}hexyl)-N-[(1r,3r)-3 -(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide do(40); 6-{4-[5-({2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo [-2,3-dihydro-1H-isoindole-5-yl]oxy)pentyl]piperazine-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-isoindole-4-yl]oxy}pliers [(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclo] Butyl]pyridine-3-carboxamide (42); 4-[4-(5-{[2-(2,6-dioxopiperidine -3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]oxy}pliers [(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclo] Butyl]benzamide (43); 4-(5-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}pen (Tyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl]benzamide (44); 4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)- 1,3-Dioxo-2,3-Dihydro-1H-Isoindole-5-yl]piperazine-1-yl} (Tyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl]benzamide (45); 4-(6-{4-[2-(2,6-dioxopiperidine-3-yl)- [6-Fluoro-1,3-Dioxo-2,3-Dihydro-1H-Isoindole-5-yl]piperaj (n-1-yl}hexyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl]benzamide (46); 4-(4-{[2-(2,6-dioxopiperid [H-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]oxybuty (Lu)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline [Robutyl]benzamide (47); 4-(5-{[2-(2,6-dioxopiperidine-3-yl)-1-o Xo-2,3-dihydro-1H-isoindole-4-yl]oxy}pentyl)-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzalkonium Mido(48); 4-[3-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-di Hydro-1H-isoindole-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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydr [H-Isoindole-4-yl]oxyethoxy)butyl]-N-[(1r,3r)-3-(3-) [Roro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (50); 4-[5-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H -Isoindole-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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-yl) Soindole-4-yl]oxyethoxy)hexyl]-N-[(1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (52); N-[(2R) -1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl]propane-2-yl [Lu]-5-{[4-(4-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-di Hydro-1H-isoindole-4-yl]amino}butyl)piperazine-1-yl]methyl}-1 H-pyrazole-3-carboxamide(53); 4-(4-{6-[2-(2,6-dioxopiperidine-3 [Isol)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]hexyl}pipette Radin-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl]benzamide (54); 4-(3-{[2-(2,6-dioxopiperidine-3 (-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]oxypropyl) -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-P Razole-1-yl]propan-2-yl]-5-[(3-{4-[2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine- 1-Il}propoxy)methyl]-1H-pyrazole-3-carboxamide (56); 4-[4-(3-{[ 2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindo [(1r,3r)- ](4-yl)oxypropyl)-1H-1,2,3-triazole-1-yl)-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (57); 6-[4-(6-{[2 -(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro -1H-isoindole-5-yl]aminohexyl)piperazine-1-yl]-N-[(1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrid n-3-carboxamide(58); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H- Pyrazole-1-yl]propan-2-yl]-5-({3-[4-(2-{[2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amine (N)ethyl)piperazine-1-yl]propoxymethyl)-1H-pyrazole-3-carbox Mido(59); (60); 4-[4-(5-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2 ,3-dihydro-1H-isoindole-4-yl]oxy}pentyl)-1H-1,2,3-triazo [(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl] Nzuamide (61); 6-{4-[2-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3 -Dioxo-2,3-dihydro-1H-isoindole-4-yl}butoxy)ethyl]piperaj 1-yl-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl]pyridine-3-carboxamide (62); 6-{4-[2-(4-{2-[(3R)-2, [6-Dioxopiperidine-3-yl]-1,3-Dioxo-2,3-dihydro-1H-isoindo [4-yl]butoxy)ethyl]piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxami do(63); 6-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo Xo-2,3-dihydro-1H-isoindole-4-yl}pentyl)oxy]ethyl}piperazi (n-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl]pyridine-3-carboxamide (64); 6-(4-{2-[(5-{2-[(3R)-2 ,6-Dioxopiperidine-3-yl]-1,3-Dioxo-2,3-Dihydro-1H-Isoindo [4-yl]pentyl)oxy]ethyl]piperazine-1-yl)-N-[(1r,3r)-3-(3-k [Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-cal Boxamide (65); 4-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1, 3-Dioxo-2,3-dihydro-1H-isoindole-4-ylpentyl)oxyethyl} Piperazine-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 Oxopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4 (-yl)pentyl)oxy]ethyl)piperazine-1-yl)-N-[(1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl]benzamide (67); 4-(4 -{6-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-iso Indole-5-yl]hexyl}piperazine-1-yl)-N-[(1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (68); 4-(3- {4-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-yl Soindole-5-yl]piperazin-1-yl}propyl)-N-[(1r,3r)-3-(3-chloro -4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (69); 4-[ 6-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1 H-isoindole-5-yl}piperazine-1-yl)hexyl]-N-[(1r,3r)-3-[4-cy Ano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]ben Zuamido (70); 4-[6-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo [-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)hexyl]-N-[ (1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethyl Lucyclobutyl]benzamide (71); 6-[4-(6-{[2-(2,6-dioxopiperidine-3-I (L)-5-fluoro-1-oxo-2,3-dihydro-1H-isoindole-4-yl]oxy} [Hexyl)piperazine-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-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydr [H-Isoindole-5-yl]oxyhexyl)piperazine-1-yl]-N-[(1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrid n-3-carboxamide (73); 4-[6-(4-{2-[(3S)-2,6-dioxopiperidine-3- (Lu)-3-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-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- [dioxopiperidine-3-yl]-3-oxo-2,3-dihydro-1H-isoindole-5- [Il}piperazine-1-yl)hexyl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoro [methyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (75); N-((1r,3 r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2 -(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindorin-5-yl)amino )Hexyl)piperazine-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-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperazin N-1-yl)nicotinamide(77); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-6-(4-(2-(1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperidine-4-yl)ethyl)piperazine-1-yl)nicotine Amide (78); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-6-(4-(2-((5-(2-((S)-2,6-Dioxopiperidine-3-yl)-1-Oxoisoindo Phosphate-4-yl)pentyl)oxy)ethyl)piperazine-1-yl)nicotinamide (79); N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(( 5-(2-((R)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)pentyl) Oxy(ethyl)piperazine-1-yl)benzamide(80); N-((1r,3r)-3-(3-chloro-4-shea Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-yl) Xyl)benzamide(81); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto (Lamethylcyclobutyl)-4-(6-(4-(2-(2,6-Dioxopiperidine-3-yl)-1-Oxoisoyl (82) (N-(( 1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((1R, 4R)-5-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindoline-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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)oxy)pen (Tyl)piperazine-1-yl)benzamide(84); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(5-((2-(2,6-dioxopiperidine-3-yl) )-1,3-dioxoisoindorin-5-yl)oxy)pentyl)-1,2,3,6-tetrahydropyridyl N-4-yl)benzamide(85); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(5-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxy Soisoindorin-5-yl)piperazine-1-yl)pentyl)benzamide(86); N-((1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(4-(2-((R )-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl )pentyl)benzamide(87); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro- 1-Oxoisoindorin-5-yl)piperazine-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-dioxopiperidine-3-yl)-6-fluoro-3-oxoisoindorin-5-yl)pipe Radin-1-yl)hexyl)benzamide(89); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(6-((2-(2,6-dioxopiperidine-3-yl )-6-fluoro-1-oxoisoindolin-5-yl)oxy)hexyl)piperazine-1-yl) Cotinamide (90); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin Dorin-5-yl)oxy)propyl)piperazine-1-yl)benzamide(91); N-((1r,3r)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-((2-(2,6- Dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)butyl)piperidine Radin-1-yl)benzamide(92); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(6-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxo Isoindorin-5-yl)piperidine-1-yl)hexyl)benzamide(93); N-((1r,3r)-3- (3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6- Dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine-1-yl)hex Sil)nicotinamide(94); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto (Lamethylcyclobutyl)-4-(5-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)-3,6-dihydropyridine-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-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)oxy)pe (N-((1r,3r)-3-(3-chloro-4-cyanophenate) (Noxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-yl)butyl) Benzamide (97); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(5-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindri N-5-yl)-3,6-dihydropyridine-1(2H)-yl)pentyl)benzamide(98); N-((1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(5-((2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)oxy)pentyl )piperidine-4-yl)benzamide(99); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-Dioxopiperidine-3-yl)-1- Oxoisoindoline-5-yl)oxy)pentyl)-1H-1,2,3-triazole-1-yl)benz Amide(100); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-4-(6-((1S,4S)-5-(2((R)-2,6-Dioxopiperidine-3-yl)-1-Oxoisoy (andrin-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)hexyl)benzamide( 101); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(4-(5-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)O Xy(pentyl)-1H-1,2,3-triazole-1-yl)nicotinamide(102); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoiisoindorin-5-yl)piperidine-1-yl) Xyl)nicotinamide (103); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoi Soindolin-5-yl)-3,6-dihydropyridine-1(2H)-yl)butyl)benzamide(104); N -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -(3-(4-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)oxy) Piperidine-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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)oxy) Zethidine-1-yl)propyl)-1H-1,2,3-triazole-1-yl)benzamide(106); N-((1r ,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-( 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl)-1H-1,2,3 -Triazole-4-yl)ethyl)piperazine-1-yl)nicotinamide(107); N-((1r,3r)-3- (3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(3-(1-(2-(2 ,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)-1H-1,2,3-Tria Zole-4-yl)propyl)piperazine-1-yl)nicotinamide(108); N-((1r,3r)-3-(3-k (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-diol) Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)hex Sil)nicotinamide(109); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1, 3-Dioxoisoindorin-5-yl)piperazine-1-yl)hexyl)nicotinamide(110); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy (111) Propylpiperazine-1-yl) Nicotinamide (111); N-((1r,3r)-3-(3-chloro-4-shya Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(1-(5-((2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperidine-4-yl ) Nicotinamide (112); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-6-(1-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)oxy)propyl)piperidine-4-yl)nicotinamide (113); N-((1r, 3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl (Lu)-6-(4-(5-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (L)oxy)pentyl)piperazine-1-yl)nicotinamide(114); N-((1r,3r)-3-(3-chloro -4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-6-(4-(4-((2-(2,6-Dioxo Piperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperazine-1- Il)nicotinamide(115); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-((3S)-4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindoline-5-yl)oxy)pentyl)-3-(hydroxymethyl)piperazine-1-yl (L)benzamide(116); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-6-(4-(3-(3-((2-(2,6-dioxopiperidine-3-yl)-1-oxoiso Indoline-5-yl)oxy)azetidine-1-yl)propyl)-1H-1,2,3-triazole-1-yl (L) Nicotinamide (117); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidine-3-yl)-1, 3-Dioxoisoindorin-5-yl)piperazine-1-yl)hexyl)nicotinamide(118); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 3-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine -1-yl)propyl)nicotinamide(119); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1, 3-Dioxoisoindorin-5-yl)piperazine-1-yl)propyl)nicotinamide(120); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-( 4-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine -1-yl)butyl)nicotinamide(121); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindoline-5-yl)oxy)ethyl)piperazine-1-yl)nicotinamide(12 2); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -6-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Peridine-1-yl)butyl)nicotinamide(123); N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)butyl)nicotinamide( 124); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pi Perazine-1-yl)butyl)nicotinamide(125); N-((1r,3r)-3-(4-cyano-3-methylphenyl (Noxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)nicotine N-amide(126); N-((1r,3r)-3-(3,4-dicyanofenoxy)-2,2,4,4-tetramethylcyclo Butyl)-6-(4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5 -yl)oxy)pentyl)piperazine-1-yl)nicotinamide(127); N-((1r,3r)-3-(3-) (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(5-(3-((2-(2,6-diol) Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)azetidine-1-yl (L)pentyl)nicotinamide(128); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)nicotine Amide(129); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-6-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)oxy)piperidine-1-yl)butyl)nicotinamide(130); N-((1r,3r)-3-(3-k (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Tyl)piperidine-1-yl)nicotinamide(131); N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(5-((2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)pyrim Zin-5-carboxamide(132); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(2-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Xisoisoindolin-5-yl)piperazine-1-yl)propoxy)ethyl)-3,5-difluorobe Nzuamide (133); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-((3S,5R)-4-(5-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)oxy)pentyl)-3,5-dimethylpiperazine-1-yl)benzamide( 134); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(2-(4-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (Oxy)butyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-yl)nicotinamide( 135); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(1-(4-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (Oxy)butyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-yl)nicotinamide( 136); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(5-(4-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (Oxy)butyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)nicotinamide( 137); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (L)-6-(5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl )piperazine-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-dioxopiper (Zin-3-yl)-6-fluoro-3-oxoisoindorin-5-yl)piperazin-1-yl)hexyl ) Nicotinamide (139); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-6-(6-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-6-fluoro-1- Oxoisoindolin-5-yl)piperazine-1-yl)hexyl)nicotinamide (140); N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-(9 -(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-1-oxa- 4,9-Diazaspiro[5.5]undecane-4-yl)ethyl)benzamide(141); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-((2-(2,6- Dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)butyl)piperidine Radin-1-yl)pyrimidine-5-carboxamide(142); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-((2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindoline-5-yl)oxypropyl)piperazine-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-dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)oxy)ethyl)piperazine-1-yl)pyrimidine-5-cal Boxamide (144); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-2-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrimidine-5-carboxami (145); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-teto (Lamethylcyclobutyl)-6-(3-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)piperazin-1-yl)propyl)nicotinamide (146); N-((R)-1-(3 -(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl)propan-2-yl)-5-((4-(4-(2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1-yl (L)butoxy(methyl)-1H-pyrazole-3-carboxamide (147); N-((1r,3r)-3-(3-chloro -4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(3-(9-(2-(2,6-Dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-1-oxa-4,9-diazaspiro[ 5.5] Undecane-4-yl)propyl)benzamide (148); N-((1r,3r)-3-(4-cyano-3-methyl Luphenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine N-1-yl)nicotinamide (149); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)pirim Zin-5-carboxamide (150); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-6-(4-(5-((2-((S)-2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)pentyl)piperazine-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-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl )piperazine-1-yl)ethyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Perazin-1-yl)ethyl)piperidine-1-yl)nicotinamide (153); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)pentyl)-3- Xopiperazine-1-yl)nicotinamide (154); N-((1r,3r)-3-(3-chloro-4-cyanophenate (Noxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(4-(3-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindoline-5-yl)oxy)azetidine-1-yl)butyl)pipette Radin-1-yl)pyrimidine-5-carboxamide (155); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3-(3-((2-(2,6-dioxopiperyl Zin-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)azetidine-1-yl)propyl )piperazine-1-yl)pyrimidine-5-carboxamide (156); 2-chloro-4-(3-(4-(5-(4-(2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1- Il(pentyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidi N-1-yl)benzonitrile (157); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzur Mido (158); 2-Chloro-4-(5-(4-(5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-diox Soisoindolin-5-yl)piperazine-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-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-1-yl )Ethyl)piperidine-1-yl)nicotinamide(160); N-((1r,3r)-3-(3,4-dicyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(2-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl (L) Pyrimidine-5-carboxamide (161); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-6-(2-(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindorin-5-yl)-2,7-diazaspiro[3.5]nonane-7-yl)nicotinamide(1 62); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-6-(7-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl)-2,7 -diazaspiro[3.5]nonan-2-yl)nicotinamide(163); N-((1r,3r)-3-(3-chloro-4-cy Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(2-(5-((2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)-2,6-dihydrop Roro[3,4-c]pyrazole-5(4H)-yl)nicotinamide(164); N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(3-(2-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)ethyl)azetidine-1-yl) (L) Pyrimidine-5-carboxamide (165); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-4-(4-(4-((2-(2,6-Dioxopiperidine-3-yl)-1, 3-Dioxoisoindoline-5-yl)oxy)butyl)piperazine-1-yl)-2,6-difluoro Benzamide (166); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-2-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin (Drin-5-yl)piperidine-4-yl)methyl)-1,4-diazepan-1-yl)pyrimidine-5-cal Boxamide (167); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-(4-(2-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)oxy)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)ben Zuamido(168); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl)-4-(4-(3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisinodindri n-5-yl)oxy)propyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-yl)ben Zuamido (169); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoi Soindolin-5-yl)piperazin-1-yl)ethyl)benzamide(170); N-((1r,3R)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((1R,4R)-5-(2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-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-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-carbonyl)piper Zin-1-yl)benzamide (172); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3,5-diph Luorobenzuamide (173); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(4-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-diox Soisoindolin-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)benzamide (174); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyrate (L)-4-(4-(((1R,4R)-5-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindri (-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidine-1-yl) Nzamide (175); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(4-(((1S,4S)-5-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxo Isoindolin-5-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidine N-1-yl)benzamide (176); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Xisoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-3-fluoro Benzamide (177); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (Tylcyclobutyl)-4-(4-((((1r,3r)-3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxo Xisoisoindoline-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)piperidine-1 -yl)benzamide (178); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-5-fluoronico Tinamide (179); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetrameth Lucyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-4-fluoro-1,3-dioxo Xisoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (180); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-4,6-difluoro-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoiisoyl (182); N -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl(methyl)cyclohexyl(benzamide(183); N-((1r,3r)-3-(4-cyano-3-methyl) Tylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-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-dioxopiperidine-3-yl)-6-fluoro -3-oxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benz Amide (185); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoiso Indolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (186); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoisoindoline-5- (Iyl)piperazine-1-yl)ethyl)piperidine-1-yl)benzamide(187); N-((1r,3r)-3- (3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(2-(4-(2-(2 ,6-Dioxopiperidine-3-yl)-6-Fluoro-3-oxoisoindorin-5-yl)piperazi N-1-yl)ethyl)piperidine-1-yl)benzamide(188); N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(2-(4-(2-(2,6-dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)ethyl) Zethidine-1-yl)benzamide(189); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-4-(4-(2-(3-((2-(2,6-Dioxopiperidine-3-yl)-1 ,3-Dioxoisoindorin-5-yl)oxy)azetidine-1-yl)ethyl)piperidine-1-yl) (L)benzamide(190); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)methyl)azepan-1-yl)pyrimidine-5-carboc Thamide (191); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-4-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline- 5-yl)piperazine-1-yl)cyclohexyl)benzamide(192); N-((1r,3R)-3-(3-chloro Ro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((3S,5R)-4-(3((2-(2, 6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)oxy)propyl)- 3,5-Dimethylpiperazine-1-yl)nicotinamide(193); N-((1r,3R)-3-(3-chloro-4-shea Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4-(3-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)propyl)-3,5-dimethyl Tylpiperazine-1-yl)benzamide(194); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-2-((3S,5R)-4-(3-((2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)propyl)-3,5-dimethylpiper Zin-1-yl)pyrimidine-5-carboxamide(195); N-((1r,3r)-3-(3-chloro-4-cyanoph Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1s,3S)-3-(((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)methyl)cyclobutyl) Perazine-1-yl)benzamide(196); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-4-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3- Dioxoisoindolin-5-yl)piperazine-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-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl (Lu)piperazine-1-yl)azetidine-1-yl)piperidine-1-yl)benzamide (198); N-(( 1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R) -3-(((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Peridine-4-yl)methyl)(methyl)amino)pyrrolin-1-yl)benzamide(199); N-((1 r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)- 3-(((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Lysine-4-yl)methyl)(methyl)amino)pyrrolinidine-1-yl)benzamide(200); N-((1r, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3- (((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperi Zin-4-yl)(methyl)amino)methyl)pyrrolidine-1-yl)benzamide (201); N-((1r,3 R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((2S,6 R)-4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl)-2,6- Dimethylpiperazine-1-yl)ethyl)benzamide (202); N-((1r,3r)-3-(3-chloro-4-cy Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3(4(2(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)-[1,3'-biazeti [Zin]-1'-yl)benzamide(203); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-4-(4-(2-(((1r,3r)-3-((2-(2,6-Dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)oxy)cyclobutyl)(methyl)amino)eth (L)piperazine-1-yl)benzamide (204); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(1-(2-((2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)oxy)ethyl)azetidine-3-yl)piperazi N-1-yl)benzamide (205); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-4-(2-(4-(1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)azetidine-3-yl)piperazine-1-yl)ethyl)benzalkonium Mido (206); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-4-(2-((2R,6R)-4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (207); N-((1r ,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3 -((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl)methyl)pyrrolidine-1-yl)benzamide (208); N-((1r,3S)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(2-((2S,6S)-4-(2-(2,6-Di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-2,6-dimethylpiperidine N-1-yl)ethyl)benzamide (209); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-Tetramethylcyclobutyl)-4-(3-((4-(2-(2,6-Dioxopiperidine-3-yl)-1, 3-Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)ben Zuamide (210); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-(3-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoin Dorin-5-yl)piperazin-1-yl)ethyl)pyrrolidine-1-yl)benzamide (211); N-( (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( 2-(4-(6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4- b) Pyrazine-2-yl)piperazine-1-yl)ethyl)piperidine-1-yl)benzamide (212); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-((4-(2-(2,6-dioxopiperidine-3-yl)-7-fluoro-1,3-dioxoisoindoline- 5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (213); N-((1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-( 2,6-Dioxopiperidine-3-yl)-4-fluoro-1-oxoisoindorin-5-yl)piperazi N-1-yl)methyl)piperidine-1-yl)benzamide (214); N-((1r,3S)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-((4aR,6R,8aS)-6-(4-(2-(2,6 (Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)Piperadin-1-yl) Octahydroisoquinoline-2(1H)-yl)nicotinamide(215); N-((1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(3-(2-(((1r,3r)-3-((2-(2 ,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-5-yl)oxy)cyclo (Tyl)(methyl)amino)ethyl)azetidine-1-yl)benzamide (216); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6- Dioxopiperidine-3-yl)-4-fluoro-1,3-dioxoisoindorin-5-yl)oxy) Propyl)piperazine-1-yl)benzamide (217); N-((1r,3R)-3-(3-chloro-4-cyanoph Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1r,3R)-3-((4-(2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)cycline (Robutyl)benzamide (218); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-((1s,3S)-3-((4-(2-(2,6-dioxopiperidine-3-yl)-1, 3-Dioxoisoindolin-5-yl)piperazine-1-yl)methyl)cyclobutyl)benzamide (219); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-6-((4aR,6S,8aR)-6-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)octahydroisoquinoline-2(1H)-yl)nicotine Amide (220); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-6-((4aR,6R,8aR)-6-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxo Isoindoline-5-yl)piperazine-1-yl)octahydroisoquinoline-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-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)piperazine-1-yl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxisoindorine-5-yl (Lu)piperazine-1-yl)pyrroridine-1-yl)benzamide (223); N-((1r,3r)-3-(3-chloro (4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(4-(1-(2-(2,6-Dioxy Sopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)piper Zin-1-yl)benzamide (224); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-((3R)-3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3 (Dioxoiisoindoline-5-yl)piperazine-1-carbonyl)pyrroridine-1-yl)benz Amide (225); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-((3R)-3-(4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo Xisoisoindorin-5-yl)piperazine-1-carbonyl)pyrroridine-1-yl)benzamide (226); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob (Cyl)-4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoiisoy (227); N -((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisindri N-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)benzamide (228); N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(2-(( 2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)eth (Lu)-2,6-diazaspiro[3.3]heptan-2-yl)benzamide (229); (3R)-N-(1-(4-(((1r, 3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamycin (Phenyl)piperidine-4-yl)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindorin-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-Dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl)ethyl)piperidine-1-yl)pyridazin-3-carboxamide (231); N-((1r,3R )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((2S,4R,6R )-4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Perazin-1-yl)methyl)-2,6-dimethylpiperidine-1-yl)pyrimidine-5-carboxami (232); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob (Chill)-2-((2S,4S,6R)-4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoy (Dimethylpiperidine-1-yl)Pyrimid N-5-carboxamide(233); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-2-((2S,6S)-4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)-2,6-dimethylpiperidine-1 -yl)pyrimidine-5-carboxamide(234); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(3-(3-((2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)oxy)azetidine-1-yl)propyl)azetidine Zin-1-yl)benzamide (235); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-6-(7-((3-(2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperidine-1-yl)methyl)octahydro-2H-pyrido[1,2- a] Pyrazine-2-yl)nicotinamide (236); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((((1r,3r)-3-((2-(2,6-dioxopiperyl (Dioxy)(3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)methyl)(meth (L)amino)piperidine-1-yl)benzamide (237); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((1'-(2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindoline-5-yl)-[1,4'-bipiperidine]-4-yl)amino)be Nzuamide (238); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(4-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (239); N -((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4 -((((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5- (I)oxy)cyclobutyl)(isopropyl)amino)methyl)piperidine-1-yl)benzal Mido (240); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-2-((1S,4S,5R)-5-((4(2(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2.2.1]heptane-2-yl (L) Pyrimidine-5-carboxamide (241); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl)-2-((1S,4S,5S)-5-((4-(2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)-2-azabi 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 Oxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperazine -1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)eth (Methyl)amino)pyrrolin-1-yl)benzamide (244); N-((1r,3R)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3R)-3-(3-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)azetidine-1-yl (L)pyrroridine-1-yl)benzamide (245); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(5-(2-((2-(2,6-dioxopiperidine-3-yl) )-1,3-dioxoisoindolin-5-yl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyro Il-2(1H)-yl)benzamide(246); N-((1r,3r)-3-(4-cyano-3-methylphenoxy)-2, 2,4,4-Tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pirimi Zin-5-carboxamide(247); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl)-4-(4-(4-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxy Soisoindolin-5-yl)piperazine-1-yl)butyl)benzamide (248); N-((1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-((R )-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperazine-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-dioxopiperidine-3-yl)-1-oxy Soisoindolin-5-yl)piperazine-1-yl)hexyl)benzamide (250); N-((1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(4-(2-( (R)-2,6-Dioxopiperidine-3-yl)-1-Oxoisoindorin-5-yl)piperazine-1-yl (L)Hexyl)Benzamide (251); N-((1r,3r)-3-(4-Cyano-3-(trifluoromethyl)F Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)ben Zuamide (252); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-4-(6-((2S,6R)-4-(2-(2,6-Dioxopiperidine-3-yl)-1, 3-Dioxoisoindolin-5-yl)-2,6-dimethylpiperazine-1-yl)hexyl)benzur Mido (253); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-4-((3-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindoline- 5-yl)-3,6-dihydropyridine-1(2H)-yl)ethyl)oxetane-3-yl)methyl)benzal Mido (254); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)ethyl)piperazine-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-dioxopiperidine-3-yl)-1-oxoisoindorin-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 (-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)Oxy)ethyl)piper Radin-1-yl)benzamide (257); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(6-((1R,4R)-5-(2-((S)-2,6-dioxopiperidine-3- (Il)-1-oxoisoindoline-5-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)he Xyl)benzamide (258); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(6-((1R,4R)-5-(2-((R)-2,6-Dioxopiperidine-3-yl)-1 -Oxoisoindoline-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-tetramethyl (Tylcyclobutyl)-4-((3-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1-Oxoisoyl (Piperadin-5-yl)piperazine-1-yl)ethyl)oxetane-3-yl)methyl)benzamide ( 260); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-6-(1-(2-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (L)oxy)ethyl)piperidine-4-yl)nicotinamide (261); N-((1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-6-(1-(4-((2-(2,6-Dioxo Piperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperidine-4- (Iyl)nicotinamide (262); N-((1r,3r)-3-((5-cyano-6-methylpyridine-2-yl)oxy (C)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-(2,6-dioxopiperidine-3-yl )-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)nicotinate Mido (263); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-5-(4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)oxy)pentyl)piperazine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)pe (N-((1r,3r)-3-(3-chloro)) (L-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperidine N-1-yl)picolinamide (266); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-1-(1-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)pentyl)piperidine-4-yl)-1H-pyrazole-4- Carboxamide (267); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-1-(1-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)oxy)pentyl)piperidine-4-yl)-1H-pyrazole-3-carboxa Mido (268); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-1-(1-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)oxy)butyl)pyrroridine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl)ethyl)benzamide (270); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy )-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-((R)-2,6-dioxopiperidine-3- Nicotine (L)-6-fluoro-3-oxoisoindolin-5-yl)piperazine-1-yl)hexyl) Amide (271); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-6-(6-(4-(2-((R)-2,6-dioxopiperidine-3-yl)-6-fluoro-1-oxoi Soindolin-5-yl)piperazine-1-yl)hexyl)nicotinamide (272); N-((1r,3r)- 3-(4-cyano-3-(trifluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Perazine-1-yl)propyl)benzamide (273); N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)-3,6-dihydropyridine-1(2H)-yl)butyl) Nicotinamide (274); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-1'-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoisoyl (Illin-5-yl)oxy)pentyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-ca Ruboxamide (275); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (Tylcyclobutyl)-6-(5-(5-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (Illin-5-yl)oxy)pentyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl) Nicotinamide (276); N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-i (L)propane-2-yl)-5-((3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)propoxy)methyl)-1H-pyrazole-3-carboxy Samide (277); N-((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl)pro Pan-2-yl)-5-((4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindo Phosphate-5-yl)oxy)butyl)piperazine-1-yl)methyl)-1H-pyrazole-3-carboxami (278); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob (Chill)-6-((2R)-4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri (2)(-5-yl)oxy)pentyl)-2-(hydroxymethyl)piperazine-1-yl)nicotinamide (2 79); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl )-1'-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Xy)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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)o Xy)pentyl)-2-oxopiperazine-1-yl)nicotinamide (281); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(1-(4-((2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)butyl)piperidine Zin-4-yl)benzamide (282); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-4-(1-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)propyl)piperidine-4-yl)benzamide (283) N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4 -(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Radin-1-yl)-3-oxopropyl)benzamide(284); N-((1r,3r)-3-(3-chloro-4-shea Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2-((R)-2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1- Il)nicotinamide (285); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-6-(3-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl)oxy)ethyl)azetidine-1-yl)nicotinamide (286); N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(3-(4 -((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy) (Cyl)azetidine-1-yl)nicotinamide (287); 4-(3-(4-(5-(4-(2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)pentyl)-3- Fluorophenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidine-1-yl)-2-(tri Fluoromethyl)benzonitrile (288); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-6-(4-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1 ,3-Dioxoisoindoline-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)pyri Dazin-3-carboxamide(289); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-5-(4-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)pyrazine- 2-Carboxamide (290); N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1- (Iyl)propane-2-yl)-5-(1-(3-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)propoxy)ethyl)-1H-pyrazole-3-cal Boxamide (291); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-5-((3S)-4-(5-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)oxy)pentyl)-3-(hydroxymethyl)piperazine-1-yl)picoli N-amide (292); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-6-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyridazine-3-carboxami (293); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-6-(9-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5-yl (Lu)-3,9-diazaspiro[5.5]undecane-3-yl)nicotinamide (294); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(9-(2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorine-5-yl)-3,9-diazaspiro[5.5] Undecane-3-yl)pyrimidine-5-carboxamide (295); N-((1r,3R)-3-(3-chloro-4-cy Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(2-((1R,4R)-5-(2-(2,6-dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)-2,5-diazabi Cyclo[2.2.1]heptan-2-yl)ethyl)benzamide (296); N-((1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-Dioxopyl Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)propyl)piperazine-1- Il)-2,6-difluorobenzamide (297); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(5-((2-(2,6-dioxopiperidine-3-yl )-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)-2,6-diph Luorobenzuamide (298); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl)oxy)butyl)piperazine-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-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl) Piperazine-1-yl)methyl)piperidine-1-yl)-4-(trifluoromethyl)pyrimidine-5- Carboxamide (300); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-3'-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoisoyl (30) 1); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Piperazine-1-yl)methyl)piperidine-1-yl)-3-(trifluoromethyl)benzamide ( 302); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-3'-(2-(4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (L)piperazin-1-yl)ethyl)-[1,1'-biphenyl]-4-carboxamide (303); N-((1r,3R )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4 -(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Lysine-4-yl)ethyl)-3,5-dimethylpiperazine-1-yl)benzamide (304); N-((1r,3 r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-((4-(2 -(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1- Il(methyl)piperidine-1-yl)pyrimidine-2-carboxamide (305); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(2-(4-(2-(2,6 (Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)Piperadin-1-yl) Ethyl)piperidine-1-yl)pyrimidine-2-carboxamide (306); N-((1r,3r)-3-(3-chloro (L-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisindoline-5-yl)piperidine-4- (Iyl)methyl)piperazine-1-yl)benzamide (307); N-((1r,3r)-3-(3-chloro-4-shea Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(4-(2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)azetidine-1-yl ) Benzamide (308); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (Tylcyclobutyl)-4-(4-(2-(3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)oxy)azetidine-1-yl)ethyl)piperazine-1-yl)benzamide (309); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5 -yl)piperazine-1-yl)methyl)piperidine-1-yl)-4-methylpyrimidine-5-carb Samide (310); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri (Piperadin-1-yl)methyl(piperidine-1-yl)-4,6-dimethylpyrimidine-5- Carboxamide (311); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-4-(2-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)ethyl)piperazine-1-yl)ethyl)benzamide (312); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3' -(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Radin-1-yl)ethoxy)-[1,1'-biphenyl]-4-carboxamide (313); N-((1r,3R)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S,5R)-4-(4-( (2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)buty (L)-3,5-dimethylpiperazine-1-yl)benzamide (314); N-((1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)methyl)pipe Radin-1-yl)benzamide (315); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)benz Amide (316); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-6-((3S)-4-(5-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (Ixyl)Pentyl)-3-(Hydroxymethyl)piperazine-1-yl)Nicotin Mido (317); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-6-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)oxy)butyl)piperazine-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-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1- Il(ethyl)-2,6-difluorobenzamide (319); N-((1r,3r)-3-(3-chloro-4-cyanoph Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(3-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindoline-5-yl)oxy)propyl)azetidine-1-yl)ben Zuamide (320); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-4-((3S)-3-((1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiso Indolin-5-yl)piperidine-4-yl)methoxy)pyrrolidine-1-yl)benzamide (321 ); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-(4-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl (Lu)pyrrolin-3-yl)methyl)piperazine-1-yl)benzamide (322); N-((1r,3R)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(((3R)-1-(2- (2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)pyrrolidine-3- (Iyl)methyl)piperazine-1-yl)benzamide (323); N-((1r,3r)-3-(3-chloro-4-shea Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-3-(4-(4-(2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)butyl)benzamide (324); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-4-((3R)-3-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindo Phosphate-5-yl)piperidine-4-yl)methoxy)pyrrolidine-1-yl)benzamide (325); N-( (1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-((3R ,5R)-4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5-yl) Oxy)propyl)-3,5-dimethylpiperazine-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-dioxopiperidine-3-yl)-1,3-dioxisoindorine-5-yl (Lu)piperazine-1-yl)methyl)pyrrolidine-1-yl)benzamide (327); N-((1r,3S)-3-( 3-Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-((3S)-3-((4-(2- (2,6-Dioxopiperidine-3-yl)-6-Fluoro-1,3-Dioxoisoindorin-5-yl) Perazin-1-yl)methyl)pyrrolidine-1-yl)benzamide (328); N-((1r,3r)-3-(3- (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-diol) Xopiperidine-3-yl)-1-oxoisoindorin-4-yl)butyl)piperazine-1-yl) Nzuamide (329); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(3-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin Dorin-5-yl)azetidine-3-yl)propyl)benzamide (330); N-((1r,3r)-3-(3-k (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-diol) Xopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)butyl)piperazine-1-yl (L)benzamide (331); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-3-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)cyclobutan-1-cal Boxamide (332); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-5-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin (Drin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrazine-2-carboxami (333); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-4-((3R)-3-((((1r,3R)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidine-1-yl) (L)benzamide (334); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-4-(4-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-diox Soysoindolin-5-yl)pyrrolidine-3-yl)methoxy)piperidine-1-yl)benzamide (335); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-4-(4-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindo Phosphate-5-yl)pyrrolidine-3-yl)methoxy)piperidine-1-yl)benzamide (336); N-( (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-( (((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) (337) ); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-((3S)-3-((((1r,3S)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoin Drin-5-yl)oxy)cyclobutyl)(methyl)amino)methyl)pyrrolidine-1-yl)benz Amide (338); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri (-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-4-fluoronicotinamide ( 339); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-4-(4((((3S)-1-(2(2,6-Dioxopiperidine-3-yl)-6-Fluoro-1,3-Dioxoi Soindolin-5-yl)pyrrolidine-3-yl)methyl)(methyl)amino)piperidine-1-yl) Nzamide (340); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(4((((3R)-1-(2-(2,6-Dioxopiperidine-3-yl)-6-Fluoro-1,3 -Dioxoisoindolin-5-yl)pyrrolidine-3-yl)methyl)(methyl)amino)piperidine N-1-yl)benzamide (341); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl)-6-((4aR,6S,8aS)-6-(4(2-(2,6-Dioxopiperidine-3-I (L)-1,3-dioxoisoindoline-5-yl)piperazine-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-dioxopiperidine-3-yl)-6-fu Luoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1- Iyl)-3-fluorobenzamide (343); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-4-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)piperidine-1-yl)benzamide ( 344); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-4-(4(((3S)-1-(2(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoiso Indolin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)benzamide (345); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6- (4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline- 5-yl)piperazine-1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Piperazine-1-yl)methyl)piperidine-1-yl)-3-(2-(2-methoxyethoxy)ethoxy)be Nzuamide (347); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-4-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindri N-4-yl)azetidine-3-yl)methyl)piperidine-1-yl)benzamide (348); N-((1r, 3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-( 2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4 -yl)oxy)piperidine-1-yl)benzamide (349); N-((1r,3r)-3-(3-chloro-4-shya Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((1-(2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-yl)methyl)piperazi N-1-yl)-4-fluoronicotinamide (350); N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-((1-(2-(2,6-dioxopiperidine-3-I (Lu)-1,3-dioxoisoindoline-5-yl)azetidine-3-yl)methyl)azetidine-1-yl ) Benzamide (351); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (Tylcyclobutyl)-4-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (Piperadin-5-yl)piperazine-1-yl)methyl)-3,6-dihydropyridine-1(2H)-yl)benz Amide (352); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-((1'-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)-[1,4'-bipiperidine]-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 Oxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperazine -1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1- (Iyl)methyl)piperidine-1-yl)benzamide (355); N-((1r,3r)-3-(4-cyano-3-(tri Fluoromethyl)phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Cyl)piperidine-1-yl)benzamide (356); N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-4-(6-(2-((2-(2,6-dioxopiperidine-3-I (L)-1,3-dioxoisoindoline-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-the Tramethylcyclobutyl)-2-(4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)oxy)propyl)piperazine-1-yl)-4,6-dimethylpyrimidine- 5-Carboxamide (358); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto (Lamethylcyclobutyl)-5-(4-(3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)oxy)propyl)piperazine-1-yl)pyrazine-2-carboxamide (359); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyrate (Lu)-6-(4-(3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl (360); 2-chloropropyl piperazine-1-yl pyridazine-3-carboxamide (360); -N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipe Radin-1-yl)methyl)piperidine-1-yl)benzamide (361); 2-chloro-N-((1r,3r)-3 -(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2, 6-Dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl)methyl)piperidine-1-yl)benzamide (362); N-((1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-5-(4-(5-((2-(2,6-Dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-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-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1- Il)picolinamide (364); N-((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-2-((3S,5S)-4-(3-((2-(2,6-Dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)oxy)propyl)-3,5-dimethylpiperazine-1-yl) Limidine-5-carboxamide (365); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2, 4,4-Tetramethylcyclobutyl)-4-(3-(2-((2-(2,6-Dioxopiperidine-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-dioxopiperyl) Din-3-yl)-1-oxoisoindolin-4-yl)oxy)butyl)-1H-1,2,3-triazole- 1-yl)benzamide (367); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-6-(4-(2-((5-(2-((R)-2,6-dioxopiperidine-3-yl)-1-O Xisoisoindolin-4-yl)pentyl)oxy)ethyl)piperazine-1-yl)nicotinamide (368); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclo Butyl)-4-(4-(2-((5-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindri (4-yl)pentyl)oxy)ethyl)piperazine-1-yl)benzamide (369); (2S)-1-(4 -(((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)cal Bamoyl)phenyl)-N-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindo Phosphate-5-yl)piperazine-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-dioxopiperidine-3-yl)-1-oxy Soisoindolin-5-yl)piperazine-1-yl)ethyl)-N-methylpyrrolidine-2-carboc Samide (371); (2S)-1-(4-(((1r,3S)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)carbamoyl)benzyl)-N-(2-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-1-oxoisoindoline-5-yl)piperazine-1-yl)ethyl)-N-methylpyrrolidine -2-Carboxamide (372); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto (Lamylcyclobutyl)-4-(2-(2-((2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl)oxy)ethoxy)ethyl)benzamide (373); N-((1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)pentyl)pyro Lysine-3-yl)-1H-pyrazole-4-carboxamide (374); N-((1r,3r)-3-(3-chloro-4-cy Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(3-(4-(2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)propoxy) Ethyl)-1H-pyrazole-4-carboxamide (375); 4-(3-(4-(4-(5-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1- (Iyl)phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidine-1-yl)-2-(triflu) Oromethyl)benzonitrile (376); 2-chloro-4-(3-(4-(4-(5-((2-(2,6-dioxopiperine Zin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl )phenyl)-4,4-dimethyl5-oxo-2-thioxoimidazolidine-1-yl)benzonitrile ( 377); 4-(5-(4-(4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri Pentyl phenyl-5-yl hydroxy piperazine-1-yl phenyl-8-oxo-6-thioxo-5,7-di Azaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (378); N-(( R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-yl)propan-2-yl)-5-((2- (2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-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 Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) Ropyr) picolinamide (380); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)pheno Xy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-(4-(2-(2,6-dioxopiperidine-3-I (Lu)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)propyl)picolinamide (381); 4-(3-(6-(4-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindo Phosphate-5-yl)oxy)pentyl)piperazine-1-yl)pyridine-3-yl)-4,4-dimethyl5-yl Xo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (382) ; 4-(3-(4-(4-(4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5 -Iyl)oxy)butyl)piperazine-1-carbonyl)-3-fluorophenyl)-4,4-dimethyl5- Oxo-2-thioxoimidazolidine-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-dioxopiperidine-3-yl)-1,3-dioxoisindoline-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)cal Bamoyl)pyridine-2-yl)-1-(5-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl)oxy)pentyl)-1-methylpiperazine-1-ium(385); 4-(3-(2 -((5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Perazine-1-yl)pentyl)oxy)phenyl)-4,4-dimethyl5-oxo-2-thioxoimid Zolidine-1-yl)-2-(trifluoromethyl)benzonitrile (386); 4-(3-(2-((6-(4-(2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1-yl Hexyl oxyphenyl-4,4-dimethyl 5-oxo-2-thioxoimidazolidine-1- (L)-2-(trifluoromethyl)benzonitrile (387); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-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-dioxopiperidine-3-yl)- 1,3-Dioxoisoindorin-4-yl)oxy)propyl)piperazine-1-yl)benzamide (389); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob (Cyl)-4-(2-(1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorine-5-yl Azethidine-3-yl ethyl benzamide (390); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine -1-yl)-2,6-difluorobenzamide (391); N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(3-((2-(2,6-dioxopiperidine-3-I (L)-1-oxoisoindolin-4-yl)oxy)propyl)piperazine-1-yl)benzamide (392); 4-(3-(2-(2-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiisoy (Piperidin-5-yl)piperidine-4-yl)methyl)piperazine-1-yl)ethyl)phenyl)-4,4- Dimethyl 5-oxo-2-thioxoimidazolidine-1-yl)-2-(trifluoromethyl)benzo Toryl (393); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl)-4-(3-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri N-4-yl)azetidine-3-yl)propyl)benzamide (394); N-((1r,3r)-3-(3-chloro- 4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-Dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-4-yl)azetidine-3-yl)methyl)pi Peridine-1-yl)benzamide (395); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2 ,2,4,4-tetramethylcyclobutyl)-1-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindorin-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1H-pi Razole-3-carboxamide(396); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4 ,4-tetramethylcyclobutyl)-1-(1-(2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)ethyl)piperidine-4-yl)-1H-P Razole-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 Oxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperazine -1-yl)methyl)piperidine-1-yl)nicotinamide (398); N-((1s,4s)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)nicotine N-amide (399); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( (4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazi N-1-yl)methyl)piperidine-1-yl)nicotinamide (400); N-((1r,4r)-4-(3-chloro- 4-Cyanofenoxy)cyclohexyl)-4-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-1 ,3-Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)ben Zuamide (401); N-((1s,4s)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-( (4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazi N-1-yl)methyl)piperidine-1-yl)benzamide (402); N-((1r,4r)-4-(3-chloro-4- Cyanophenoxy(cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pirimi Zin-5-carboxamide (403); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohex Sil)-5-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5- Il)piperazine-1-yl)methyl)piperidine-1-yl)pyrazine-2-carboxamide (404); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)meth (L)piperidine-1-yl)pyridazine-3-carboxamide (405); N-((1r,4r)-4-(3-chloro-4- Cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6- Fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1 -yl)pyridazine-3-carboxamide(406); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy (Cy)cyclohexyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-di Oxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrimid N-5-carboxamide(407); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl (L)-5-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoin (Drin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrazine-2-carboxami (408); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(4-(2-(2 ,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1-yl (L)piperidine-1-yl)benzamide (409); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy (Cyclohexyl)-4-(4-(1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoiisoyl (Piperidin-5-yl)piperidine-4-yl)piperazine-1-yl)benzamide (410); N-((1r,4 r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(1-(2-(2,6-dioxopiperyl) (Zin-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)piperazine-1-yl (L) Pyridazine-3-carboxamide (411); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) Cyclohexyl)-2-(4-(1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoin (4)Drin-5-yl)piperidine-4-yl)piperazine-1-yl)pyrimidine-5-carboxamide (4 12); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(4-(2-(2,6- (Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)Piperazine-1-yl) Piperidine-1-yl)pyridazine-3-carboxamide (413); N-((1r,4S)-4-(3-chloro-4-syl Anofenoxy(cyclohexyl)-2-((3S)-3-((4-(2-(2,6-dioxopiperidine-3-yl)- 1,3-Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)pi Limidine-5-carboxamide(414); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclo Hexyl)-6-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline -5-yl)oxy)ethyl)piperazine-1-yl)pyridazine-3-carboxamide (415); N-((1 r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-((2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazine-1-yl) (L)benzamide (416); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl) -2-(4-(2-((2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-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-dioxoisoindoline-5-yl)oxy)propyl)piperazine-1-yl)pi Limidine-5-carboxamide (418); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)-4-me (Tylcyclohexyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (419); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-5-(4-(2-((2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)ethyl)piperazi N-1-yl)pyrazine-2-carboxamide (420); N-((1r,4r)-4-(3-chloro-4-cyanopheno (Xy)cyclohexyl)-5-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoi Soindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)picolinamide (4 21); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6- Dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)oxy) Ethyl)piperazin-1-yl)-5-fluoronicotinamide (422); N-((1r,4r)-4-(3-chloro -4-Cyanofenoxy)Cyclohexyl)-5-(4-(3-((2-(2,6-Dioxopiperidine-3-yl)- 6-Fluoro-1,3-Dioxoisoindorin-5-yl)oxy)propyl)piperazine-1-yl) Pyrazine-2-carboxamide (423); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy) cyclamine (Rohexyl)-2-(4-(2-(4-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)pyrimidine-5-carboxamyl (424); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-4-(4-(2-(4-(2 -(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1- (Iyl)ethyl)piperidine-1-yl)benzamide (425); N-((1r,4r)-4-(3-chloro-4-shea (Nophenoxy)cyclohexyl)-5-(4-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)propyl)piperazine-1-yl)pyrazine-2-carb Xamid (426); N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( 2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipera (427); N-((1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-(5-((2- (1-methyl-2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) (C)pentyl)piperazine-1-yl)nicotinamide (428); N-((1r,3r)-3-(3-chloro-4-cy) Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2,6-diol) Xopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)pentyl)piperidine (4-yl)-1H-pyrazole-4-carboxamide (429); N-((1r,3r)-3-(3-chloro-4-sia Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperidine N-4-yl)-1H-pyrazole-3-carboxamide (430); N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(4-((2-(1-methyl-2,6-dioxo Piperidine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)pyrrolidine-3- Il)-1H-pyrazole-4-carboxamide (431); N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-1-(1-(5-((2-(1-methyl-2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)pyrrolidine-3-yl) (Lu)-1H-pyrazole-4-carboxamide (432); N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-1-(2-(3-(4-(2-(1-methyl-2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)propoxy) (Chill)-1H-pyrazole-4-carboxamide (433); N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(1-methyl-2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl) (Lu) picolineamide (434); N-((1r,3r)-3-(4-cyano-3-(trifluoromethyl)phenoxy )-2,2,4,4-tetramethylcyclobutyl)-5-(4-(5-((2-(1-methyl-2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazine-1-yl)pi Cholineamide (435); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl (Tylcyclobutyl)-5-(3-(4-(2-(1-methyl-2,6-dioxopiperidine-3-yl)-1,3-diox Soisoindorin-5-yl)piperazine-1-yl)propyl)picolinamide (436); 6-(4-(4 -((2-(1-butyl-2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-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-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5- Il(oxy)butyl)piperazine-1-yl)pyrimidine-5-carboxamide (438); N-((1r,3 r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2 -(1-methyl-2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piper Radin-1-yl)methyl)piperidine-1-yl)benzamide (439); N-((1r,3r)-3-(3-chloro (L-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(1-methyl-2 ,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1-yl (L)methyl)piperidine-1-yl)pyrimidine-5-carboxamide (440); (3-(5-(4-((1-(4-(( (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carb Moyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3-dioxoiisoin (Drin-2-yl)-2,6-dioxopiperidine-1-yl)methyl methyl carbonate (441); ( 3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3 (-Dioxoisoindoline-2-yl)-2,6-Dioxopiperidine-1-yl)Methyl Ethyl Cal Bonate (442); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4, 4-Tetramethylcyclobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piper (Dioxo-1-yl)-1,3-dioxoisoindoline-2-yl)-2,6-dioxopiperidine-1-yl) Chil isopropyl carbonate (443); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3 (-Dioxoisoindolin-2-yl)-2,6-Dioxopiperidine-1-yl)methyl (tetrahydro) (2H-pyran-4-yl) carbonate (444); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl)phenyl)piperyl)piperyl) (Dioxin-4-yl)methyl)piperazin-1-yl)-1,3-dioxoisoindorin-2-yl)-2,6-di Oxopiperidine-1-yl)methyl (2-acetamidoethyl)carbamate (445); (3-(5-(4 -((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (L)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3-dioxy Soisoindolin-2-yl)-2,6-dioxopiperidine-1-yl)methyl (2-(2-aminoacetone) 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- (Iyl)methyl)piperazine-1-yl)-1,3-dioxoisoindoline-2-yl)-2,6-dioxop Peridine-1-yl)methyl (2-((S)-2-aminopropanamide)ethyl)carbamate (447); (3-(5-(4-((1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)carbamoyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1 ,3-Dioxoisoindorin-2-yl)-2,6-Dioxopiperidine-1-yl)methyl (2-((S)-2 -amino-3-methylbutanamide)ethyl)carbamate (448); (3-(5-(4-((1-(4-(((1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamoyl) Phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3-dioxoisoindoline- 2-yl)-2,6-dioxopiperidine-1-yl)methyl (2-((S)-2-((S)-2-amino-3-methyl Tanamide)-3-methylbutanamide)ethyl)carbamate (449); (3-(5-(4-((1-(4-(((1 r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (Iyl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-1,3-dioxoisoindo Phosphate-2-yl)-2,6-dioxopiperidine-1-yl)methyl (2,5,8,11-tetraoxatrideca 13-yl) carbonate (450); 2-chloro-4-(3-(3-fluoro-4-(5-(4-(2-(1-methyl-2 ,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1-yl Pentyl phenyl-4,4-dimethyl 5-oxo-2-thioxoimidazolidine-1-yl phenyl Zonitrile (451); 2-chloro-4-(5-(3-fluoro-4-(5-(4-(2-(1-methyl-2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)pentyl) Benyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)benzonitrile (452); 4-{3-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2, 3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azadodecane- 12-yloxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazo Lysine-1-yl}-2-(trifluoromethyl)benzonitrile (453); 4-(3-{4-[2-(2 -{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-yl Soindole-4-yl]amino}ethoxy)ethoxy]phenyl}-4,4-dimethyl-5-oxy (So-2-sulfanylideneimidazolidin-1-yl)-2-(trifluoromethyl)benzo Trill (454); 4-{3-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Xo-2,3-dihydro-1H-isoindole-4-yl]-4,7,10,13,16-pentaoxa-1 -Azaoctadecane-18-yl}oxy)phenyl]-4,4-dimethyl-5-oxo-2-sulf Phanylidene imidazolidine-1-yl-2-(trifluoromethyl)benzonitrile (455 ); 4-[3-(4-{2-[2-(2-{[2-(2,6-dioxopiperidine-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 (456); 4-[3-(4-{2-[2-(2-{[2-(2,6 (-Dioxopiperidine-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)benzonitrate Lil (457); 4-{3-[4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-diox So-2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azateto Radecan-14-yloxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylide Imidazolidine-1-yl}-2-(trifluoromethyl)benzonitrile (458); 4-{3- [4-({1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1 H-isoindole-4-yl]-4,7,10-trioxa-1-azatridecane-13-yl}o [Xy)phenyl]-4,4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1- Il-2-(trifluoromethyl)benzonitrile (459); 4-(3-{4-[(1-{2-[(3R)-2 ,6-Dioxopiperidine-3-yl]-1,3-Dioxo-2,3-Dihydro-1H-Isoindo Ru-4-yl}-4,7,10-trioxa-1-azadodecane-12-yl)oxy]phenyl}-4, 4-dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2-(trif Luoromethyl)benzonitrile (460); 4-(3-{4-[(1-{2-[(3S)-2,6-dioxopipe Lysine-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)ben Zonitrile (461); 4-[3-(4-{3-[3-(2-{[2-(2,6-dioxopiperidine-3-yl) -1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminoethoxy)pro [poxy]propoxy}phenyl)-4,4-dimethyl-5-oxo-2-sulfanylideneimida Zolidine-1-yl]-2-(trifluoromethyl)benzonitrile (462); 4-{4,4-dimethicone Ru-3-[4-({1-[2-(3-methyl-2,6-dioxopiperidine-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindole-4-yl]-4,7,10-trioxa-1-azatride [Can-13-yl]oxy)phenyl]-5-oxo-2-sulfanylideneimidazolidin-1 -yl}-2-(trifluoromethyl)benzonitrile (463); 4-[3-(4-{4-[(5-{[2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxo-2,3-dihydro-1H-isoindo [4-yl]amino}pentyl)oxy]phenyl}phenyl)-4,4-dimethyl-5-oxy [S-2-sulfanylideneimidazolidin-1-yl]-2-(trifluoromethyl)benzo Trill (464); 4-{[5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo -2,3-dihydro-1H-isoindole-4-yl]aminopropoxy)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-dioxopiperidine-3-yl )-1-oxo-2,3-dihydro-1H-isoindole-4-yl]-1,4,7,10-tetraox Saturidecane-13-yloxy)phenyl]-4,4-dimethyl-5-oxo-2-sulfani Redeneimidazolidine-1-yl}-2-(trifluoromethyl)benzonitrile (466); 6- [4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H- Isoindole-4-yl]aminoethyl)piperazine-1-yl]-N-[(1r,3r)-3-(3- Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3- Ruboxamide (467); 6-{4-[2-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)ethyl]p 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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindo (Il-4-yl]oxyethyl)-1H-1,3-benzodiazole-5-yl]phenyl)-4,4 -dimethyl-5-oxo-2-sulfanylideneimidazolidin-1-yl)-2- (Trifluoromethyl)benzonitrile (469); 4-{[5-(3-{[2-(2,6-dioxopiper [zin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-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-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindo [(1r,3r)-3-(3-chloro-4)yl-oxyethyl)piperazine-1-yl]-N-[(1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxami (471); 6-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3 -Dihydro-1H-isoindole-4-yl]aminoethyl)piperazine-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- Il)-1-oxo-2,3-dihydro-1H-isoindole-4-yl]propyl}piperazine -1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl [Tylcyclobutyl]pyridine-3-carboxamide (473); 6-{4-[2-(2-{[2-(2,6-di Oxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl [Oxyethoxy)ethyl]piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4- Cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (474); 4-{4-[4-(2-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3- Dihydro-1H-isoindole-4-yl]oxyethyl)piperazine-1-yl]butyl} -N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-teto [Lamethylcyclobutyl]benzamide (475); 6-{4-[2-(3-{[2-(2,6-dioxopipette Lysine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]amine [Propoxyethyl]piperazin-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (476); 6-{4-[2-(3-{[2-(2,6-dioxopiperidine-3-yl)-7-fluoro-1,3-dioxo Xo-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)ethyl]piper 1-yl-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto [Lamethylcyclobutyl]pyridine-3-carboxamide (477); 4-(6-{4-[2-(2,6-diode Xopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5- [yl]piperazine-1-yl}hexyl)-N- [(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4-tetramethyl Lucyclobutyl]benzamide (478); 4-{3-[4-(3-{[2-(2,6-dioxopiperidine -3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]amino}p [Pipyl]piperazin-1-yl]propyl}-N-[(1r,3r)-3-[4-cyano-3-(trifluoro [Methyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (479); 4-[ 5-(3-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H -Isoindole-4-yl]amino}propoxy)pentyl]-N-[(1r,3r)-3-(3-chloro Ro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (480); 6-{4-[2-(3-{[2-(2,6-dioxopiperidine-3-yl)-5-fluoro-1,3-diox So-2,3-dihydro-1H-isoindole-4-yl]amino}propoxy)ethyl]piperazi 1-yl-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl]pyridine-3-carboxamide (481); 4-(4-{4-[2-({2-[(3S)- 2,6-Dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoindole -5-yl}oxy)ethyl]piperazin-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro -4-Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl]benzamide (482); 4 -(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine-3-yl]-1- Oxo-2,3-dihydro-1H-isoindole-4-yl}oxy)ethyl]piperazine-1- Il-butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- Tetramethylcyclobutyl]benzamide (483); 4-{4-[4-(2-{[2-(2,6-dioxop Peridine-3-yl)-7-fluoro-1,3-dioxo-2,3-dihydro-1H-isoindo [4-yl]aminoethyl)piperazin-1-yl]butyl}-N-[(1r,3r)-3-(3-chloro] Ro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (484); 6-{4-[5-({2-[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydr Ro-1H-isoindole-4-yl}oxy)pentyl]piperazine-1-yl}-N-[(1r,3r )-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrid n-3-carboxamide (485); 4-(4-{4-[2-({2-[(3S)-2,6-dioxopiperidine [-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl}oxy) [Tyl]piperazine-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl]benzamide (486); 6-{4-[5-({2-[(3S) -2,6-Dioxopiperidine-3-yl]-1-oxo- 2,3-dihydro-1H-isoindole-5-yl}oxy)pentyl]piperazine-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-isoindole-4-yl [Lu]piperazine-1-yl}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl]benzamide (488); 4-{4-[4-(2-{[2-(2,6 -Dioxopiperidine-3-yl)-5-fluoro-1,3-dioxo-2,3-dihydro-1H- Isoindole-4-yl]aminoethyl)piperazine-1-yl]butyl}-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzalkonium Mido (489); 6-(4-{6-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3- Dihydro-1H-isoindole-4-yl]hexyl}piperazine-1-yl)-N-[(1r,3r) -3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyrid n-3-carboxamide(490); 4-(4-{4-[2-(2,6-dioxopiperidine-3-yl)-4 [fluoro-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine -1-Il}butyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-Te Tramethylcyclobutyl]benzamide (491); 4-(6-{4-[2-(2,6-dioxopiperidine [n-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-yl]piperaj (n-1-yl}hexyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4 -Tetramethylcyclobutyl]benzamide (492); 6-{4-[5-({2-[(3S)-2,6-diode Xopiperidine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5- [(Iyl)oxy)pentyl]piperazine-1-yl]-N-[(1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (493) ; 6-[4-(5-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro- 1H-isoindole-4-yl]oxy}pentyl)piperazine-1-yl]-N-[(1r,3r)-3 -(3-chloro-4-cyanophenoxy)cyclobutyl]pyridine-3-carboxamide (494) ; 4-[4-(5-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro- 1H-isoindole-4-yl]oxy}pentyl)piperazine-1-yl]-N-[(1r,3r)-3 -(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (495); 4-(5-{4-[2 -(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoin [Dol-5-yl]piperazine-1-yl}pentyl)-N-[(1r,3r)-3-(3-chloro-4-cyan Anofenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (496); 4-(4-{4 -[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-iso Indole-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-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-di Hydro-1H-isoindole-5-yl]piperazine-1-yl}hexyl)-N-[(1r,3r)- 3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzalkonium Mido (498); 4-(4-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihy [Dro-1H-isoindole-4-yl]oxy}butyl)-N-[(1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (499); 4-(5 -{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoyl Ndol-4-yl]oxypentyl)-N-[(1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl]benzamide (500); 4-[3-(2-{[2-(2, 6-Dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4 -yl]oxy}ethoxy)propyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl]benzamide (501); 4-[4-(2-{[2-(2,6 (-Dioxopiperidine-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 Oxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl [Lu]oxyethoxy)pentyl]-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)- 2,2,4,4-tetramethylcyclobutyl]benzamide (503); 4-[6-(2-{[2-(2,6-diode Xopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl] [Oxyethoxy)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-Pyrazole-1-yl]propan-2-yl]-5-{[4-(4-{[2 -(2,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoin [Dol-4-yl]amino}butyl)piperazin-1-yl]methyl}-1H-pyrazole-3-ca Ruboxamide (505); 4-(4-{6-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxopiperidine-3-yl)-1,3-dioxopiperidine-3-yl) Xo-2,3-dihydro-1H-isoindole-5-yl]hexyl}piperazine-1-yl)- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob [Cyl]benzamide (506); 4-(3-{[2-(2,6-dioxopiperidine-3-yl)-1-oxy So-2,3-dihydro-1H-isoindole-4-yl]oxy}propyl)-N-[(1r,3r)-3 -(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (507); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole-1- [Lu]propane-2-yl]-5-[(3-{4-[2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxo-2,3-dihydro-1H-isoindole-5-yl]piperazine-1-yl}prop [Xy(methyl)]-1H-pyrazole-3-carboxamide (508); 4-[4-(3-{[2-(2,6-diode Xopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-4-yl] Oxypropyl)-1H-1,2,3-triazol-1-yl]-N-[(1r,3r)-3-(3-chloro -4-Cyanofenoxy)Cyclobutyl]benzamide (509); 6-[4-(6-{[2-(2,6-diode Xopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-isoyl [Ndol-5-yl]aminohexyl)piperazine-1-yl]-N-[(1r,3r)-3-(3-chloro (L-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carb Xamide (510); N-[(2R)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazole -1-yl]propane-2-yl]-5-({3-[4-(2-{[2-(2,6-dioxopiperidine-3- (yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]aminoethyl) Piperazine-1-yl]propoxymethyl)-1H-pyrazole-3-carboxamide (511); 4-[4-(5-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1 H-isoindole-4-yl]oxypentyl)-1H-1,2,3-triazole-1-yl]- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (512); 4-[4-(6-{[2-(2,6-dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1 H-isoindole-4-yl]oxyhexyl)-1H-1,2,3-triazole-1-yl]- N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)cyclobutyl]benzamide (513); 6-{4-[2-(4-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3 -Dihydro-1H-isoindole-4-yl}butoxy)ethyl]piperazine-1-yl}-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty [Lu]pyridine-3-carboxamide (514); 6-{4-[2-(4-{2-[(3R)-2,6-dioxopipe Lysine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl}but [Xy(ethyl)]piperazin-1-yl}-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy C)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (515); 6-(4- {2-[(5-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2,3-dihy Dro-1H-isoindole-4-yl}pentyl)oxy]ethyl}piperazine-1-yl)-N -[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty [Lu]pyridine-3-carboxamide (516); 6-(4-{2-[(5-{2-[(3R)-2,6-dioxop [Peridine-3-yl]-1,3-dioxo-2,3-dihydro-1H-isoindole-4-yl]per [(1r,3r)-3-(3-chloro-4-cyano) Phenoxy)-2,2,4,4-tetramethylcyclobutyl]pyridine-3-carboxamide (517); 4-(4-{2-[(5-{2-[(3S)-2,6-dioxopiperidine-3-yl]-1,3-dioxo-2, 3-Dihydro-1H-isoindole-4-yl}pentyl)oxy]ethyl}piperazine-1- (Iyl)-N-[(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyanophenoxy Clobutyl]benzamide (518); 4-(4-{2-[(5-{2-[(3R)-2,6-dioxopiperid [n-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-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl]benzamide (519); 4-(4-{6-[2-(2,6 (-Dioxopiperidine-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5 [-yl]hexyl}piperazine-1-yl)-N-[(1r,3r)-3-(3-chloro-4-cyanophen [Noxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (520); 4-(3-{4-[2-(2 ,6-dioxopiperidine-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindo [Lu-5-yl]piperazin-1-yl}propyl)-N-[(1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl]benzamide (521); 4-[6-(4-{2 -[(3S)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3-dihydro-1H-isoyl [Ndol-5-yl}piperazine-1-yl)hexyl]-N-[(1r,3r)-3-[4-cyano-3- [(trifluoromethyl)phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (522); 4-[6-(4-{2-[(3R)-2,6-dioxopiperidine-3-yl]-1-oxo-2,3- Dihydro-1H-isoindole-5-yl}piperazine-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-dioxopiperidine-3-yl)-5 -Fluoro-1-oxo-2,3-dihydro-1H-isoindole-4-yl]oxy}hexy [(1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4] ,4-tetramethylcyclobutyl]pyridine-3-carboxamide (524); 6-[4-(6-{[2-( 2,6-Dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H -Isoindole-5-yl]oxy}hexyl)piperazine-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-dioxopiperidine-3-yl] (-3-oxo-2,3-dihydro-1H-isoindole-5-yl}piperazine-1-yl)hex [Syl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)phenoxy]-2,2,4,4- Tetramethylcyclobutyl]benzamide (526); 4-[6-(4-{2-[(3R)-2,6-dioxo Piperidine-3-yl]-3-oxo-2,3-dihydro-1H-isoindole-5-yl}piperidine-3-yl] [Radin-1-yl)hexyl]-N-[(1r,3r)-3-[4-cyano-3-(trifluoromethyl)f [Phenoxy]-2,2,4,4-tetramethylcyclobutyl]benzamide (527); N-((1r,3r)-3-(3 -Chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6- Dioxopiperidine-3-yl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin (6-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (528); rac-N-( (1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-( (4-(2-(2,6-dioxopiperidine-3-yl)-4-methylene-1-oxo-1,2,3,4-tetrahydroyl Soquinoline-6-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (529); rac-N-(1-(4-(((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)carbamoyl)phenyl)azetidine-3-yl)-1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindoline-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-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisindri (5-yl)oxy)propyl)piperazine-1-yl)pyridazine-3-carboxamide (531); r ac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 5-(4-(3-((2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisindri (5-yl)oxy)propyl)piperazine-1-yl)pyrazine-2-carboxamide (532); rac -N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(3-((2-(2,6-diode Xopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)oxy)pro Pyrimidine-1-yl)pyrimidine-5-carboxamide (533); rac-N-((1r,4r)-4-(3- (4-Cyanofenoxy)Cyclohexyl)-2-(4-(2-(4-(2-(2,6-Dioxopiperidine-3- (Iyl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)ethyl)piperazine Lysine-1-yl)pyrimidine-5-carboxamide (534); rac-N-((1r,3r)-3-(3-chloro-4-cy Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopipette Lysine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Cyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-2,6-dimethyl Piperazine-1-yl)ethyl)benzamide (536); rac-N-((1r,3r)-3-(3,4-dicyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3- (Iyl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl (L)benzamide (537); rac-N-((1r,3r)-3-(4-cyano-2-methylphenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (5 38); rac-N-((1r,3r)-3-(2,4-dicyanofenoxy)-2,2,4,4-tetramethylcyclobutyl) -4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Piperazine-1-yl)methyl)piperidine-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-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)piperazine-1- (Iyl)methyl)piperidine-1-yl)benzamide (540); rac-N-((1r,3r)-3-(4-cyano-3- Methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)pip Peridine-1-yl)benzamide (541); N-((1r,4r)-4-(4-cyano-3-methylphenoxy) Chlohexyl)-5-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindoline-5-yl(oxy)cyclobutyl(isopropyl)amino(methyl)piperidine -1-yl)pyrazine-2-carboxamide (542); rac-N-((1r,4r)-4-(3-chloro-4-cyanophen (Noxy)cyclohexyl)-4-(4-(2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxo Isoindolin-5-yl)thio)ethyl)piperazine-1-yl)benzamide (543); rac-N-(( 1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-(3 -((2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl (5)Oxypropylpiperazine-1-yl-4,6-dimethylpyrimidine-5-carboxamide (5 44); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6,7-difluoro1,3-dioxoisoin (Drin-5-yl)piperazin-1-yl)methyl)piperidine-1-yl)-4,6-dimethylpyrimidine -5-Carboxamide (545); rac-2-chloro-4-(((1r,4r)-4-(5-(4-((4-(2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)piperazine Lysine-1-yl)-1H-benzo[d]imidazole-2-yl)cyclohexyl)oxy)benzonitrate Ryl (546); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-( 2-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pipera Zin-1-yl)ethyl)piperidine-1-yl)nicotinamide (547); rac-N-((1r,4r)-4-(3- Chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopipette Lysine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Cyl)piperidine-1-yl)pyridazine-3-carboxamide (548); rac-N-((1r,4r)-4-(4-cy Ano-3-methylphenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-I (L)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piper Zin-1-yl)pyridazine-3-carboxamide (549); rac-N-((1r,3r)-3-(4-cyano-3-meth Luphenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine N-1-yl)benzamide (550); rac-N-((1r,3r)-3-((5-cyano-6-methylpyridine-2-yl (L)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1 -yl)benzamide (551); rac-N-((1r,3r)-3-((5-cyanopyridine-2-yl)oxy)-2,2 ,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benz Amide (552); rac-N-((1r,3r)-3-(3,4-dicyanophenoxy)-2,2,4,4-tetramethylcycline Robyl)-2-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindoline -5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrimidine-5-carboxamide ( 553); rac-N-((1r,3r)-3-((5-cyano-6-methylpyridine-2-yl)oxy)-2,2,4,4-tetra Methylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrimidine-5-carb Xamido(554); rac-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethicone Lucyclobutyl)-2-((1R,4R,5S)-5-((4(2(2,6-dioxopiperidine-3-yl)-1,3-dioxo Xisoisoindoline-5-yl)piperazin-1-yl)methyl)-2-azabicyclo[2.2.1]hepta (n-2-yl)pyrimidine-5-carboxamide (555); rac-N-((1r,3r)-3-((5-cyano-3-meth Lupyridine-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Cyl)piperidine-1-yl)benzamide (556); rac-N-((1r,3r)-3-((5-cyanopyrimidine -2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piper Zin-1-yl)benzamide (557); rac-N-((1r,3r)-3-(4-cyano-3,5-dimethylphenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl )-1,3-Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl) Benzamide (558); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl )-5-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl) Piperazine-1-yl)piperidine-1-yl)pyrazine-2-carboxamide (559); rac-N-((1r, 4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(4-(4-(2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)piperidine-1- Il)pyrimidine-5-carboxamide (560); rac-N-((1r,3R)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-2-((1R,4R,5R)-5-((4-(2-(2,6-dioxop Peridine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy) (Tyl)(methyl)amino)pyrrolidine-1-yl)benzamide (562); rac-N-((1r,3R)-3-(3-C (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1R,3S)-3-((2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindorin-5-yl)oxy)cyclop (Nthyl)piperazine-1-yl)benzamide (563); rac-N-((1r,3r)-3-((6-cyano-5-meth Lupyridine-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-di Oxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl) (Cyl)piperidine-1-yl)benzamide (564); rac-N-((1r,3r)-3-((6-cyano-5-(trif (Oromethyl)pyridine-3-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4- (2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine- 1-yl)methyl)piperidine-1-yl)benzamide (565); rac-N-((1r,3r)-3-(3-chloro-4 -Cyanofenoxy)-2,2,4,4-Tetramethylcyclobutyl)-5-(3-((4-(2-(2,6-Dioxopyl Peridine-3-yl)-1,3-dioxoisoindorin-5-yl)piperazine-1-yl)methyl)aze Thidine-1-yl)pyrazine-2-carboxamide (566); rac-N-((1r,4r)-4-(3-chloro-4-sia (Nophenoxy)cyclohexyl)-5-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)pyrazine- 2-Carboxamide (567); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-the Tramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoiso Indolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)benzamide (568); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-(2-((2-(2,6- Dioxopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindorin-5-yl)oxy) Ethyl)piperazine-1-yl)-4-fluoronicotinamide (569); rac-N-((1r,4r)-4-(3- (4-Cyanofenoxy)Cyclohexyl)-6-(4-((4-(2-(2,6-Dioxopiperidine-3-I (L)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piper Zin-1-yl)pyridazine-3-carboxamide (570); rac-N-((1r,3r)-3-(3-chloro-4-sia Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperyl (Zin-3-yl)-7-fluoro-1,3-dioxoisoindorin-5-yl)piperazin-1-yl)meth (Lu)piperidine-1-yl)pyrimidine-5-carboxamide (571); rac-N-((1r,3r)-3-(4-sya (-3-methylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxy Sopiperidine-3-yl)-6-fluoro-1,3-dioxoisoindoline-5-yl)piperazine-1- (Iyl)methyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pi Perazin-1-yl)methyl)azetidine-1-yl)pyridazine-3-carboxamide (573); rac-N -((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl) Azethidine-1-yl)pyrimidine-5-carboxamide (574); rac-N-((1r,4r)-4-(4-cyano-3 -Methylphenoxy)cyclohexyl)-2-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1, 3-Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)pyri Midine-5-carboxamide(575); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2 ,4,4-tetramethylcyclobutyl)-6-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fu Luoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)azetidine-1- Il)pyridazine-3-carboxamide (576); rac-N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-I (L)-7-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piper Zin-1-yl)pyridazine-3-carboxamide (577); rac-N-((1r,3r)-3-(3-chloro-4-sia Nophenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((4-(2-(2,6-dioxopiperyl (Zin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1 -yl)pyrimidine-5-carboxamide (578); rac-N-((1r,4r)-4-(3-chloro-4-cyanophen (Noxy)cyclohexyl)-5-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl) Piperidine-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-dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amine (N)methyl)piperidine-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 (-Dioxopiperidine-3-yl)-4,6-difluoro1,3-dioxoisoindorin-5-yl)piper Radin-1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-4,6-difluoro1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)ethyl)piperidine-1-yl)pyridazine-3-category Ruboxamide (582); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetra Methylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3- Dioxoisoindoline-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)-4-(2- Morpholinoethoxy)nicotinamide (583); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy (C)-2,2,4,4-tetramethylcyclobutyl)-2-(3-((((1r,3r)-3-((2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)cyclobutyl)(isopropyl) )amino)methyl)azetidine-1-yl)pyrimidine-5-carboxamide (584); rac-N-((1r,3 r)-3-((5-cyano-6-ethylpyridine-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl )-4-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindorin-5-yl) Piperazine-1-yl)methyl)piperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy) (Isopropyl)aminomethyl)azetidine-1-yl)pyridazine-3-carboxamyl (586); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-6-fluoro-1,3-dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)azetidine-1-yl)benzamide (5 87); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob Chil)-4-(1-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5- (Iyl)piperidine-4-yl)methyl)piperidine-4-yl)benzamide (588); rac-N-((1r,3 r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(3-(((1-( 2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4 -yl)oxy)methyl)pyrrolidine-1-yl)benzamide (589); rac-N-((1r,3r)-3-(3- (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-diol) Xopiperidine-3-yl)-6-fluoro-3-oxoisoindorin-5-yl)piperidine-4-yl (L)methyl)piperazine-1-yl)benzamide (590); rac-N-((1r,3r)-3-(3-chloro-4-sil Anofenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((1-(2-(2,6-dioxopipette Lysine-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-4-yl)methyl )piperazine-1-yl)benzamide (591); rac-N-((1r,3r)-3-(3-chloro-4-cyanopheno Xy)-2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-I (Lu)-4,6-difluoro1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl) Peridine-1-yl)pyridazine-3-carboxamide (592); rac-2-chloro-4-(((1r,4r)-4-(5- (4'-(2-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-1- Methyl-1H-imidazole-5-yl)-[1,1'-biphenyl]-4-yl)-1-methyl-1H-imidazole (2-yl)cyclohexyl)oxy)benzonitrile (593); rac-N-((1r,4r)-4-(3-chloro -4-Cyanofenoxy)Cyclohexyl)-6- (4-((4-(2-(2,6-dioxopiperidine-3-yl)-4,6-difluoro1,3-dioxoisindri (Piperazine-1-yl)methyl(piperidine-1-yl)pyridazine-3-carboxamide (594); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-2-(4-((4-(2-(2,6-Dioxopiperidine-3-yl)-4,6-Difluoro1,3-Dioxo Isoindolin-5-yl)piperazine-1-yl)methyl)piperidine-1-yl)pyrimidine-5-yl Ruboxamide (595); rac-N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl) -4-(3-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl) Piperazine-1-yl)methyl)azetidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy) Cyclobutyl)(isopropyl)amino)methyl)piperidine-1-yl)pyrazine-2-carbox Mido (597); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Cyclobutyl)-2-(1-((1-(2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindo Phosphate-5-yl)piperidine-4-yl)methyl)piperidine-4-yl)pyrimidine-5-carboxamyl (598); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcycline (Robutyl)-6-(4-(4-(2-(2,6-dioxopiperidine-3-yl)-7-fluoro-1,3-dioxoiso Indoline-5-yl)piperazine-1-yl)piperidine-1-yl)pyridazine-3-carboxamyl (599); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-6-(4-((((1r,3r)-3-((2-(2,6-Dioxopiperidine-3-yl)-1,3-Dioxoi Soindolin-5-yl(oxy)cyclobutyl(isopropyl)amino(methyl)piperidine-1 -yl)pyridazine-3-carboxamide (600); rac-N-((1r,4r)-4-(3-chloro-4-cyanophen (Noxy)cyclohexyl)-5-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3 -Dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amino)methyl) Piperidine-1-yl)picolinamide (601); rac-N-((1r,3r)-3-(3-chloro-4-cyanophen (Noxy)-2,2,4,4-tetramethylcyclobutyl)-6-(6-(4-(2-(2,6-dioxopiperidine-3- (Iyl)-6-fluoro-1-oxoisoindoline-5-yl)piperazine-1-yl)hexyl)nicotine Namide (602); rac-2-chloro-4-(((1r,4r)-4-(2-(4-(3-((4-(2-(2,6-dioxopiperid (-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl)azetidine -1-yl)phenyl)-1H-imidazole-5-yl)cyclohexyl)oxy)benzonitrile (6 03); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob Chil)-1-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorine-5- (60)piperazine-1-yl)methyl)cyclohexyl)-1H-pyrazole-3-carboxamide 4); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclob (Cyl)-1-(3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxisoindorin-5-yl )Oxypropyl)-1H-pyrazole-3-carboxamide (605); rac-N-((1r,4r)-4-(3-chloro (4-Cyanofenoxy)Cyclohexyl)-1-(4-((4-(2-(2,6-Dioxopiperidine-3-yl) )-1,3-Dioxoisoindolin-5-yl)piperazine-1-yl)methyl)cyclohexyl)-1H- Pyrazole-3-carboxamide (606); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxopipe Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)piperidine-4-yl)methyl)piper Zin-4-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octa (n-7-yl)picolinonitrile (607); 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxopiperyl (Zin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine 1-yl)phenyl)-8-oxo-6-thioxo-5,7- Diazaspiro[3.4]octan-7-yl)picolinonitrile (608); rac-N-((1r,3r)-3-(3-c (Lolo-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-diol) Xopiperidine-3-yl)-3-methyl-1-oxoisoindorin-5-yl)piperazine-1-yl) Methyl)piperidine-1-yl)benzamide (609); rac-N-((1r,3r)-3-(3-chloro-4-cyano Phenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-(2,6-dioxopiperid (Pipe-3-yl)-1-methyl-3-oxoisoindolin-5-yl)piperazine-1-yl)methyl)piperazine Lysine-1-yl)benzamide (610); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy) -2,2,4,4-tetramethylcyclobutyl)-6-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-4 -Fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1-yl)methyl)piperidine- 1-yl)pyridazine-3-carboxamide(611); 3-chloro-5-(5-(4-(4-((4-(2-(2,6-dioxy Sopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)piperazine-1-yl)methyl) Piperidine-1-yl)-3-fluorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4] Octane-7-yl)picolinonitrile (612); 3-chloro-5-(5-(4-(1-((1-(2-(2,6-dioxo Piperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)methyl)pip Peridine-4-yl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3,4]octan-7-yl Picolinonitrile (613); 5-(4-((1-(2-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazo (Phenoxyethyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-(2,6 -Dioxopiperidine-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-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy) (Isopropyl)aminomethyl)piperidine-1-yl)pyrimidine-5-carboxamyl (615); rac-N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethyl Clobutyl)-4-(5-(4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisindri (n-5-yl)piperazine-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl) Benzamide (616); rac-N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-teto (Lamethylcyclobutyl)-1-((1r,4R)-4-((1(2-(2,6-Dioxopiperidine-3-yl)-1,3-di Oxoisoindolin-5-yl)piperidine-4-yl)(methyl)amino)cyclohexyl)-1H- Pyrazole-3-carboxamide (617); 5-(4-((1-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imi Dazole-3-yl)phenyl)piperidine-4-yl)methyl)piperazine-1-yl)-2-(2,6-diole Xopiperidine-3-yl)isoindoline-1,3-dione (618); rac-N-((1r,3r)-3-(3-chloro (L-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-5-(3-((((1r,3r)-3-((2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-5-yl)oxy)cyclo (Isopropyl)aminomethyl)azetidine-1-yl)pyrazine-2-carboxamide (61 9); N-((1r,3R)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl) -1-((1R,4R)-4-((((1r,3R)-3-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoiso Indoline-5-yl(oxy)cyclobutyl(isopropyl)amino(methyl)cyclohexyl )-1H-pyrazole-3-carboxamide (620); N-((1r,3r)-3-(4-cyano-3-methoxypheno Xy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxopipette Lysine-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl) (L)aminomethyl)piperidine-1-yl)pyrimidine-5-carboxamide (621); N-((1r,3r) -3-(4-cyano-3-methylphenoxy)-2,2,4,4- Tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxopiperidine-3-yl)- 1,3-Dioxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl)amino)meth (Lu)piperidine-1-yl)pyrimidine-5-carboxamide (622); N-((1r,3r)-3-(4-cyano-3 ,5-dimethylphenoxy)-2,2,4,4-tetramethylcyclobutyl)-2-(4-((((1r,3r)-3-((2-( 2,6-Dioxopiperidine-3-yl)-1,3-Dioxoisoindoline-5-yl)oxy)cyclo (Isopropyl)aminomethyl)piperidine-1-yl)pyrimidine-5-carboxamide ( 623); N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobuty (Lu)-4-(4-((4-((2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)pi Perazin-1-yl)methyl)piperidine-1-yl)benzamide (624); and N-((1r,4r)-4- (3-Chloro-4-cyanophenoxy)cyclohexyl)-2-(4-((((1r,3r)-3-((2-(2,6-dioxo Piperidine-3-yl)-1-oxoisoindoline-5-yl)oxy)cyclobutyl)(isopropyl (625) aminomethyl piperidine-1-yl pyrimidine-5-carboxamide.

[0251] In another embodiment, the disclosure provides a library of compounds. The library comprises multiple The compound comprises a compound having the formula ABM-L-ULM, where ULM is ubiquitous The tin pathway protein binding site (preferably the E3 ubiquitous protein as otherwise disclosed herein) The lin ligase portion is, for example, CLM, and ABM is the AR protein binding portion. In this case, the ABM is coupled to the ULM (preferably via the linker portion), and this In some cases, the ubiquitin pathway protein binding site is the ubiquitin pathway protein, particularly E3 It recognizes ubiquitin ligase.

[0252] This specification includes, where applicable, pharmaceutically acceptable salts, particularly acid addition salts, of the compounds of this disclosure. Or the composition may include a base addition salt.

[0253] The term "pharmaceutically acceptable salt" is used throughout this specification when it is used in summary. Used to describe one or more salt forms of the compounds described in the specification, those salts are The compound showed increased solubility in the gastric juice of the patient's digestive tract, and the dissolution of the compound and biological To promote utilization efficiency. For pharmaceutically acceptable salts, where applicable, pharmaceutically acceptable Examples include those derived from inorganic or organic bases and acids. Suitable salts include Among the many other acids and bases known in the field of pharmacy, for example, potassium and sodium Alkali metals such as lium, alkaline earth metals such as calcium and magnesium, And those derived from ammonium salts. Sodium and potassium salts are, Particularly preferred as a neutralized salt of phosphate according to this disclosure.

[0254] Used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds useful in this disclosure. The acid being added is a non-toxic acid addition salt, i.e., a salt containing a pharmacologically acceptable anion. For example, among many other acids, hydrochloride salts, hydrobromide salts, hydroiodide salts, nitrates, sulfur Salts, bisulfates, phosphates, superphosphates, acetates, lactates, citrates, percitrates, Tartrate, beetartrate, succinate, maleate, fumarate, gluconate, sucrose Rad, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates , p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxyl Examples of acids that form (C-3 naphthoic acid) include those that form (C-3 naphthoic acid).

[0255] A pharmaceutically acceptable base addition salt is a pharmaceutically acceptable base addition salt of the compound or derivative according to this disclosure. It can also be used to produce a suitable salt form. This compound, being inherently acidic, is pharmaceutically acceptable. Chemical bases that can be used as reagents for preparing acceptable base salts are non-acceptable to such compounds. It forms toxic base salts. Such non-toxic base salts are not limited to, but are particularly... For example, alkali metal cations (e.g., potassium and sodium) and alkaline earth metals pharmaceutically acceptable cations such as genus cations (e.g., calcium, zinc, and magnesium) A base salt derived from thione, an ammonium salt, or a water-soluble amine-added salt, such as N-methyl Chilglucamine-(meglumine), as well as lower alkanol ammonium, and others Examples include pharmaceutically acceptable organic amine base salts.

[0256] composition In another embodiment, this specification includes compounds described herein, including salts thereof, and pharmaceutically acceptable compounds The present invention provides a composition containing a suitable carrier. In a particular embodiment, the composition is as described herein. A therapeutic or pharmaceutical composition comprising an effective amount of the compound described and an acceptable carrier. ru.

[0257] Chemicals in the pharmaceutical composition of this disclosure that can be combined with a carrier material to produce a single dosage form The amount of the compound will vary depending on the host being treated, the disease, and the specific mode of administration. The amount of the active ingredient per day ranges from 0.1 mg / kg body weight to 1000 mg / kg body weight, depending on the efficacy of the drug. It is administered. The toxicity and therapeutic effects of such compounds are standard in cell cultures or experimental animals. Pharmaceutical procedures, for example, LD50 (lethal dose for 50% of the population) and ED50 (lethal dose for 50% of the population) The effective therapeutic dose (in this case) can be determined by the procedure. Between toxicity and therapeutic effect The dose ratio is an indicator of treatment and can be expressed as LD50 / ED50. Compounds are preferred. While compounds exhibiting toxic side effects can be used, they should be applied to uninfected cells. To minimize the potential for damage and reduce side effects, such compounds are applied to the affected tissue. Care must be taken to design a delivery system that targets the cell culture aggregate. (i) and data obtained from animal experiments are used to determine the dosage range for use in humans. Yes, it is possible. The dosage of such compounds is such that the circulating concentration of ED50 is such that it is little to no toxicity. It is preferable that it be within the range. The dosage depends on the dosage form used and the route of administration used. Accordingly, it may vary within this range. With respect to any compound used in the method disclosed herein, The therapeutically effective dose can be initially estimated from cell culture assays. The IC50 determined by cell culture... (i.e., the concentration of the test compound that achieves a 50% inhibition of symptoms) to achieve a circulating plasma concentration range. The appropriate dosage is determined in animal models. Using this information, a useful dosage for humans is determined. Plasma values ​​can be determined more accurately, for example, by high-performance liquid chromatography. It is also used for measurement.

[0258] The compositions of this disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. It may be converted and administered in a controlled-release formulation. Used in these pharmaceutical compositions Possible pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, Aluminum stearate, lecithin, serum proteins, e.g., human serum albumin, Compensating substances, such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fats. A mixture of partial glycerides of acids, water, salt or electrolyte, such as prolamin sulfate, hydrogen phosphate diphosphate. Sodium, potassium hydrogen phosphate, sodium hydrochloride, zinc salt, colloidal silica, trisilicic acid Magnesium oxide, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, Sodium carboxymethylcellulose, polyacrylate, wax, polyethylene - Examples include polyoxypropylene block polymers, polyethylene glycol, and wool fat. It is possible.

[0259] The active compound is sufficient to deliver a therapeutically effective amount to the patient for the desired indication. , in an amount that does not cause serious toxicity to the patient being treated, and in a pharmaceutically acceptable carrier or The diluent contains the active compound. For all conditions referred to herein The preferred dose of the active compound is in the range of approximately 10 ng / kg to 300 mg / kg, preferably per day The range is 0.1 to 100 mg / kg, more generally 0.0 mg per kg of recipient / patient body weight per day. The dosage ranges from 5 to approximately 25 mg. Typical topical doses are in the range of 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 the active ingredient per unit dosage form. It can be conveniently administered in any suitable unit dosage form, but is not limited to this. Approximately 25-250 mg Oral administration is often convenient.

[0261] The active ingredient is the peak plasma concentration of the active compound at approximately 0.00001 to 30 mM, preferably approximately 0.1 to 30 μM. It is preferable to administer it in order to achieve the desired degree. This is, for example, a solution of the active ingredient or The preparation can be administered by intravenous injection in physiological saline solution or an aqueous medium, if desired. This can be achieved by bolus administration of the active ingredient. Oral administration allows for effective plasma concentration of the active drug. It is also suitable for producing a degree of temperature.

[0262] The concentration of the active compound in the drug composition affects the absorption, distribution, inactivation, and elimination rates of the drug. Furthermore, it will depend on other factors known to those skilled in the art. The dosage value will be reduced. Please note that this will also vary depending on the severity of the condition. Furthermore, any specific For the target population, a specific medication regimen may be administered according to the individual's needs and the composition in question. Alternatively, the dosage should be adjusted over time according to the professional judgment of the person managing the administration. The concentration ranges described herein are illustrative and do not extend to the claimed compositions. Please understand that this is not intended to limit the implementation. The active ingredient is administered at once. It may be administered as a single dose, or divided into many smaller doses and administered at various time intervals. That's good too.

[0263] When administered intravenously, the preferred carrier is physiological saline or phosphate-buffered saline (PBS). )

[0264] In one embodiment, the active compound is used, for example, in implants and microencapsulated deliveries. Release control formulations, including the Tatsu system, protect compounds from rapid elimination from the body. It is prepared with a carrier. For example, ethylene vinyl acetate, polyanhydride, polyglycolic acid, etc. Biodegradable and biocompatible polymers such as lagen, polyorthoesters, and polylactic acid. These can be used. The method for preparing such formulations will be obvious to those skilled in the art.

[0265] Liposome suspensions can also be pharmaceutically acceptable carriers. These are, for example, U.S. patents. Those described in Patent No. 4,522,811 (which is incorporated herein by reference in its entirety) However, they may be prepared according to methods known to those skilled in the art. For example, liposome formulations are Appropriate lipids (e.g., stearoylphosphatidylethanolamine, stearoylphosph Phosphatidylcholine, arachadoyl phosphatidylcholine, and cholesterol The lipids (such as ole) are dissolved in an inorganic solvent, then evaporated, and a thin layer of dried lipids is left on the surface of the container. It may also be prepared by leaving a film. Next, an aqueous solution of the active compound is placed in a container. Then, rotate the container by hand to peel off the lipid material from the sides of the container, disperse the lipid clumps, and apply liposomal solution. Form a suspension.

[0266] Mode of administration In any of the embodiments or models described herein, the compound described herein A therapeutic composition containing substances is configured to be delivered by any suitable route. The appropriate dosage form may be used. The compound may be administered, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or It can be administered via any suitable route, such as topically, for example, as a liquid, cream, or gel. , or in solid form, percutaneously, intrarectally, transnasally, intraorally, transvaginally, or via a transplant container, Alternatively, it can be administered in aerosol form.

[0267] As used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intra-articular, and synovial membrane. This includes intracellular, intrasternal, subarachnoid, intrahepatic, intralesional, and intracranial injection or infusion techniques. The composition is preferably administered orally, intraperitoneally, or intravenously.

[0268] The compounds described herein are administered orally, parenterally, or topically in a single dose, or It may be administered in divided doses. Administration of the active compound may range from continuous (intravenous drip) to daily doses. It may be limited to several oral doses (e.g., QID), and among other routes of administration... Oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (this may include penetration enhancers), oral Administration may include intraoral, sublingual, and suppository administration. Enteric-coated oral tablets may be used. This may be used to enhance the bioavailability of the compound via the oral administration route. The most effective dosage form. This will depend on the pharmacokinetics of the specific drug selected, as well as the severity of the patient's disease. .

[0269] As a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration. Compound administration may be used. The compounds described herein are either immediate-release or sustained-release. It may be administered as a sustained-release or controlled-release formulation. Sustained-release or controlled-release formulations should be administered orally. Preferably, it is also administered as a suppository and / or transdermal or other topical form. Intramuscular injection may be used to control or maintain the release of the compound at the injection site.

[0270] The sterile injection form of the compositions described herein may be an aqueous suspension or an oily suspension. These suspensions are prepared using a suitable dispersant or wetting agent and a suspending agent known in the art. It may be formulated using the following technology. A sterile injection preparation may be, for example, a 1,3-butanediol solution and Sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents. It may be a turbid solution. Among the acceptable vehicles and solvents that may be used, Ringer's solution There are liquid and isotonic sodium chloride solutions. In addition, sterilized fixative oil is used as a solvent or suspension medium. It is conventionally used for this purpose. For this purpose, synthetic monoglycerides or diglycerides are included. Any brand of fixed oil may be used. For example, olive oil or castor oil, in particular Just as there are naturally occurring, pharmaceutically acceptable oils such as those polyoxyethylated forms, for example Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable drugs. These oily solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as Ph. Helv or It may also contain similar alcohols.

[0271] The pharmaceutical compositions described herein include, but are not limited to, capsules, tablets, aqueous suspensions, or water It may be administered orally in any orally acceptable dosage form, including solutions. For tablets, commonly used carriers include lactose and corn starch. Typically, lubricants such as magnesium stearate are also added. For oral administration, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, specific sweeteners, flavorings, or colorings may also be added. Oral compositions are generally It may contain an inert diluent or food carrier. It may also be encapsulated in gelatin capsules. , or it may be compressed into a tablet. For oral therapeutic administration, the active compound or its prod LAG derivatives are used in combination with excipients in the form of tablets, lozenges, or capsules. It is possible to compose a composition of a pharmaceutically compatible binder and / or adjuvant substance. It is included as part of the product.

[0272] Tablets, pills, capsules, lozenges, etc. may contain the following ingredients or compounds with similar properties. It may contain any of the following: for example, microcrystalline cellulose, tragacanth gum, or gelatin. Binders such as starch or lactose; excipients such as alginic acid, prim Dispersants such as ogel or cornstarch; for example, magnesium stearate or Sterot Lubricants such as ES; flow promoters such as colloidal silicon dioxide; for example, sucrose or sweeteners such as saccharin; or for example, peppermint, methyl salicylate or Flavoring agents such as microwave flavorings. When the drug unit dosage form is a capsule, the above-mentioned type of substance In addition, it may include a liquid carrier such as a fatty acid. Furthermore, the drug unit dosage form may be, for example... various methods to modify the physical shape of physical medication units such as sugars, shellac, or enteric-coated materials. It may also contain other substances.

[0273] The active compound or its pharmaceutically acceptable salt is used in elixirs, suspensions, syrups, and other applications. It can be administered as an ingredient in products such as mouthwash and chewing gum. The syrup is active. In addition to chemical compounds, sucrose is used as a sweetener, or certain preservatives, dyes, and colorants. It may also contain flavorings.

[0274] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These are solid at room temperature but become liquid at rectal temperature when mixed with a suitable non-irritating excipient. It can be prepared by combining, and therefore will dissolve in the rectum and release the drug. Examples of such substances include cocoa butter, beeswax, and polyethylene glycol. It can be done.

[0275] The pharmaceutical compositions of this disclosure may be administered topically. Suitable topical formulations may be used for each of these regions. It is easily prepared for each region or organ. Topical application to the lower intestinal tract is done using rectal suppositories. The drug can be administered using a formulation (see above) or an appropriate enema. Locally tolerable. A transdermal patch may be used. With regard to topical application, the pharmaceutical composition contains one or more carriers The disclosed compound may be formulated as a suitable ointment containing the suspended or dissolved active ingredient. While not limited to carriers for topical administration of substances, mineral oil, liquid petrolatum, white petrolatum, proteopropyl alcohol are also used. Pyrene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and Water is one example. In certain preferred embodiments of this disclosure, the compound is surgically implanted in a patient. It may also be coated on the stent, thereby preventing occlusion of the stent within the patient. The possibility of this happening is suppressed or reduced.

[0276] Alternatively, the pharmaceutical composition may be suspended or dissolved in one or more pharmaceutically acceptable carriers. It may be formulated as a suitable lotion or cream containing the active ingredient. Suitable carrier While not limited to these, mineral oil, sorbitan monostearate, polysorbate 60, Cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol Examples include call water and water.

[0277] For ophthalmic use, the pharmaceutical composition is an isotonic, pH-adjusted sterile saline solution in a finely powdered form. As a turbidity, or preferably together with a preservative such as benzylalkonium chloride. Formulated as, or without, an isotonic, pH-adjusted sterile saline solution. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated with an ointment such as petrolatum. It's okay.

[0278] The pharmaceutical compositions disclosed herein may be administered by nasal aerosol or inhalation. The product is prepared according to techniques known in the field of pharmaceutical formulation, and as a solution of physiological saline, Benzyl alcohol or other suitable preservatives, absorption to improve bioavailability Promoter, fluorocarbon, and / or other conventional solubilizers or dispersions It may be prepared using an agent.

[0279] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain the following components: Elements may be included: for example, water for injection, physiological saline solution, fixative oil, polyethylene glyco Sterilizing diluents such as glycerin, propylene glycol, or other synthetic solvents; For example, antibacterial agents such as benzyl alcohol or methylparaben; for example, ascorbic acid or antioxidants such as sodium bisulfite; for example, chelates such as ethylenediaminetetraacetic acid. Buffering agents; for example, buffering agents such as acetates, citrates, or phosphates, and for example, sodium chloride. Tension-modifying agents such as um or dextrose. Parenteral preparations are glass or plastic. Enclosed in ampoules, disposable syringes, or multi-dose vials manufactured using a stick. That's fine.

[0280] The specific dosage and treatment regimen for any particular patient will be determined by the specific patient used. Compound activity, age, weight, general health status, sex, diet, administration time, excretion rate, drug combination The combination of factors, the judgment of the treating physician, and the severity of the specific disease or condition being treated. It should be understood that the outcome depends on various factors, including the severity of the condition.

[0281] Patients or subjects requiring treatment with the compounds described herein should be pharmaceutically appropriate. An effective amount of this compound, including acceptable salts, solvates, or polymorphs, may be optionally pharmaceutically acceptable. Administer to the patient (subject) alone or in combination with other known agents in a suitable carrier or diluent. It can be treated by [method].

[0282] Co-administration The conditions of symptoms that can be treated with the compounds or compositions described herein are limited to: Examples of conditions that are not included include cancer (e.g., prostate cancer) and Kennedy disease. Specific embodiments Therefore, the therapeutic composition or pharmaceutical composition contains additional biological agents or bioactive agents, for example It contains an effective amount of a cancer treatment agent that is administered simultaneously.

[0283] The terms "co-administration" or "combination therapy" refer to the use of at least two compounds or compositions. The patient is administered these two or more compounds simultaneously, thereby achieving an effective dose or effective amount of each of them. This means that the concentration may be present in the patient for a given period of time. The compounds disclosed herein Although they may be administered to patients simultaneously, the term refers to all compounds or compositions that are co-administered. As long as the effective concentration of a substance is present in the patient for a given time, two substances can be detected simultaneously or at different times. This also includes administering the above agents. In certain preferred embodiments of this disclosure, the above One or more of these compounds, in particular, when used in combination with at least one additional bioactive agent, including an anticancer agent, It is administered. In a particularly preferred embodiment of this disclosure, co-administration of the compound includes anticancer therapy. This results in a synergistic therapeutic effect.

[0284] In another embodiment, this specification provides effective amounts of two or more PROTAC compounds described herein, and The present invention provides a composition comprising a pharmaceutically acceptable carrier. In a particular embodiment, the composition is P The formula 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 as disclosed herein, and separately as otherwise provided herein. A combination of one or more of the listed compounds in an effective amount, in a pharmaceutically effective quantity. Pharmaceutical compositions containing a body, additive, or excipient represent further embodiments of this disclosure.

[0286] The term "biological agent" refers to agents other than the PROTAC compounds described herein. Used for the purpose of treatment, inhibition, and / or control of the intended use of this compound. To enhance the preventive effect, this compound is used in combination with a biologically active agent. The bioactive agents preferred for use in this specification are those in which the compound is used or administered. Examples of agents with pharmacological activity similar to that of the agent being administered include anticancer agents.

[0287] The term "additional anticancer agent" is used in conjunction with the PROTAC compounds described herein to treat cancer. It is used to describe anticancer drugs that may be used. Examples of these drugs include 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 quinol -ase 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), oregobomab, Lep-etu, nolatrexed azd2171, batabulin, ofatumumab, zanorimumab 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, IPdR1KRX-0402, Le Quanton (lucanthone), LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311 Romidepsin, ADS-100380, Sunitinib, 5-Fluoro Fluorouracil, vorinostat, etoposide gemcitabine, doxorubicin, liposomal doxorubicin Syn (liposomal doxorubicin), 5'-deoxy-5-fluorouridine, vincristine (v incristine, temozolomide, ZK-304709, seliclib ), PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-( 2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]ben Zoyl disodium salt, heptahydrate, camptothecin, PEG-labeled ylyl Notecan (irinotecan), tamoxifen, toremifene citrate (tor emifene citrate, anastrazole, exemestane Letrozole, DES (diethylstilbestrol) Estradiol, estrogen, complexed estrogen n, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonyl pipette) 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-NH2 acetate [C 59 H 84 N 18 Oi4-(C2H4O2) X In the formula, x = 1 to 2.4] acetate, Gossellelli Goserelin acetate, leuprolide acetate, triptor elin pamoate, medroxyprogesterone acetate, hydrox Cyprogesterone caprylate, megestrol acetate, raloxifene (raloxifene), bicalutamide, flutamide, niltamide Nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272 Erlotinib, lapatinib, canertinib ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, Ronafa Lunib (Ionafarnib), BMS-214662, Tipifarnib, Amifostine ( amifostine), NVP-LAQ824, suberoyl analide hydroxamic acid Roxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib (sora fenib), KRN951, aminoglutethimide, arnsa crine), anagrelide, L-asparaginase, Calmette-Guélain bacilli ( BCG vaccine, adriamycin, bleomycin, Bucephalandra buserelin, busulfan, carboplatin, Carmustine, chlorambucil, cisplatin n), cladribine, clodronate, cyproterone Roterone, cytarabine, dacarbazine, dactynomycete Dactinomycin, daunorubicin, diethylstilbestrol (diethylstilbestrol), epirubicin, fludarabine , fludrocortisone, fluoxymesterone Flutamide, Gleevec, gemcitabine, Hydroxyurea, idarubicin, ifosfamide amide), imatinib, leuprolide, levamizole isole, lomustine, mechlorethamine, melphala Melphalan, 6-mercaptopurine, mesna, methoto Lexate (methotrexate), mitomycin, mitotane, Mitoxantrone, nilutamide, octreotide eotide, oxaliplatin, pamidronate, pento Statins (pentostatin), plicamycin, porfimers , 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- Oxyuridine (5-deooxyuridine), cytosine arabinoside, 6-mecaptopurine (6-mec aptopurine, deoxycoformycin, calcitriol Triol, valrubicin, mithramycin, vinblastic Vinblastine, vinorelbine, topotecan, razocy Razoxin, Marimastat, COL-3, Neovastat ), BMS-275291, squalamine, endostatin, SU5416 SU6668, EMD121974, Interleukin-12, IM862, Angiostatin Vitaxin, droloxifene, idoxyf ene), spironolactone, finasteride, Shimichi Cimitidine, trastuzumab, deniloikin difutitox Ileukin diftitox, gefitinib, bortezimib, paprika Paclitaxel, cremophor-free paclitaxel Litaxel, docetaxel, epithilone B, BMS-247550 BMS-310705, droloxifene, 4-hydroxytamoxifene oxytamoxifen, pipendoxifene, ERA-923, alzoxifen Arzoxifene, fulvestrant, acolbifene, ra Sofoxifene, Idoxifene, TSE-424, HMR-3339 ZK186619, Topotecan, PTK787 / ZK222584, VX-745, PD184352, Rapamai rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus (temsi 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 Ronnie's stimulating factor, zolendronate, prednisone, cetacean cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin elin), pegylated interferon alpha-2a, interferon alpha-2a, pegylated Interferon alpha-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, ibriumomab thiuxetane itgumomab tiuxetan, androgen, decitabine, hexamethylmelamine (hexamethylmelamine), bexarotene, tositumomab ), arsenic trioxide, cortisone, etidronate, mitotane, Cyclosporine, liposomal daunorubicin ), Edwina-asparaginase, strontium-89, cassopi Tant (casopitant), netupitant, NK-1 receptor antagonist, palonosetro Palonosetron, aprepitant, diphenhydramine amine, hydroxyzine, metoclopramide, Lola Lorazepam, alprazolam, haloperidol droperidol, dronabinol, dexamethasone xamethasone), methylprednisolone, prochlorperazine (p rochlorperazine, granisetron, ondansetron ), drasetron, tropisetron, pegfill glass Tim (pegfilgrastim), erythropoietin, epoetin alpha (e poetin alfa, darbepoetin alfa, and mixtures thereof. These are some examples.

[0288] Treatment method In another aspect, the disclosure relates to, for example, cells, tissues, mammals, or human patients. This invention provides a method for regulating protein ubiquitination and degradation, and the method provides a method for regulating protein ubiquitination and degradation. , an effective amount of the PROTAC compound described herein, or an effective amount of said compound This includes administering a composition to a target, wherein the compound or a composition containing the compound. This is effective in regulating protein ubiquitination and proteolysis in the target substance. In certain embodiments, the protein is an androgen receptor (AR).

[0289] In certain embodiments, this specification describes administering to a patient an amount of the compound described herein. This includes providing androgen receptor protein activity control to patients who need it. To provide a method.

[0290] In further embodiments, this specification proposes methods for treating a patient's symptoms or condition. It is provided, and in this case the unregulated protein activity is the symptom or state The cause is the method of administering an effective amount of the compound described herein to the patient. This includes administering the substance to control the protein activity in the patient. In certain embodiments, The protein is AR.

[0291] As used herein, “to treat,” “to treat,” and “treatment” The term refers to any effect that brings benefit to the patient, and for that benefit, this compound It may be administered to any symptoms or conditions regulated via the protein to which this compound binds. This includes treatment of conditions. Symptoms or conditions, including cancer, that may be treated using the compounds of this disclosure. This is described above in this specification.

[0292] In another aspect, the disclosure relates to, for example, cells, tissues, mammals, or human patients. This invention provides a method for regulating the ubiquitination and degradation of AR proteins, and the method This refers to an effective amount of the compound described herein, or an effective amount of the compound described herein. This includes administering a composition containing the compound, or a composition containing the compound. The composition is effective in regulating AR protein ubiquitination and proteolysis in the subject. be.

[0293] In another aspect, the disclosure relates to, for example, cells, tissues, mammals, or human patients. This invention provides a method for treating or improving the symptoms of a disease related to AR activity, and the method This refers to an effective amount of the compound described herein, or a composition containing an effective amount of said compound. This includes administering the compound, or a set containing the compound, to subjects in need of such treatment. The product is effective in treating or improving symptoms of diseases related to AR activity in the subject in question.

[0294] In certain embodiments, the disease or disorder is asthma, multiple sclerosis, cancer, prostate cancer, Kennedy Illness, ciliary disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood Disabilities, obesity, refractive errors, infertility, Angelman syndrome, Canavani syndrome, celiac disease, Charcol-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromocytic disorder Hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic cysts Renal, (PKD1) or 4(PDK2) Prader-Willi syndrome, sickle cell anemia, Tay-Sachs disease , Turner syndrome. The aforementioned cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and 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 cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, In particular, Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; bone marrow Proliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroma, Synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, gliablastoma, neuroblastoma, Gangiocarcinoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, nerve fiber tumors, and sarcomas including schwannomas; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, egg cancer Cancer of the urinary tract, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colorectal cancer, melanoma ;Carcinosarcoma, Hodgkin's disease, Wilms' tumor, or teratoma. In certain embodiments, treatment The diseases to be treated are cancers, for example, prostate cancer or Kennedy disease. In a preferred embodiment, And the subject is human beings.

[0295] In another aspect, the disclosure relates to, for example, cells, tissues, mammals, or human patients. This invention provides a method for treating or improving the symptoms of a disease related to AR activity, and the method This includes an effective amount of the compound described herein, or a composition containing an effective amount of said compound, This includes administering an effective or synergistic dose of another bioactive agent to the subject in need, Herein, the composition containing the compound is used to treat the symptoms of a disease related to AR activity in the subject. Or it is effective in improving the condition. In certain embodiments, the disease being treated is cancer, for example, prostate cancer. , or Kennedy disease. In a preferred embodiment, the subject is human. In additional embodiments, the additional bioactive agent is an anticancer agent.

[0296] In another aspect, the disclosure describes how symptoms can be caused by the degradation of proteins or polypeptides. This provides a method of treatment, which involves the protein or polypeptide in question. The symptoms or condition are controlled, and the method provides the patient or subject with at least the above-mentioned This also includes administering an effective amount of another compound, and optionally additional bioactive agents in combination. Using the method disclosed herein, an effective amount of at least one compound described herein is administered. By doing so, many symptoms or conditions, including cancer, can be treated.

[0297] In another embodiment, the present disclosure describes the use of the compounds according to the present disclosure in biological systems. This provides a method for identifying the degradation effects of elephant proteins.

[0298] kit In another embodiment, this specification provides a kit comprising a compound or composition described herein. The kit may be advertised, distributed, or sold as a unit for carrying out the methods described herein. It is also preferable that the kit of this disclosure includes instructions explaining proper use. There are cases where such kits can be used, for example, in clinical settings, for example, for cancer It can treat patients exhibiting symptoms such as prostate cancer or Kennedy disease. [Examples]

[0299] Overall chemical properties - analysis and synthesis Unless otherwise stated, all materials / reagents are obtained from suppliers and do not undergo further purification. It was used for the reaction, and / or covered with aluminum foil beforehand, Glass-reinforced silica gel 60F 254 Thin-layer chromatography (TLC) on a (0.2 mm) surface It was monitored and visualized with UV light. Flash chromatography (or " ISCO chromatography (also known as "ISCO chromatography") uses RediSep's normal phase silica gel cartridges. This was done using an ISCO CombiFiash RF 75 PSI or equivalent equipped with a jigging device. Preparative TLC was performed. A 20x20cm plate of Whatman LK6F Silica Gel 60A with a thickness of 1000μm or equivalent. I went there.

[0300] 1 HNMR (300 or 400 MHz), and 13The CNMR (100.6 MHz) spectrum was obtained at room temperature, internally. Recorded using a Bruker spectrometer with TMS or residual solvent peaks as standard. Line position The position or overlap is given by (δ), and the coupling constant (J) is given as the absolute value of Hertz (Hz). It can be obtained. The multiplicity in the 1H NMR spectrum is abbreviated as follows: s (single line), d (double line), t (triple line), q (quadruple line), m (multiple lines), br or broad (broad line).

[0301] Preparative HPLC purification is performed using the 2545 Binary Gradient Module, 2767 Sample Manager, and 2489 Waters with UV / Visible Detector (登録商標) On UV-Directed Purification System It was performed and controlled with MassLynx V4.1 software. All columns below were used. The purification process has been completed for: Atlantis Prep T3 OBD columns, SunFire Prep C18 OBD columns. and XBridge Prep Phenyl OBD column. Mobile phase is water (0.1% TFA or 0.01% NH4HCO3). The reagents used were HPLC grade and acetonitrile. The flow rate was 30 ml / min. After the column, a 1:1000 LC packing flow splitter was used. Then, a small portion of the eluent was transferred to the UV detector. The electric spray source was a 3.0kV capillary. - Voltage, cone voltage of 30 V, source temperature of 110°C, desolvation temperature of 350°C, desolvation rate of 600 L / hour The gas flow rate was set to 60 L / hour and the...

Claims

1. Compounds having the following structure, ABM-L-CLM, or a pharmaceutically acceptable salt thereof: (a) In the formula, ABM is 【Chemistry 1】 And, During the ceremony: W １ This is a phenyl compound, which is optionally substituted with one or more halogens, CN, and C12. １～６ C optionally substituted with alkyl or one or more halogens １～６ It is optionally substituted with an alkoxyl, Each Y ３ , Y ４ , and Y ５ are each independently O, NR Ｙ２ , CR Ｙ１ R Ｙ２ , or C=O; Q is 0 to 6 R Ｑ It is a four-membered alicyclic compound substituted with, Each R Ｑ C is independent １～６ It is alkyl; R Ｙ１ and R Ｙ２ These are H or C, each independent of the others. １～６ It is alkyl; W 2 This can be any 1 to 4 R Ｗ２ It is a heteroaryl substituted by; Each R Ｗ２ C is independently replaced by a halogen, or optionally replaced by one or more Fs. １～６ OC optionally substituted with alkyl or one or more F １～３ It is alkyl; and, 【Chemistry 2】 This is the connection point where ABM bonds to the chemical linker group (L), (b) L is a chemical linker group that is covalently bonded to ABM and CLM, and the chemical structure is (A Ｌ ) ｑ - has, q is an integer greater than or equal to 1. Each A Ｌ CR Ｌ１ R Ｌ２ O, S, NR Ｌ３ CO, CR Ｌ１ =CR Ｌ２ , C≡C, 1 to 6 R Ｌ１ C which is optionally replaced by ３～１１ Cycloalkyl, 1 to 9 R Ｌ１ C which is optionally replaced by ５～１３ Spirocycloalkyl, 1 to 6 R Ｌ１ C which is optionally replaced by ３～１１ Heterocycline, 1 to 8 R Ｌ１ C which is optionally replaced by ５～１３ Spiroheterocycloalkyl, 1 to 4 R Ｌ１ Aryls optionally substituted with, and 1 to 4 R Ｌ１ Selected from heteroaryls optionally substituted with; and, R Ｌ１ , R Ｌ２ and R Ｌ３ Each of these is independently H, halogen, and C. １～８ Alkyl, OC １～８ Alkyl, NHC １～８ Alkyl, N(C) １～８ Alkyl) ２ , C ３～１１ Cycloalkyl, aryl, heteroaryl, C ３～１１ Heterocyclyl, OC ３～８ Cycloalkyl, NHC ３～８ Cycloalkyl, N(C) ３～８ Cycloalkyl) ２ , N(C ３～８ Cycloalkyl) (C １～８ Alkyl), OH, NH ２ COC １～８ Alkyl, CO ２ H, CN, CF ３ CHF ２ ,CH ２ F, NO ２ CONHC １～８ Alkyl, or -CON(C) １～８ Alkyl) ２ , and or, R Ｌ１ and R Ｌ２ It binds to form a cycloalkyl or heterocycline moiety, and (c) CLM is: 【Transformation 3】 And, W is CH ２ Or C = O; A is H; n is an integer between 1 and 4; Here, if n is 1, R is OR' covalently bonded to the linker group (L); If n is 2, 3, or 4, one R is OR' covalently bonded to the linker group (L), and the remaining R is C １～６ Alkyl, Cl, F, Br, I, CF ３ , CN, and OCF ３ Selected from; R' is a cycloalkyl, aryl, heteroaryl, or heterocyclyl, and, 【Chemistry 4】 teeth, A compound, or a pharmaceutically acceptable salt thereof, representing a bond that may be stereospecific ((R) or (S)) or non-stereospecific. However, this excludes compounds represented by the following formula. 【Transformation 5】 。

2. ABM, 【Transformation 6】 And, W １ teeth, 【Transformation 7】 And; R ２２ is H or CN; Each R ２３ It is independently halogen or CF ３ And; Y ３ , Y ４ , Y ５ These are O and NR, respectively, independently. Ｙ２ CR Ｙ１ R Ｙ２ Or C = O; R Ｙ１ , R Ｙ２ H or C respectively １～６ It is alkyl; R １ and R ２ These are, independently, H or methyl; W ２ This can be any one, two, or three R Ｗ２ It is a heteroaryl substituted by; and, Each R Ｗ２ is independently halogen; C optionally substituted with one or more F １～６ alkyl; or OC optionally substituted with one or more F １～３ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Each R １ and R ２ The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

4. W １ but, 【Transformation 8】 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. W １ but, 【Chemistry 10】 The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof.

6. W １ but, 【Chemistry 11】 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. W ２ The compound according to any one of claims 1 to 6, wherein the compound is pyrrolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, indolyl, isoindolyl, indoridineyl, azaindoridineyl, furanyl, isoxazolyl, or oxazolyl, or a pharmaceutically acceptable salt thereof.

8. W ２ is pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, indolyl, isoindolyl, indolizinyl, azaindolizinyl, furanyl, isoxazolyl or oxazolyl, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. W ２ The compound according to any one of claims 1 to 8, wherein the compound is pyrimidinyl, or a pharmaceutically acceptable salt thereof.

10. W １ but, 【Chemistry 12】 And, W ２ The compound according to any one of claims 1 to 9, wherein the compound is pyrimidinyl, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R' is a cycloalkyl group covalently bonded to the linker group (L).

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R' is cyclobutyl covalently bonded to the linker group (L).

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 1; R is OR', and R' is a cycloalkyl group covalently bonded to the linker group (L).

14. The compound according to any one of claims 1 to 10 or 13, or a pharmaceutically acceptable salt thereof, wherein n is 1; R is OR', and R' is cyclobutyl covalently bonded to the linker group (L).

15. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein n is 2; one R is OR', the R' being a cycloalkyl group covalently bonded to a linker group (L); and the other R is F.

16. The compound according to any one of claims 1 to 10 or 15, or a pharmaceutically acceptable salt thereof, wherein n is 2; one R is OR', where R' is cyclobutyl covalently bonded to the linker group (L); and the other R is F.

17. Each A Ｌ CR Ｌ１ R Ｌ２ , NR Ｌ３ , or 1 to 6 R Ｌ１ C arbitrarily substituted with ３－１１ A compound according to any one of claims 1 to 16, selected from heterocyclyls, or a pharmaceutically acceptable salt thereof.

18. Each A Ｌ CH ２ NR Ｌ３ A compound according to any one of claims 1 to 17, selected from piperazinil or piperidinil, or a pharmaceutically acceptable salt thereof.

19. Each A Ｌ CH ２ , NR Ｌ３ A compound according to any one of claims 1 to 18, selected from piperidinyl, or a pharmaceutically acceptable salt thereof.

20. R Ｌ３ The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein is H, methyl, ethyl, or isopropyl.

21. R Ｌ３ The compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein is isopropyl.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, a pharmaceutically acceptable salt thereof, and an acceptable carrier.

23. Furthermore, the pharmaceutical composition according to claim 22, comprising at least one additional anticancer agent.

24. The aforementioned at least one additional anticancer agent is estramustine, docetaxel, ketoconazole, goserelin acetate, histrelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, zoledronate, zolendronate, mitoxantrone, pemetrexed, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin, vincristine, temozolomide, capecitabine, PEG-labeled irinotecan Irinotecan, tamoxifen, anastrazole, exemestane, letrozole, diethylstilbestrol, estradiol, estrogen, bevacizumab, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caprylateThe pharmaceutical composition according to claim 23, wherein the active ingredient is caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, arzoxifene, fulvestrant, or prednisone.

25. The pharmaceutical composition according to claim 23 or 24, wherein the at least one additional anticancer agent is estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, or zolendronate.

26. The pharmaceutical composition according to claim 23, wherein the at least one additional anticancer agent is an FLT-3 inhibitor, an androgen receptor inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a CDK inhibitor, an anti-HGF antibody, an IGFR-TK inhibitor, a PI3 kinase inhibitor, an AKT inhibitor, a JAK / STAT inhibitor, a checkpoint 1 inhibitor, a checkpoint 2 inhibitor, a focal adhesion kinase inhibitor, a MAP kinase kinase inhibitor, or a VEGF trap antibody.

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